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Wiesner-Kiełczewska A, Zagrodzki P, Paśko P. The Impact of Dietary Interventions on the Pharmacokinetics of Antifungal Drugs: A Systematic Review with Meta-analyses. Clin Pharmacokinet 2025:10.1007/s40262-025-01511-6. [PMID: 40347349 DOI: 10.1007/s40262-025-01511-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2025] [Indexed: 05/12/2025]
Abstract
BACKGROUND AND OBJECTIVE Managing food-drug interactions may help to optimize the efficacy and safety of antifungal therapy. This systematic review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to evaluate how food, beverages, antacids, and mineral supplements influence the pharmacokinetic (PK) parameters or pharmacokinetic/pharmacodynamic (PK/PD) indices of 14 orally administered antifungal drugs. METHODS We considered all studies evaluating the effects of food, beverages, antacids, and mineral supplements on PK parameters and PK/PD indices of oral antifungal drugs for inclusion. We excluded in vitro, in silico, animal studies, reviews, and alcohol-related investigations. Searches were conducted in Medline (via PubMed), Embase, and Cochrane Library from database inception to June 2024. We evaluated the risk of bias using the National Institutes of Health (NIH) tool for before-after studies and the Cochrane tool for parallel and cross-over trials. We performed meta-analyses when two or more studies with comparable designs were available; otherwise, results were summarized qualitatively. RESULTS The review included 73 studies from 68 reports. Only studies investigating the effect of dietary interactions on PK parameters were found. Meta-analyses were conducted for seven antifungal drugs, while qualitative synthesis covered the remaining drugs. Open-label, cross-over studies accounted for 58% of trials, aligning with Food and Drug Administration (FDA) recommendations. A high risk of bias appeared in 33% of studies, while only 7% showed low risk. Among 11 antifungals with food-effect data, seven (64%) exhibited clinically important interactions. High positive food effects (area under the concentration-time curve (AUC) or peak serum concentration (Cmax) increased by > 45%) were seen for griseofulvin, itraconazole capsules and tablets (except rice-based meals), and posaconazole immediate-release tablets and suspension. A moderate positive impact of high-fat meals (AUC or Cmax increased in the range of 35-45%) occurred for ibrexafungerp and oteseconazole. A high negative food effect was observed on the absorption of voriconazole and itraconazole oral suspension or super bioavailable (SUBA) capsules (AUC or Cmax decreased by > 40%). Antacids strongly reduced itraconazole and ketoconazole absorption, while nutritional supplements improved posaconazole bioavailability. Acidic beverages such as Coca Cola substantially enhanced the absorption of itraconazole, ketoconazole, and posaconazole, whereas orange juice significantly reduced itraconazole bioavailability. CONCLUSION Interactions were influenced by such factors as drug physicochemical properties, type of dietary intervention, drug formulation, and patient characteristics. Although the review largely filled the existing gaps in recommendations, we judged the overall quality of evidence as low owing to outdated studies, methodological inconsistencies, and uneven data availability. Further research involving PK/PD indices is needed to link the postprandial changes in the bioavailability of antifungal drugs with their clinical efficacy. OTHER The protocol of the systematic review was registered in March 2024 in the Open Science Framework (OSF) Registries ( https://doi.org/10.17605/OSF.IO/HAVK9 ).
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Affiliation(s)
- Agnieszka Wiesner-Kiełczewska
- Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 16, 31-530, Kraków, Poland
- Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Paweł Zagrodzki
- Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Paweł Paśko
- Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
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Schroeder JA, Wilson CM, Pappas PG. Invasive Candidiasis. Infect Dis Clin North Am 2025; 39:93-119. [PMID: 39706747 DOI: 10.1016/j.idc.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2024]
Abstract
Invasive candidiasis (IC) is a term that refers to a group of infectious syndromes caused by a variety of Candida species, 6 of which cause the vast majority of cases globally. Candidemia is probably the most commonly recognized syndrome associated with IC; however, Candida species can cause invasive infection of any organ, especially visceral organs, vasculature, bones and joints, eyes, and central nervous system. The optimal use of these newer diagnostics coupled with a thoughtful clinical assessment of at-risk patients and the judicious use of effective antifungal therapy is a key to achieving good antifungal stewardship and improved patient outcomes.
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Affiliation(s)
- Julia A Schroeder
- The University of Alabama at Birmingham, 1900 University Boulevard, 223 THT, Birmingham, AL 35294, USA
| | - Cameron M Wilson
- The University of Alabama at Birmingham, 1900 University Boulevard, 223 THT, Birmingham, AL 35294, USA
| | - Peter G Pappas
- The University of Alabama at Birmingham, 1900 University Boulevard, 223 THT, Birmingham, AL 35294, USA.
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Rudolph N, Charbe N, Plano D, Shoyaib AA, Pal A, Boyce H, Zhao L, Wu F, Polli J, Dressman J, Cristofoletti R. A physiologically based biopharmaceutics modeling (PBBM) framework for characterizing formulation-dependent food effects: Paving the road towards fed state virtual BE studies for itraconazole amorphous solid dispersions. Eur J Pharm Sci 2025; 209:107047. [PMID: 39983931 DOI: 10.1016/j.ejps.2025.107047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 02/13/2025] [Accepted: 02/19/2025] [Indexed: 02/23/2025]
Abstract
This study leverages physiologically based biopharmaceutics modeling (PBBM) to predict the clinical performance of two itraconazole (ITRA) amorphous solid dispersions (ASDs), Sempera® and Tolsura®, under fasted and fed state conditions, exploring the potential of PBBM in predicting formulation-specific food interactions. The ITRA formulations were subjected to extensive in vitro biopharmaceutical testing, including solubility studies and dissolution tests under fasted and fed state conditions, revealing significant differences in dissolution behaviors between Sempera® and Tolsura®. The impact of food and hypochlorhydria on drug absorption was evaluated using a stepwise mechanistic deconvolution-reconvolution PBBM approach, integrating fundamental parameters based on the in vitro data into the final model. Our model not only successfully predicted the effects of acid reducing agents (ARA) and food on the oral absorption of ITRA, but also captured the between-subject variability, demonstrating the utility of this approach in understanding the complex interplay between drug, formulation, and gastrointestinal environment. Most importantly, the PBBM was able to accurately predict the positive impact of food on the absorption of Sempera® and the negative food effect of Tolsura®. The findings highlight the importance of considering formulation characteristics and gastrointestinal physiology, underscoring the potential of PBBM in bioequivalence (BE) assessment of generic formulations under varying physiological conditions, including in the fed state and in hypochlorhydric patients. The successful application of this stepwise and mechanistic PBBM approach suggests a potential pathway for streamlining drug development and may contribute to more informed decision-making for BE assessment.
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Affiliation(s)
- Niklas Rudolph
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
| | - Nitin Charbe
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - David Plano
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
| | - Abdullah Al Shoyaib
- Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
| | - Arindom Pal
- Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
| | - Heather Boyce
- Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
| | - Liang Zhao
- Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
| | - Fang Wu
- Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
| | - James Polli
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA
| | - Jennifer Dressman
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany.
| | - Rodrigo Cristofoletti
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA.
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de Lima AF, Fagundes VL, Marques NB, Borba HL, Domingos EL, Tonin FS, Pontarolo R. The Efficacy and Safety of Antifungal Agents for Managing Oral Candidiasis in Oncologic Patients: A Systematic Review With Network Meta-Analysis. Cureus 2024; 16:e69340. [PMID: 39398751 PMCID: PMC11471217 DOI: 10.7759/cureus.69340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2024] [Indexed: 10/15/2024] Open
Abstract
This study aimed at synthesizing the available evidence on the comparative safety and efficacy of antifungal agents for preventing or treating oral candidiasis (OC) in oncologic patients. A systematic review following international recommendations was performed (PROSPERO CRD42024507745). A comprehensive search was conducted in PubMed, Scopus, and Web of Science (Feb 2024) to retrieve randomized controlled trials evaluating the clinical effects of antifungal agents in the management of OC in this vulnerable population. Network meta-analyses were performed to evaluate the most prevalent outcomes, with findings reported as odds ratios (ORs) with 95% confidence intervals (CIs). Overall, 24 trials were included, of which 10 addressed OC treatment and 14 disease prophylaxis (n=3449 patients). Fluconazole had the most significant rates of clinical cure when compared to placebo (OR 0.09 [95% CI 0.01-0.69]), amphotericin B (0.21 [95% CI 0.07-0.65]) and itraconazole (OR 0.58 [95% CI 0.34-0.99]); ketoconazole was also superior to placebo for this outcome (OR 0.10 [95% CI 0.03, 0.36]). All antifungal agents presented significantly higher rates of prophylaxis success compared to the absence of an active agent. While these therapies were generally considered safe, only four studies provided data on adverse events, primarily related to gastrointestinal issues. In oncologic patients, azoles (fluconazole, ketoconazole) should be used as a first-line approach for OC treatment. The selection of antifungal agents for disease prophylaxis should consider, among others, patients' clinical characteristics and preferences. Economic and quality of life-related outcomes should be further addressed in future studies.
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Affiliation(s)
- Amanda F de Lima
- Department of Pharmacy, Federal University of Paraná, Curitiba, BRA
| | - Vitor L Fagundes
- Department of Pharmacy, Federal University of Paraná, Curitiba, BRA
| | | | - Helena L Borba
- Department of Pharmacy, Federal University of Paraná, Curitiba, BRA
| | - Eric L Domingos
- Department of Pharmacy, Federal University of Paraná, Curitiba, BRA
| | - Fernanda S Tonin
- Health and Technology Research Center, Escola Superior de Tecnologia da Saúde de Lisboa (ESTeSL) - Instituto Politécnico de Lisboa (IPL), Lisbon, PRT
- Department of Pharmacy, Federal University of Paraná, Curitiba, BRA
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Lehner AF, Johnson SD, Dirikolu L, Johnson M, Buchweitz JP. Mass spectrometric methods for evaluation of voriconazole avian pharmacokinetics and the inhibition of its cytochrome P450-induced metabolism. Toxicol Mech Methods 2024; 34:654-668. [PMID: 38389412 DOI: 10.1080/15376516.2024.2322675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
Invasive fungal aspergillosis is a leading cause of morbidity and mortality in many species including avian species such as common ravens (Corvus corax). Methods were developed for mass spectral determination of voriconazole in raven plasma as a means of determining pharmacokinetics of this antifungal agent. Without further development, GC/MS/MS (gas chromatography-tandem quadrupole mass spectrometry) proved to be inferior to LC/MS/MS (liquid chromatography-tandem quadrupole mass spectrometry) for measurement of voriconazole levels in treated raven plasma owing to numerous heat-induced breakdown products despite protection of voriconazole functional groups with trimethylsilyl moieties. LC/MS/MS measurement revealed in multi-dosing experiments that the ravens were capable of rapid or ultrarapid metabolism of voriconazole. This accounted for the animals' inability to raise the drug into the therapeutic range regardless of dosing regimen unless cytochrome P450 (CYP) inhibitors were included. Strategic selection of CYP inhibitors showed that of four selected compounds including cimetidine, enrofloxacin and omeprazole, only ciprofloxacin (Cipro) was able to maintain voriconazole levels in the therapeutic range until the end of the dosing period. The optimal method of administration involved maintenance doses of voriconazole at 6 mg/kg and ciprofloxacin at 20 mg/kg. Higher doses of voriconazole such as 18 mg/kg were also tenable without apparent induction of toxicity. Although most species employ CYP2C19 to metabolize voriconazole, it was necessary to speculate that voriconazole might be subject to metabolism by CYP1A2 in the ravens to explain the utility of ciprofloxacin, a previously unknown enzymatic route. Finally, despite its widespread catalog of CYP inhibitions including CYP1A2 and CYP2C19, cimetidine may be inadequate at enhancing voriconazole levels owing to its known effects on raising gastric pH, a result that may limit voriconazole solubility.
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Affiliation(s)
- Andreas F Lehner
- Section of Toxicology, Michigan State University Veterinary Diagnostic Laboratory, Michigan State University, East Lansing, MI, USA
| | - Sharmie D Johnson
- Department of Veterinary Services, Wildlife World Zoo & Aquarium & Safari Park, Litchfield Park, AZ, USA
| | - Levent Dirikolu
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA
| | - Margaret Johnson
- Section of Toxicology, Michigan State University Veterinary Diagnostic Laboratory, Michigan State University, East Lansing, MI, USA
| | - John P Buchweitz
- Section of Toxicology, Michigan State University Veterinary Diagnostic Laboratory, Michigan State University, East Lansing, MI, USA
- Department of Pathobiology & Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
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Shenoy MM, De A, Shah B, Das A, Saraswat A, Lahiri K, Yadav S, Sarda A, Chakraborty D, J D, Kamat S, Doshi Y, Gonsalves N, Choudhary A, Dhoot D, Mahadkar N, Bhushan S, Gadkari R, Barkate H. Efficacy of Super-Bioavailable Itraconazole and Conventional Itraconazole at Different Dosing Regimens in Glabrous Tinea Infection - A Randomized Clinical Trial. Drug Des Devel Ther 2023; 17:2899-2908. [PMID: 37766823 PMCID: PMC10520254 DOI: 10.2147/dddt.s421583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
Introduction Itraconazole follows non-linear pharmacokinetics and hence is recommended once daily, but in real-world practice, is commonly prescribed as twice daily. Hence, this study aimed to evaluate the efficacy and safety of super-bioavailable-itraconazole-130 mg (SB-130) and conventional-itraconazole-200 mg (CITZ-200) once daily compared with conventional-itraconazole-100 mg (CITZ-100) twice daily in glabrous tinea. Methods A total of 261 eligible patients were enrolled in this prospective, randomized, clinical study from December-2021 to August-2022 at seven centers in India. Efficacy and safety assessments were done at week-3 and 6, with follow-up at week-10 for relapse. The primary objective was to assess the proportion of patients who achieved complete cure at week-6 following treatment in all itraconazole groups. The secondary outcomes were safety and clinical and mycological cure rates. Results Of 261 patients, 240 were included in the analysis. At week-6, 140 patients were completely cured; thus, overall cure rate was 58.33%. Fifty-five patients (69%) in SB-130 while 47/77 (61%) and 38/83 (46%) patients were completely cured in CITZ-200 and CITZ-100 groups respectively (p<0.05; SB-130: CITZ-100, p=0.32; SB-130: CITZ-200, p=0.058; CITZ-200: CITZ-100). There was no statistical difference in the mycological cure rate and area clearance rate between any of the groups (p=0.14); however, a statistically significant difference was noted for OD dosing over BD dosing in achieving clinical cure rates (p<0.05). A total of 13/140 patients (9%) relapsed following complete cure, with no statistically significant difference between any of the groups (p=0.50). All treatments were safe and well-tolerated, with no discontinuation. Conclusion In this clinical study, moderate efficacy with all doses of ITZ was reported but was better with OD dosing. Although there was no statistical difference between SB-130 and CITZ-200, SB-130 may be preferred over CITZ-200 owing to the advantage of SB over the conventional ITZ.
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Affiliation(s)
| | - Abhishek De
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Bela Shah
- Department of Dermatology, BJ Medical College and Civil Hospital, Ahmedabad, Gujarat, India
| | - Anupam Das
- Department of Dermatology, Iris Multispecialty Hospital, Kolkata, West Bengal, India
| | - Abir Saraswat
- Department of Dermatology, Indushree Skin Clinic, Lucknow, Uttar Pradesh, India
| | - Koushik Lahiri
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Sheetal Yadav
- Department of Dermatology, ABVIMS and Dr. RML Hospital, New Delhi, India
| | - Aarti Sarda
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Disha Chakraborty
- Department of Dermatology, Calcutta National Medical College, Kolkata, West Bengal, India
| | - Dharmender J
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Shruti Kamat
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Yashika Doshi
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Nelry Gonsalves
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Ankita Choudhary
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Dhiraj Dhoot
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Namrata Mahadkar
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Sumit Bhushan
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Rujuta Gadkari
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Hanmant Barkate
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
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Yang E, Yu K, Lee S. Prediction of gastric pH-mediated drug exposure using physiologically-based pharmacokinetic modeling: A case study of itraconazole. CPT Pharmacometrics Syst Pharmacol 2023; 12:865-877. [PMID: 36967484 PMCID: PMC10272297 DOI: 10.1002/psp4.12959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 02/01/2023] [Accepted: 02/14/2023] [Indexed: 05/24/2024] Open
Abstract
Abnormal gastric acidity, including achlorhydria, can act as a significant source of variability in orally administered drugs especially with pH-sensitive solubility profiles, such as weak bases, potentially resulting in an undesirable therapeutic response. This study aimed to evaluate the utility of physiologically-based pharmacokinetic (PBPK) modeling in the prediction of gastric pH-mediated drug exposure by using itraconazole, a weak base, as a case. An itraconazole PBPK model was developed on the mechanistic basis of its absorption kinetics in a middle-out manner from a stepwise in vitro-in vivo extrapolation to in vivo refinement. Afterward, an independent prospective clinical study evaluating gastric pH and itraconazole pharmacokinetics (PKs) under normal gastric acidity and esomeprazole-induced gastric hypoacidity was conducted for model validation. Validation was performed by comparing the predicted data with the clinical observations, and the valid model was subsequently applied to predict PK changes under achlorhydria. The developed itraconazole PBPK model showed reasonable reproducibility for gastric pH-mediated exposure observed in the clinical investigation. Based on the model-based simulations, itraconazole exposure was expected to be decreased up to 65% under achlorhydria, and furthermore, gastric pH-mediated exposure could be mechanistically interpreted according to sequential variation in total solubility, dissolution, and absorption. This study suggested the utility of PBPK modeling in the prediction of gastric pH-mediated exposure, especially for drugs whose absorption is susceptible to gastric pH. Our findings will serve as a leading model for further mechanistic assessment of exposure depending on gastric pH for various drugs, ultimately contributing to personalized pharmacotherapy.
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Affiliation(s)
- Eunsol Yang
- Department of Clinical Pharmacology and TherapeuticsSeoul National University College of Medicine and Hospital101 Daehak‐ro, Jongno‐guSeoul03080Republic of Korea
- Kidney Research InstituteSeoul National University Medical Research Center103 Daehak‐ro, Jongno‐guSeoul03080Republic of Korea
| | - Kyung‐Sang Yu
- Department of Clinical Pharmacology and TherapeuticsSeoul National University College of Medicine and Hospital101 Daehak‐ro, Jongno‐guSeoul03080Republic of Korea
| | - SeungHwan Lee
- Department of Clinical Pharmacology and TherapeuticsSeoul National University College of Medicine and Hospital101 Daehak‐ro, Jongno‐guSeoul03080Republic of Korea
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Naqvi SMH, Gala MYN, Muchhala S, Arumugam A, Panigrahi D, Patil D, Rathod R, Mane A. Pharmacokinetics/Pharmacodynamics study of Fixtral SB as compared to supra bioavailable itraconazole and conventional itraconazole. World J Pharmacol 2023; 12:1-11. [DOI: 10.5497/wjp.v12.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/11/2022] [Accepted: 02/07/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND Itraconazole is a broad-spectrum triazole antifungal inhibiting fungal growth by inhibiting ergosterol synthesis and exhibits a nonlinear pharmacokinetic profile. Erratic absorption pattern with wide fluctuations in blood levels causes inconsistent and unpredictable clinical behaviour of this drug despite its low minimum inhibitory concentration (MIC) as compared to other antifungal agents.
AIM To compare the oral bioavailability and bioequivalence of Fixtral SB (supra bioavailable itraconazole) with reference product R2 (supra bioavailable 2 × 50 mg itraconazole).
METHODS The study population consisted of 54 healthy volunteers, aged between 18-45 years and randomized to receive a single oral dose of either test [T; Fixtral SB (supra bioavailable itraconazole) 100 mg] or reference product (R1; Sporanox 100 mg × 2 capsules and R2; Lozanoc capsules 50 mg × 2 capsules). Blood samples were taken pre-dose and post-dose up to 96 h. The study evaluated bioequivalence by comparing the oral bioavailability of the test product with reference product R2. The pharmacodynamic characteristics of the drug were evaluated by comparing the test product with reference product R1. Pharmacokinetics (PK)-PD comparative analysis [area under the concentration-time curve (AUC)/ minimum inhibitory concentration (MIC) > 25] was performed for conventional itraconazole 100 mg and supra bioavailable itraconazole 50 mg. Adverse events (AEs) assessments were performed in each study period and post-study evaluation.
RESULTS Statistical analysis of primary PK variables revealed bioequivalence, with confidence intervals being completely inside the acceptance criteria of 80%-125%. The peak concentration levels of itraconazole were achieved at 10 h (T) and 8.5 h (R2), respectively. Pharmacodynamic parameter assessment showed that AUC/MIC for R1 are comparable to Fixtral SB 100mg for MIC levels up to 16mcg/mL (P > 0.05 and observed P = 0.3196). Six AEs were observed that were mild to moderate in severity and resolved. No severe AE was reported.
CONCLUSION Test product itraconazole Capsule 100 mg is bioequivalent with the reference product (R2) at 100 mg dose (2 capsules of Lozanoc® 50 mg) under fed conditions. Pharmacodynamics activity in terms of AUC/MIC is comparable between the test product at 100 mg dose and marketed itraconazole 200 mg. Fixtral SB is expected to have therapeutically similar efficacy at half the equivalent dose. Tested formulations were found to be safe and well tolerated.
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Affiliation(s)
| | | | - Snehal Muchhala
- Medical Affairs, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | - Anand Arumugam
- Global Clinical Management, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | | | - Dipak Patil
- Global Clinical Management, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | - Rahul Rathod
- Medical Affairs, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | - Amey Mane
- Medical Affairs, Dr Reddy’s Laboratories, Hyderabad 500016, India
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Kambayashi A, Shirasaka Y. Food effects on gastrointestinal physiology and drug absorption. Drug Metab Pharmacokinet 2023; 48:100488. [PMID: 36737277 DOI: 10.1016/j.dmpk.2022.100488] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/01/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022]
Abstract
Food ingestion affects the oral absorption of many drugs in humans. In this review article, we summarize the physiological factors in the gastrointestinal (GI) tract that affect the in vivo performance of orally administered solid dosage forms in fasted and fed states in humans. In particular, we discuss the effects of food ingestion on fluid characteristics (pH, bile concentration, and volume) in the stomach and small intestine, GI transit of water and dosage forms, and microbiota. Additionally, case examples of food effects on GI physiology and subsequent changes in oral drug absorption are provided. Furthermore, the effects of food, especially fruit juices (e.g., grapefruit, orange, apple) and green tea, on transporter-mediated permeation and enzyme-catalyzed metabolism of drugs in intestinal epithelial cells are also summarized comprehensively.
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Affiliation(s)
- Atsushi Kambayashi
- Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka, 425-0072, Japan; School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Yoshiyuki Shirasaka
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
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Systemic Antifungal Therapy for Invasive Pulmonary Infections. J Fungi (Basel) 2023; 9:jof9020144. [PMID: 36836260 PMCID: PMC9966409 DOI: 10.3390/jof9020144] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/13/2023] [Accepted: 01/19/2023] [Indexed: 01/24/2023] Open
Abstract
Antifungal therapy for pulmonary fungal diseases is in a state of flux. Amphotericin B, the time-honored standard of care for many years, has been replaced by agents demonstrating superior efficacy and safety, including extended-spectrum triazoles and liposomal amphotericin B. Voriconazole, which became the treatment of choice for most pulmonary mold diseases, has been compared with posaconazole and itraconazole, both of which have shown clinical efficacy similar to that of voriconazole, with fewer adverse events. With the worldwide expansion of azole-resistant Aspergillus fumigatus and infections with intrinsically resistant non-Aspergillus molds, the need for newer antifungals with novel mechanisms of action becomes ever more pressing.
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Rauseo AM, Olsen MA, Stwalley D, Mazi PB, Larson L, Powderly WG, Spec A. Creation and Internal Validation of a Clinical Predictive Model for Fluconazole Resistance in Patients With Candida Bloodstream Infection. Open Forum Infect Dis 2022; 9:ofac447. [PMID: 36119958 PMCID: PMC9472663 DOI: 10.1093/ofid/ofac447] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/27/2022] [Indexed: 11/20/2022] Open
Abstract
Background Fluconazole is recommended as first-line therapy for candidemia when risk of fluconazole resistance (fluc-R) is low. Lack of methods to estimate resistance risk results in extended use of echinocandins and prolonged hospitalization. This study aimed to develop a clinical predictive model to identify patients at low risk for fluc-R where initial or early step-down fluconazole would be appropriate. Methods Retrospective analysis of hospitalized adult patients with positive blood culture for Candida spp from 2013 to 2019. Multivariable logistic regression model was performed to identify factors associated with fluc-R. Stepwise regression was performed on bootstrapped samples to test individual variable stability and estimate confidence intervals (CIs). We used receiver operating characteristic curves to assess performance across the probability spectrum. Results We identified 539 adults with candidemia and 72 Candida isolates (13.4%) were fluc-R. Increased risk of fluc-R was associated with older age, prior bacterial bloodstream infection (odds ratio [OR], 2.02 [95% CI, 1.13-3.63]), myelodysplastic syndrome (OR, 3.09 [95% CI, 1.13-8.44]), receipt of azole therapy (OR, 5.42 [95% CI, 2.90-10.1]) within 1 year of index blood culture, and history of bone marrow or stem cell transplant (OR, 2.81 [95% CI, 1.41-5.63]). The model had good discrimination (optimism-corrected c-statistic 0.771), and all of the selected variables were stable. The prediction model had a negative predictive value of 95.7% for the selected sensitivity cutoff of 90.3%. Conclusions This model is a potential tool for identifying patients at low risk for fluc-R candidemia to receive first-line or early step-down fluconazole.
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Affiliation(s)
- Adriana M Rauseo
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
| | - Margaret A Olsen
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
| | - Dustin Stwalley
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
| | - Patrick B Mazi
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
| | - Lindsey Larson
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
| | - William G Powderly
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
| | - Andrej Spec
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
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12
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Choi Y, Koo Y, Yun T, Chae Y, Lee D, Jeong JW, Lee KR, Kim H, Yang MP, Kang BT. Pharmacokinetics of fluconazole after oral administration to healthy beagle dogs. Vet Dermatol 2022; 33:509-515. [PMID: 36000582 DOI: 10.1111/vde.13112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 05/07/2022] [Accepted: 06/25/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Fluconazole can be effective in the treatment of superficial mycoses in dogs. However, the pharmacokinetics of fluconazole have not yet been evaluated to determine its optimal dosing regimen. OBJECTIVES This study aimed to determine the plasma concentration of fluconazole after single and multiple administrations at two different dosages in dogs. METHODS AND MATERIALS Eight healthy beagle dogs were divided into two groups, and each group received either 5 or 10 mg/kg of fluconazole per os. The pharmacokinetics of fluconazole was determined following single and multiple administrations p.o. Single- and multiple-dose treatment periods were separated by a washout period of seven days. Plasma concentrations of fluconazole were determined by established high-performance liquid chromatography coupled with tandem mass spectrometry system. RESULTS In the 5 mg/kg group, the mean maximum concentrations (Cmax ) and the area under the plasma concentrations (AUC0-24h ) were 4.84 μg/mL and 85.56 μg*h/mL, respectively, after single administration and 6.58 μg/mL and 119.52 μg*h/mL, respectively, after multiple administrations. In the 10 mg/kg group, the Cmax and AUC0-24h were 5.67 μg/mL and 109.19 μg*h/mL, respectively, after single administration and 15.10 μg/mL and 291.51 μg*h/mL, respectively, after multiple administrations. The Cmax (p < 0.001) and AUC0-24h (p < 0.001) were significantly lower in the 5 mg/kg group than those in the 10 mg/kg group at multiple administrations. CONCLUSIONS AND CLINICAL RELEVANCE Fluconazole accumulates in plasma and exhibits dose-proportional pharmacokinetics after multiple doses, and was safe and well tolerated at these doses for short-term administration.
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Affiliation(s)
- Yujin Choi
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Yoonhoi Koo
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Taesik Yun
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Yeon Chae
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Dohee Lee
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Jong-Woo Jeong
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Korea
| | - Kyeong-Ryoon Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Korea
| | - Hakhyun Kim
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Mhan-Pyo Yang
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Byeong-Teck Kang
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Korea
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13
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Mármol ÁL, Fischer PL, Wahl A, Schwöbel D, Lenz V, Sauer K, Koziolek M. Application of tiny-TIM as a mechanistic tool to investigate the in vitro performance of different itraconazole formulations under physiologically relevant conditions. Eur J Pharm Sci 2022; 173:106165. [DOI: 10.1016/j.ejps.2022.106165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 11/26/2022]
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14
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Chau MM, Daveson K, Alffenaar JWC, Gwee A, Ho SA, Marriott DJE, Trubiano JA, Zhao J, Roberts JA. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy and haemopoietic stem cell transplant recipients, 2021. Intern Med J 2021; 51 Suppl 7:37-66. [PMID: 34937141 DOI: 10.1111/imj.15587] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Antifungal agents can have complex dosing and the potential for drug interaction, both of which can lead to subtherapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy and haemopoietic stem cell transplant recipients. Antifungal agents can also be associated with significant toxicities when drug concentrations are too high. Suboptimal dosing can be minimised by clinical assessment, laboratory monitoring, avoidance of interacting drugs, and dose modification. Therapeutic drug monitoring (TDM) plays an increasingly important role in antifungal therapy, particularly for antifungal agents that have an established exposure-response relationship with either a narrow therapeutic window, large dose-exposure variability, cytochrome P450 gene polymorphism affecting drug metabolism, the presence of antifungal drug interactions or unexpected toxicity, and/or concerns for non-compliance or inadequate absorption of oral antifungals. These guidelines provide recommendations on antifungal drug monitoring and TDM-guided dosing adjustment for selected antifungal agents, and include suggested resources for identifying and analysing antifungal drug interactions. Recommended competencies for optimal interpretation of antifungal TDM and dose recommendations are also provided.
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Affiliation(s)
- Maggie M Chau
- Pharmacy Department, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Kathryn Daveson
- Department of Infectious Diseases and Microbiology, The Canberra Hospital, Garran, Australian Capital Territory, Australia
| | - Jan-Willem C Alffenaar
- Faculty of Medicine and Health, School of Pharmacy, University of Sydney, Camperdown, New South Wales, Australia.,Pharmacy Department, Westmead Hospital, Westmead, New South Wales, Australia.,Marie Bashir Institute of Infectious Diseases and Biosecurity, University of Sydney, Camperdown, New South Wales, Australia
| | - Amanda Gwee
- Infectious Diseases Unit, The Royal Children's Hospital, Parkville, Victoria, Australia.,Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.,Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Su Ann Ho
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Deborah J E Marriott
- Department of Clinical Microbiology and Infectious Diseases, St Vincent's Hospital, Darlinghurst, New South Wales, Australia.,Faculty of Science, University of Technology, Ultimo, New South Wales, Australia.,Faculty of Medicine, The University of New South Wales, Kensington, New South Wales, Australia
| | - Jason A Trubiano
- Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia.,Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
| | - Jessie Zhao
- Department of Haematology, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Jason A Roberts
- The University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Department of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.,Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
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15
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Czyrski A, Resztak M, Świderski P, Brylak J, Główka FK. The Overview on the Pharmacokinetic and Pharmacodynamic Interactions of Triazoles. Pharmaceutics 2021; 13:pharmaceutics13111961. [PMID: 34834376 PMCID: PMC8620887 DOI: 10.3390/pharmaceutics13111961] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/09/2021] [Accepted: 11/15/2021] [Indexed: 12/24/2022] Open
Abstract
Second generation triazoles are widely used as first-line drugs for the treatment of invasive fungal infections, including aspergillosis and candidiasis. This class, along with itraconazole, voriconazole, posaconazole, and isavuconazole, is characterized by a broad range of activity, however, individual drugs vary considerably in safety, tolerability, pharmacokinetics profiles, and interactions with concomitant medications. The interaction may be encountered on the absorption, distribution, metabolism, and elimination (ADME) step. All triazoles as inhibitors or substrates of CYP isoenzymes can often interact with many drugs, which may result in the change of the activity of the drug and cause serious side effects. Drugs of this class should be used with caution with other agents, and an understanding of their pharmacokinetic profile, safety, and drug-drug interaction profiles is important to provide effective antifungal therapy. The manuscript reviews significant drug interactions of azoles with other medications, as well as with food. The PubMed and Google Scholar bases were searched to collect the literature data. The interactions with anticonvulsants, antibiotics, statins, kinase inhibitors, proton pump inhibitors, non-nucleoside reverse transcriptase inhibitors, opioid analgesics, benzodiazepines, cardiac glycosides, nonsteroidal anti-inflammatory drugs, immunosuppressants, antipsychotics, corticosteroids, biguanides, and anticoagulants are presented. We also paid attention to possible interactions with drugs during experimental therapies for the treatment of COVID-19.
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Affiliation(s)
- Andrzej Czyrski
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland; (M.R.); (F.K.G.)
- Correspondence: ; Tel.: +48-61-854-64-33
| | - Matylda Resztak
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland; (M.R.); (F.K.G.)
| | - Paweł Świderski
- Department of Forensic Medicine, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland;
| | - Jan Brylak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 27/33 Szpitalna Street, 60-572 Poznań, Poland;
| | - Franciszek K. Główka
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland; (M.R.); (F.K.G.)
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16
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An Assessment of Occasional Bio-Inequivalence for BCS1 and BCS3 Drugs: What are the Underlying Reasons? J Pharm Sci 2021; 111:124-134. [PMID: 34363838 DOI: 10.1016/j.xphs.2021.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/02/2021] [Accepted: 08/02/2021] [Indexed: 11/20/2022]
Abstract
Despite having adequate solubility properties, bioequivalence (BE) studies performed on immediate release formulations containing BCS1/3 drugs occasionally fail. By systematically evaluating a set of 17 soluble drugs where unexpected BE failures have been reported and comparing to a set of 29 drugs where no such reports have been documented, a broad assessment of the risk factors leading to BE failure was performed. BE failures for BCS1/3 drugs were predominantly related to changes in Cmax rather than AUC. Cmax changes were typically modest, with minimal clinical significance for most drugs. Overall, drugs with a sharp plasma peak were identified as a key factor in BE failure risk. A new pharmacokinetic term (t½Cmax) is proposed to identify drugs at higher risk due to their peak plasma profile shape. In addition, the analysis revealed that weak acids, and drugs with particularly high gastric solubility are potentially more vulnerable to BE failure, particularly when these features are combined with a sharp Cmax peak. BCS3 drugs, which are often characterised as being more vulnerable to BE failure due to their potential for permeation and transit to be altered, particularly by excipient change, were not in general at greater risk of BE failures. These findings will help to inform how biowaivers may be optimally applied in the future.
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17
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The Impact of Diet and Exercise on Drug Responses. Int J Mol Sci 2021; 22:ijms22147692. [PMID: 34299312 PMCID: PMC8304791 DOI: 10.3390/ijms22147692] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 07/15/2021] [Indexed: 12/14/2022] Open
Abstract
It is well known that lifestyle changes can alter several physiological functions in the human body. For exercise and diet, these effects are used sensibly in basic therapies, as in cardiovascular diseases. However, the physiological changes induced by exercise and a modified diet also have the capacity to influence the efficacy and toxicity of several drugs, mainly by affecting different pharmacokinetic mechanisms. This pharmacological plasticity is not clinically relevant in all cases but might play an important role in altering the effects of very common drugs, particularly drugs with a narrow therapeutic window. Therefore, with this review, we provide insights into possible food–drug and exercise–drug interactions to sharpen awareness of the potential occurrence of such effects.
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18
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Cohen-Rabbie S, Zhou L, Vishwanathan K, Wild M, Xu S, Freshwater T, Jain L, Schalkwijk S, Tomkinson H, Zhou D. Physiologically Based Pharmacokinetic Modeling for Selumetinib to Evaluate Drug-Drug Interactions and Pediatric Dose Regimens. J Clin Pharmacol 2021; 61:1493-1504. [PMID: 34196005 PMCID: PMC9290801 DOI: 10.1002/jcph.1935] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 06/29/2021] [Indexed: 12/02/2022]
Abstract
Selumetinib (ARRY‐142886), an oral, potent and highly selective allosteric mitogen‐activated protein kinase kinase 1/2 inhibitor, is approved by the US Food and Drug Administration for the treatment of pediatric patients aged ≥2 years with neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. A physiologically based pharmacokinetic (PBPK) model was constructed to predict plasma concentration–time profiles of selumetinib, and to evaluate the impact of coadministering moderate cytochrome P450 (CYP) 3A4/2C19 inhibitors/inducers. The model was also used to extrapolate pharmacokinetic exposures from older children with different body surface area to guide dosing in younger children. This model was built based on physiochemical data and clinical in vivo drug‐drug interaction (DDI) studies with itraconazole and fluconazole, and verified against data from an in vivo rifampicin DDI study and an absolute bioavailability study. The pediatric model was updated by changing system‐specific input parameters using the Simcyp pediatric module. The model captured the observed selumetinib pharmacokinetic profiles and the interactions with CYP inhibitors/inducers. The predictions from the PBPK model showed a DDI effect of 30% to 40% increase or decrease in selumetinib exposure when coadministered with moderate CYP inhibitors or inducers, respectively, which was used to inform dose management and adjustments. The pediatric PBPK model was applied to simulate exposures in specific body surface area brackets that matched those achieved with a 25 mg/m2 dose in SPRINT clinical trials. The pediatric PBPK model was used to guide the dose for younger patients in a planned pediatric clinical study.
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Affiliation(s)
- Sarit Cohen-Rabbie
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology and Safety Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Li Zhou
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology and Safety Science, BioPharmaceuticals R&D, AstraZeneca, Boston, Massachusetts, USA
| | - Karthick Vishwanathan
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology and Safety Science, BioPharmaceuticals R&D, AstraZeneca, Boston, Massachusetts, USA
| | | | - Sherrie Xu
- Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck & Co., Inc., Kenilworth, New Jersey, USA
| | - Tomoko Freshwater
- Quantitative Pharmacology & Pharmacometrics (QP2) Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck & Co., Inc., Kenilworth, New Jersey, USA
| | - Lokesh Jain
- Quantitative Pharmacology & Pharmacometrics (QP2) Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck & Co., Inc., Kenilworth, New Jersey, USA
| | - Stein Schalkwijk
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology and Safety Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Helen Tomkinson
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology and Safety Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Diansong Zhou
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology and Safety Science, BioPharmaceuticals R&D, AstraZeneca, Boston, Massachusetts, USA
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19
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Kofoed-Djursner C, Jamil A, Selen A, Müllertz A, Berthelsen R. Drug solubilization during simulated pediatric gastro-intestinal digestion. Eur J Pharm Sci 2021; 162:105828. [PMID: 33819625 DOI: 10.1016/j.ejps.2021.105828] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/17/2021] [Accepted: 03/31/2021] [Indexed: 10/21/2022]
Abstract
To increase the understanding of how drugs behave following oral administration to the pediatric population, the aim of the present study was to investigate the solubilization of fluconazole and ibuprofen during simulated gastro-intestinal (GI) digestion, using an immediate transfer model mimicking pediatric GI digestion. The effects of infant formula and digestion, on the drug solubilization, were studied using simulated fasted and fed state digestion media in the presence and absence of digestive enzymes. Additionally, the effect of digestion media viscosity on the solubilization process was investigated. It was found that the solubilization of fluconazole was unaffected by all tested parameters, as the entire estimated dose equivalent was solubilized in the aqueous phase throughout all digestion studies. In contrast, the solubilization of ibuprofen was affected by all the tested parameters, i.e. in the fasted state, the solubilization of ibuprofen was limited by its solubility in the aqueous phase of the simulated GI digestion media, whereas the solubilization in the fed state was affected by drug partitioning between the lipid and the aqueous phases, and therefore by the digestion of the lipid phase. Adding Nestlé Thicken Up™, containing xanthan gum as a thickening agent, to the digestion medium increased its viscosity, which in turn resulted in a reduced initial digestion rate, increased pH fluctuations, as well as high variability in all drug solubilization data as evident in large standard deviations. Furthermore, the increased digestion medium viscosity decreased the drug recovery from the combined pellet and aqueous phase. The observed viscosity effects might translate into a more variable and lower oral bioavailability.
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Affiliation(s)
- Caroline Kofoed-Djursner
- Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
| | - Ali Jamil
- Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
| | - Arzu Selen
- US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Testing and Research, Silver Spring, MD, United States.
| | - Anette Müllertz
- Bioneer: FARMA, Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Ragna Berthelsen
- Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
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20
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Kallee S, Scharf C, Schroeder I, Paal M, Vogeser M, Irlbeck M, Zander J, Zoller M, Jung J, Kneidinger N, Schneider C, Michel S, Liebchen U. Comparing posaconazole and itraconazole for antifungal prophylaxis in critically ill lung transplant recipients: Efficacy and plasma concentrations. Transpl Infect Dis 2021; 23:e13675. [PMID: 34166573 DOI: 10.1111/tid.13675] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 05/19/2021] [Accepted: 05/30/2021] [Indexed: 01/20/2023]
Abstract
BACKGROUND Posaconazole and itraconazole are commonly used for systemic antifungal prophylaxis after lung transplantation. The aim of this study on critically ill lung transplant recipients was to assess the rate of adequate plasma concentrations and the frequency of fungal-induced transitions from antifungal prophylaxis to therapy after the administration of either posaconazole or itraconazole for systemic prophylaxis. METHODS Critically ill lung transplant recipients with postoperative posaconazole or itraconazole prophylaxis and therapeutic drug monitoring from February 2016 to November 2019 were retrospectively included in the study. Positive fungal cultures or Aspergillus antigen tests resulting in a transition from antifungal prophylaxis to therapy were analyzed from the first day of prophylaxis until 7 days after the last sample for each patient. Adequate plasma concentrations were defined as ≥500 µg/L for itraconazole and ≥700 µg/L for posaconazole. RESULTS Two hundred seventy-five samples from 73 patients were included in the analysis. Overall, 60% of the posaconazole and 55% of the itraconazole concentrations were subtherapeutic. Administration of posaconazole suspension resulted significantly (P < .01) more often in subtherapeutic concentrations than tablets (68% vs 10%). Patients treated with posaconazole showed less positive fungal records resulting in a transition from prophylaxis to therapy than patients treated with itraconazole (10% vs 33%, P-value: .029). The detection of a fungal pathogen was not associated with the measured plasma concentrations or the achievement of the target concentrations. CONCLUSION Our findings suggest that posaconazole should be used instead of itraconazole for systemic prophylaxis in critically ill lung transplant recipients.
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Affiliation(s)
- Simon Kallee
- Department of Anesthesiology, University Hospital, LMU Munich, Munich, Germany
| | - Christina Scharf
- Department of Anesthesiology, University Hospital, LMU Munich, Munich, Germany
| | - Ines Schroeder
- Department of Anesthesiology, University Hospital, LMU Munich, Munich, Germany
| | - Michael Paal
- Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Michael Vogeser
- Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Michael Irlbeck
- Department of Anesthesiology, University Hospital, LMU Munich, Munich, Germany
| | | | - Michael Zoller
- Department of Anesthesiology, University Hospital, LMU Munich, Munich, Germany
| | - Jette Jung
- Max-von-Pettenkofer-Institute Munich, Ludwig Maximilian University, Munich, Germany
| | - Nikolaus Kneidinger
- Department of Internal Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Christian Schneider
- Department of Thoracic Surgery, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Sebastian Michel
- Department of Cardiac Surgery, University Hospital LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Uwe Liebchen
- Department of Anesthesiology, University Hospital, LMU Munich, Munich, Germany
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Abstract
Invasive candidiasis (IC) is a collective term that refers to a group of infectious syndromes caused by a variety of species of Candida, 6 of which cause most cases globally. Candidemia is probably the most commonly recognized syndrome associated with IC; however, Candida can cause invasive infection of any organ, especially visceral organs, vasculature, bones and joints, the eyes and central nervous system. Targeted prevention and empirical therapy are important interventions for patients at high risk for IC, and the current approach should be based on a combination of clinical risk factors and non-culture-based diagnostics, when available.
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Affiliation(s)
- Todd P McCarty
- University of Alabama at Birmingham, Birmingham VA Medical Center, 1900 University Boulevard, THT 229, Birmingham, AL 35294, USA.
| | - Cameron M White
- University of Alabama at Birmingham, 1900 University Boulevard, THT 229, Birmingham, AL 35294, USA
| | - Peter G Pappas
- University of Alabama at Birmingham, 1900 University Boulevard, THT 229, Birmingham, AL 35294, USA
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22
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Wilmes D, Coche E, Rodriguez-Villalobos H, Kanaan N. Fungal pneumonia in kidney transplant recipients. Respir Med 2021; 185:106492. [PMID: 34139578 DOI: 10.1016/j.rmed.2021.106492] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 10/21/2022]
Abstract
Fungal pneumonia is a dreaded complication encountered after kidney transplantation, complicated by increased mortality and often associated with graft failure. Diagnosis can be challenging because the clinical presentation is non-specific and diagnostic tools have limited sensitivity and specificity in kidney transplant recipients and must be interpreted in the context of the clinical setting. Management is difficult due to the increased risk of dissemination and severity, multiple comorbidities, drug interactions and reduced immunosuppression which should be applied as an important adjunct to therapy. This review will focus on the main causes of fungal pneumonia in kidney transplant recipients including Pneumocystis, Aspergillus, Cryptococcus, mucormycetes and Histoplasma. Epidemiology, clinical presentation, laboratory and radiographic features, specific characteristics will be discussed with an update on diagnostic procedures and treatment.
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Affiliation(s)
- D Wilmes
- Division of Internal Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - E Coche
- Division of Radiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - H Rodriguez-Villalobos
- Division of Microbiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - N Kanaan
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
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23
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Murakami T, Bodor E, Bodor N. Factors and dosage formulations affecting the solubility and bioavailability of P-glycoprotein substrate drugs. Expert Opin Drug Metab Toxicol 2021; 17:555-580. [PMID: 33703995 DOI: 10.1080/17425255.2021.1902986] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate drugs. Oral bioavailability of poorly soluble P-gp substrate drugs is low and varied but increases with high-fat meals that supply lipoidal components and bile in the duodenum.Areas covered: Absorption properties of P-gp substrate drugs along with factors and oral dosage formulations affecting their solubility and bioavailability were reviewed with PubMed literature searches. An overview is provided from the viewpoint of the 'spring-and-parachute approach' that generates supersaturation of poorly soluble P-gp substrate drugs.Expert opinion: The oral bioavailability of P-gp substrate drugs is difficult to predict because of their low solubility, preferential absorption sites, and overlapping substrate specificities with CYP3A4, along with the scattered intestinal P-gp expression/function. To attain high and steady oral bioavailability of poorly soluble P-gp substrate drugs, physicochemical modification of drugs to improve solubility, or oral dosage formulations that generate long-lasting supersaturation in the duodenum, is preferred. In particular, supersaturable lipid-based drug delivery systems that can increase passive diffusion and/or lymphatic absorption are effective and applicable to many poorly soluble P-gp substrate drugs.
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Affiliation(s)
| | | | - Nicholas Bodor
- Bodor Laboratories, Miami, Florida, USA.,College of Pharmacy, University of Florida, Gainesville, Florida, USA
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Rojo-Solís C, García-Párraga D, Montesinos A, Ardiaca-García M, Álvaro T, Valls M, Barros-García C, Encinas T. Pharmacokinetics of single dose oral Terbinafine in common shelducks (Tadorna tadorna). J Vet Pharmacol Ther 2020; 44:510-515. [PMID: 33377208 DOI: 10.1111/jvp.12942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 12/06/2020] [Indexed: 11/27/2022]
Abstract
Fungal disease is a major cause of morbidity and mortality in avian species; thus, antifungals are the treatment of choice. Despite widely used in clinical practice, terbinafine pharmacokinetic studies are scarce in literature and only cover some avian families, with marked differences between them. This study evaluates the pharmacokinetic behaviour of terbinafine after a single oral administration of 60 mg/kg in 7 healthy adult common shelducks (Tadorna tadorna) by measuring plasma concentrations through high-performance liquid chromatography (HPLC) at times 0, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hr postadministration. Noncompartmental analyses of the data showed a Cmax (geometric mean) of 5.43 µg/ml, tmax (median) 1.0 hr and AUC0-∞ 29.70 mg h/L. Elimination half-life was 6.33 hr and MRT 6.61 hr. Plasma concentrations remained above previously described MIC for terbinafine in some fungal species for at least 6 to 8 hr. A single oral administration of 60 mg/kg terbinafine did not produce adverse effects and could be a good treatment choice for fungal diseases in anatids.
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Affiliation(s)
- Carlos Rojo-Solís
- Veterinary Services, Oceanogràfic, Ciudad de las Artes y las Ciencias, València, Spain.,Pharmacology & Toxicology Department, Veterinary Faculty, Complutense University of Madrid, Madrid, Spain
| | - Daniel García-Párraga
- Veterinary Services, Oceanogràfic, Ciudad de las Artes y las Ciencias, València, Spain
| | - Andrés Montesinos
- Pharmacology & Toxicology Department, Veterinary Faculty, Complutense University of Madrid, Madrid, Spain.,Centro Veterinario los Sauces, Madrid, Spain
| | | | - Teresa Álvaro
- Veterinary Services, Oceanogràfic, Ciudad de las Artes y las Ciencias, València, Spain
| | - Mónica Valls
- Veterinary Services, Oceanogràfic, Ciudad de las Artes y las Ciencias, València, Spain
| | - Carlos Barros-García
- Veterinary Services, Oceanogràfic, Ciudad de las Artes y las Ciencias, València, Spain
| | - Teresa Encinas
- Pharmacology & Toxicology Department, Veterinary Faculty, Complutense University of Madrid, Madrid, Spain
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25
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Formulation technologies and advances for oral delivery of novel nitroimidazoles and antimicrobial peptides. J Control Release 2020; 324:728-749. [PMID: 32380201 DOI: 10.1016/j.jconrel.2020.05.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 05/01/2020] [Accepted: 05/02/2020] [Indexed: 02/06/2023]
Abstract
Antibiotic resistance has become a global crisis, driving the exploration for novel antibiotics and novel treatment approaches. Among these research efforts two classes of antibiotics, bicyclic nitroimidazoles and antimicrobial peptides, have recently shown promise as novel antimicrobial agents with the possibility to treat multi-drug resistant infections. However, they suffer from the issue of poor oral bioavailability due to disparate factors: low solubility in the case of nitroimidazoles (BCS class II drugs), and low permeability in the case of peptides (BCS class III drugs). Moreover, antimicrobial peptides present another challenge as they are susceptible to chemical and enzymatic degradation, which can present an additional pharmacokinetic hurdle for their oral bioavailability. Formulation technologies offer a potential means for improving the oral bioavailability of poorly permeable and poorly soluble drugs, but there are still drawbacks and limitations associated with this approach. This review discusses in depth the challenges associated with oral delivery of nitroimidazoles and antimicrobial peptides and the formulation technologies that have been used to overcome these problems, including an assessment of the drawbacks and limitations associated with the technologies that have been applied. Furthermore, the potential for supercritical fluid technology to overcome the shortcomings associated with conventional drug formulation methods is reviewed.
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26
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Yadav YC, Pathak K, Pathak D. Review on Preclinical and Clinical Evidence of Food (Beverages, Fruits and Vegetables) and Drug Interactions: Mechanism and Safety. CURRENT DRUG THERAPY 2020. [DOI: 10.2174/1574885514666190126141424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background:The therapeutic potency and efficacy of drugs can be affected by a patient’s dietary habit. The food composition and their nutritional value interact with drugs that lead to alteration of the therapeutic response of drugs in patients.Objective:This present review is an attempt to illustrate clinical reports of food-drug interaction. Further, it also highlights specific interaction mechanism(s) and the safety thereof.Methods:Through the search engine “Scopus”; literature on recent advances in food and drug interactions includes almost all therapeutic categories such as antimicrobials, antiviral, antifungal, antihistamines, anticoagulants, non-steroidal anti-inflammatory drugs, and drugs acting on the central nervous system and cardiovascular system.Results:Preclinical and clinical studies that have been conducted by various researchers affirm significant drug-food interactions across the various therapeutic categories of drugs. Preclinical studies have documented the effects of food, milk products, alcohols, fruit and vegetables on the drug absorption, metabolizing enzymes and drug transporters. The clinical studies on fruits/vegetables and drugs interactions report significant alteration in therapeutic response.Conclusion:Based on the preclinical and clinical reports, it can be concluded that the interaction of food with drug(s) significantly alters their therapeutic potential. The inputs from clinical practitioners to elucidate potential risk of food-drug interaction need to be intensified in order to prevent adverse clinical consequences.
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Affiliation(s)
- Yogesh C. Yadav
- Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Saifai, Etawah, 206130, Uttar Pradesh, India
| | - Kamla Pathak
- Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Saifai, Etawah, 206130, Uttar Pradesh, India
| | - Devender Pathak
- Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Saifai, Etawah, 206130, Uttar Pradesh, India
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Characteristics of Skin Deposition of Itraconazole Solubilized in Cream Formulation. Pharmaceutics 2019; 11:pharmaceutics11040195. [PMID: 31013633 PMCID: PMC6523664 DOI: 10.3390/pharmaceutics11040195] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/16/2019] [Accepted: 04/16/2019] [Indexed: 01/26/2023] Open
Abstract
Itraconazole (ITZ) is an anti-fungal agent generally used to treat cutaneous mycoses. For efficient delivery of ITZ to the skin tissues, an oil-in-water (O/W) cream formulation was developed. The O/W cream base was designed based on the solubility measurement of ITZ in various excipients. A physical mixture of the O/W cream base and ITZ was also prepared as a control formulation to evaluate the effects of the solubilized state of ITZ in cream base on the in vitro skin deposition behavior of ITZ. Polarized light microscopy and differential scanning calorimetry demonstrated that ITZ was fully solubilized in the O/W cream formulation. The O/W cream formulation exhibited considerably enhanced deposition of ITZ in the stratum corneum, epidermis, and dermis compared with that of the physical mixture, largely owing to its high solubilization capacity for ITZ. Therefore, the O/W cream formulation of ITZ developed in this study is promising for the treatment of cutaneous mycoses caused by fungi such as dermatophytes and yeasts.
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Hatton GB, Madla CM, Rabbie SC, Basit AW. Gut reaction: impact of systemic diseases on gastrointestinal physiology and drug absorption. Drug Discov Today 2018; 24:417-427. [PMID: 30453059 DOI: 10.1016/j.drudis.2018.11.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 10/25/2018] [Accepted: 11/13/2018] [Indexed: 12/17/2022]
Abstract
It was in 400 BC that Hippocrates reportedly stated that "death sits in the colon". The growth in our knowledge of the intestinal microbiome, the gut-brain axis and their function and imbalance has distinctly uncovered the complex relationship between the gut to disease predisposition and development, heralding the problem and the solution to disease pathology. Human studies of new drug molecules are typically performed in healthy volunteers and their specific disease indication. Approved drugs, however, are used by patients with diverse disease backgrounds. Here, we review the current literature of the gastrointestinal tract reacting to systemic disease pathology that elicits physiological and functional changes that consequently affect oral drug product performance.
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Affiliation(s)
- Grace B Hatton
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Christine M Madla
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Sarit C Rabbie
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Abdul W Basit
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
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29
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Koziolek M, Kostewicz E, Vertzoni M. Physiological Considerations and In Vitro Strategies for Evaluating the Influence of Food on Drug Release from Extended-Release Formulations. AAPS PharmSciTech 2018; 19:2885-2897. [PMID: 30155808 DOI: 10.1208/s12249-018-1159-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 08/18/2018] [Indexed: 02/08/2023] Open
Abstract
Food effects on oral drug bioavailability are a consequence of the complex interplay between drug, formulation and human gastrointestinal (GI) physiology. Accordingly, the prediction of the direction and the extent of food effects is often difficult. With respect to novel formulations, biorelevant in vitro methods can be extremely powerful tools to simulate the effect of food-induced changes on the physiological GI conditions on drug release and absorption. However, the selection of suitable in vitro methods should be based on a thorough understanding not only of human GI physiology but also of the drug and formulation properties. This review focuses on in vitro methods that can be applied to evaluate the effect of food intake on drug release from extended release (ER) products during preclinical formulation development. With the aid of different examples, it will be demonstrated that the combined and targeted use of various biorelevant in vitro methods can be extremely useful for understanding drug release from ER products in the fed state and to be able to forecast formulation-associated risks such as dose dumping in early stages of formulation development.
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30
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Torrence GM, Schmidt BM. Fungal Osteomyelitis in Diabetic Foot Infections: A Case Series and Comparative Analysis. INT J LOW EXTR WOUND 2018; 17:184-189. [PMID: 30092692 DOI: 10.1177/1534734618791607] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Fungal osteomyelitis (OM) is relatively rare. There is scarce literature discussing fungal OM in diabetic foot infections (DFIs). This case series explores the clinical characteristics of patients treated at a large tertiary academic center for DFI and found to have a causative agent of fungal origin in their bone on surgical intervention. Between July 2017 and March 2018, a prospective longitudinal analysis was performed of patients with diabetes admitted to our institution who underwent operative management of OM. Demographic, clinical, radiographic, and laboratory data were collected for all patients. Data between bacterial and fungal OM cohorts was analyzed for differences and similarities in patient characteristics and outcomes. All patients were followed 20 weeks postoperatively. Five patients with fungal OM were identified from the 35 cases where OM was confirmed through podiatric surgical intervention. In each fungal case, a Candida species was isolated from operative bone culture which included subspecies Candida albicans, C parapsilosis, and C glabrata. A P value ⩾.05 was found in clinical characteristics between our cohorts. Wound healing was achieved in 40% of patients with fungal OM, and oral fluconazole successfully treated Candida OM in the cases that achieved healing. Diabetes can increase the risk of Candida OM. In DFIs, fungus can impede wound healing if not recognized and treated. Because Candida OM is typically indolent in nature, bone biopsy and mycological culture is recommended for definitive diagnosis and treatment.
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Affiliation(s)
| | - Brian M Schmidt
- 1 University of Michigan Hospital and Health Systems, Ann Arbor, MI, USA
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31
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Grimm M, Koziolek M, Saleh M, Schneider F, Garbacz G, Kühn JP, Weitschies W. Gastric Emptying and Small Bowel Water Content after Administration of Grapefruit Juice Compared to Water and Isocaloric Solutions of Glucose and Fructose: A Four-Way Crossover MRI Pilot Study in Healthy Subjects. Mol Pharm 2018; 15:548-559. [DOI: 10.1021/acs.molpharmaceut.7b00919] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Michael Grimm
- Institute
of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, D-17487 Greifswald, Germany
| | - Mirko Koziolek
- Institute
of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, D-17487 Greifswald, Germany
| | - Marwa Saleh
- Institute
of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, D-17487 Greifswald, Germany
| | - Felix Schneider
- Institute
of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, D-17487 Greifswald, Germany
| | | | - Jens-Peter Kühn
- Institute
of Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany
- Department
of Radiology, University Medicine Dresden, 17475 Greifswald, Germany
| | - Werner Weitschies
- Institute
of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, D-17487 Greifswald, Germany
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Selby-Pham SN, Osborne SA, Howell KS, Dunshea FR, Bennett LE. Transport rates of dietary phytochemicals in cell monolayers is inversely correlated with absorption kinetics in humans. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.10.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
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Deng J, Zhu X, Chen Z, Fan CH, Kwan HS, Wong CH, Shek KY, Zuo Z, Lam TN. A Review of Food–Drug Interactions on Oral Drug Absorption. Drugs 2017; 77:1833-1855. [DOI: 10.1007/s40265-017-0832-z] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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34
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Groll AH, Townsend R, Desai A, Azie N, Jones M, Engelhardt M, Schmitt-Hoffman AH, Brüggemann RJM. Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4. Transpl Infect Dis 2017; 19. [PMID: 28722255 DOI: 10.1111/tid.12751] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 05/15/2017] [Accepted: 05/15/2017] [Indexed: 01/03/2023]
Abstract
Patients undergoing treatment with immunosuppressant drugs following solid organ or hematopoietic stem cell transplantation are at particular risk for development of serious infections such as invasive aspergillosis. Four triazole antifungal drugs, voriconazole, posaconazole, itraconazole, and isavuconazole, are approved to treat invasive aspergillosis either as first- or second-line therapy. All of these agents are inhibitors of cytochrome P450 3A4, which plays a key role in metabolizing immunosuppressant drugs such as cyclosporine, tacrolimus, and sirolimus. Thus, co-administration of a triazole antifungal drug with these immunosuppressant drugs can potentially increase plasma concentrations of the immunosuppressant drugs, thereby resulting in toxicity, or upon discontinuation, inadvertently decrease the respective concentrations with increased risk of rejection or graft-versus-host disease. In this article, we review the evidence for the extent of inhibition of cytochrome P450 3A4 by each of these triazole antifungal drugs and assess their effects on cyclosporine, tacrolimus, and sirolimus. We also consider other factors affecting interactions of these two classes of drugs. Finally, we examine recommendations and strategies to evaluate and address those potential drug-drug interactions in these patients.
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Affiliation(s)
- Andreas H Groll
- Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany
| | - Robert Townsend
- Astellas Pharma Global Development, Inc., Northbrook, IL, USA
| | - Amit Desai
- Astellas Pharma Global Development, Inc., Northbrook, IL, USA
| | - Nkechi Azie
- Astellas Pharma Global Development, Inc., Northbrook, IL, USA
| | - Mark Jones
- Basilea Pharmaceutica International Ltd, Basel, Switzerland
| | | | | | - Roger J M Brüggemann
- Department of Pharmacy, Radboud University Nijmegen Medical Centre, and Centre of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands
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Tan EH, Parmentier J, Low A, Möschwitzer JP. Downstream drug product processing of itraconazole nanosuspension: Factors influencing tablet material properties and dissolution of compacted nanosuspension-layered sugar beads. Int J Pharm 2017; 532:131-138. [PMID: 28859940 DOI: 10.1016/j.ijpharm.2017.08.107] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 08/21/2017] [Accepted: 08/22/2017] [Indexed: 01/18/2023]
Abstract
There has been limited research done on the downstream processing of nanosuspensions into solid oral dosage forms. This paper demonstrates the bead layering process with a layering level at 150% and 240%, as well as the selection and justification of the outer phase excipients for tabletability and disintegrating properties. In a previous study, an itraconazole nanosuspension stabilised by SDS and HPMC E5 was layered onto sugar beads with coating polymer HPMC VLV. In the current study, compression studies with these layered beads utilising the small bead size at 150% or 240% layering levels with outer phase cushioning excipients MCC, copovidone or isomalt were performed. Other excipients such as co-compressed crospovidone-PEG 4000; DCP functioning as a disintegrant; and HPC as a binder was also added. Target output variables were achieved with a balance between an adequate tensile strength and fast dissolution rate with a release of 99.0% (±1.0% SD) within 10min, which is in accordance with the FDA guidance for dissolution testing. The results show that the compaction of nanosuspension-layered beads is a suitable process for processing an itraconazole nanosuspension into a solid dosage form such as a compacted tablet without compromising on drug release.
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Affiliation(s)
- En Hui Tan
- AbbVie Pte Ltd, Research and Development, 9 North Buona Vista Drive, The Metropolis Tower One #19-01, Singapore 138588, Singapore
| | - Johannes Parmentier
- Gustav Parmentier GmbH, Eichendorffstr. 37, 60320 Frankfurt am Main, Germany
| | - Ariana Low
- AbbVie GmbH & Co. KG, Knollstrasse 50, 67061 Ludwigshafen, Germany.
| | - Jan Peter Möschwitzer
- Department of Pharmaceutical Technology, Biotechnology and Quality Management, Free University of Berlin, 14195 Berlin, Germany
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Selby-Pham SNB, Miller RB, Howell K, Dunshea F, Bennett LE. Physicochemical properties of dietary phytochemicals can predict their passive absorption in the human small intestine. Sci Rep 2017; 7:1931. [PMID: 28512322 PMCID: PMC5434065 DOI: 10.1038/s41598-017-01888-w] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/13/2017] [Indexed: 01/02/2023] Open
Abstract
A diet high in phytochemical-rich plant foods is associated with reducing the risk of chronic diseases such as cardiovascular and neurodegenerative diseases, obesity, diabetes and cancer. Oxidative stress and inflammation (OSI) is the common component underlying these chronic diseases. Whilst the positive health effects of phytochemicals and their metabolites have been demonstrated to regulate OSI, the timing and absorption for best effect is not well understood. We developed a model to predict the time to achieve maximal plasma concentration (Tmax) of phytochemicals in fruits and vegetables. We used a training dataset containing 67 dietary phytochemicals from 31 clinical studies to develop the model and validated the model using three independent datasets comprising a total of 108 dietary phytochemicals and 98 pharmaceutical compounds. The developed model based on dietary intake forms and the physicochemical properties lipophilicity and molecular mass accurately predicts Tmax of dietary phytochemicals and pharmaceutical compounds over a broad range of chemical classes. This is the first direct model to predict Tmax of dietary phytochemicals in the human body. The model informs the clinical dosing frequency for optimising uptake and sustained presence of dietary phytochemicals in circulation, to maximise their bio-efficacy for positively affect human health and managing OSI in chronic diseases.
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Affiliation(s)
- Sophie N B Selby-Pham
- Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, 3010, Australia
- CSIRO Agriculture and Food, 671 Sneydes Road, Werribee, 3030, Australia
| | | | - Kate Howell
- Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, 3010, Australia
| | - Frank Dunshea
- Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, 3010, Australia
| | - Louise E Bennett
- CSIRO Agriculture and Food, 671 Sneydes Road, Werribee, 3030, Australia.
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Downstream drug product processing of itraconazole nanosuspension: Factors influencing drug particle size and dissolution from nanosuspension-layered beads. Int J Pharm 2017; 524:443-453. [DOI: 10.1016/j.ijpharm.2017.04.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 04/04/2017] [Accepted: 04/05/2017] [Indexed: 11/20/2022]
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Stelzer D, Weber A, Ihle F, Matthes S, Ceelen F, Zimmermann G, Kneidinger N, Schramm R, Winter H, Zoller M, Vogeser M, Behr J, Neurohr C. Comparing Azole Plasma Trough Levels in Lung Transplant Recipients: Percentage of Therapeutic Levels and Intrapatient Variability. Ther Drug Monit 2017; 39:93-101. [PMID: 28282366 PMCID: PMC5348107 DOI: 10.1097/ftd.0000000000000371] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND This study compared therapeutic azole plasma trough levels (APL) of the azole antimycotics itraconazole (ITR), voriconazole (VOR), and posaconazole (POS) in lung transplant recipients and analyzed the influencing factors. In addition, intrapatient variability for each azole was determined. METHODS From July 2012 to July 2015, 806 APL of ITR, VOR, posaconazole liquid (POS-Liq), and posaconazole tablets (POS-Tab) were measured in 173 patients of the Munich Lung Transplantation Program. Therapeutic APL were defined as follows: ITR, ≥700 ng/mL; VOR, 1000-5500 ng/mL; and POS, ≥700 ng/mL (prophylaxis) and ≥1000 ng/mL (therapy). RESULTS VOR and POS-Tab reached the highest number of therapeutic APL, whereas POS-Liq showed the lowest percentage (therapy: ITR 50%, VOR 70%, POS-Liq 38%, and POS-Tab 82%; prophylaxis: ITR 62%, VOR 85%, POS-Liq 49%, and POS-Tab 76%). Risk factors for subtherapeutic APL of all azoles were the azole dose (ITR, P < 0.001; VOR, P = 0.002; POS-Liq, P = 0.006) and age over 60 years (ITR, P = 0.003; VOR, P = 0.002; POS-Liq, P = 0.039; POS-Tab, P < 0.001). Cystic fibrosis was a significant risk factor for subtherapeutic APL for VOR and POS-Tab (VOR, P = 0.002; POS-Tab, P = 0.005). Double lung transplantation (LTx) was significantly associated with less therapeutic APL for VOR and POS-Liq (VOR, P = 0.030; POS-Liq, P < 0.001). Concomitant therapy with 80 mg pantoprazole led to significantly fewer therapeutic POS APL as compared to 40 mg (POS-Liq, P = 0.015; POS-Tab, P < 0.001). VOR displayed the greatest intrapatient variability (46%), whereas POS-Tab showed the lowest (32%). CONCLUSIONS Our study showed that VOR and POS-Tab achieve the highest percentage of therapeutic APL in patients with LTx; POS-Tab showed the lowest intrapatient variability. APL are significantly influenced by azole dose, age, cystic fibrosis, type of LTx, and comedication with proton-pump inhibitors. Considering the high number of subtherapeutic APL, therapeutic drug monitoring should be integrated in the post-LTx management.
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Affiliation(s)
- Daniela Stelzer
- Department of Internal Medicine V, LMU-Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research DZL, Munich, Germany
- Departments of Hospital Pharmacy,
| | | | - Franziska Ihle
- Department of Internal Medicine V, LMU-Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research DZL, Munich, Germany
| | - Sandhya Matthes
- Department of Internal Medicine V, LMU-Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research DZL, Munich, Germany
| | - Felix Ceelen
- Department of Internal Medicine V, LMU-Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research DZL, Munich, Germany
| | - Gregor Zimmermann
- Department of Internal Medicine V, LMU-Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research DZL, Munich, Germany
| | - Nikolaus Kneidinger
- Department of Internal Medicine V, LMU-Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research DZL, Munich, Germany
| | | | | | | | - Michael Vogeser
- Institute of Laboratory Medicine, LMU-Munich, Munich, Germany
| | - Juergen Behr
- Department of Internal Medicine V, LMU-Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research DZL, Munich, Germany
| | - Claus Neurohr
- Department of Internal Medicine V, LMU-Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research DZL, Munich, Germany
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Fed-state gastric media and drug analysis techniques: Current status and points to consider. Eur J Pharm Biopharm 2016; 107:234-48. [DOI: 10.1016/j.ejpb.2016.07.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 06/07/2016] [Accepted: 07/11/2016] [Indexed: 11/22/2022]
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Palanisamy A, Chao SD, Fouts M, Kerr D. Central nervous system aspergillosis in an immunocompetent patient: Cure in a hospice setting with very high-dose itraconazole. Am J Hosp Palliat Care 2016; 22:139-44. [PMID: 15853093 DOI: 10.1177/104990910502200212] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Aspergillosis of the central nervous system (CNS) is a rare condition with exceedingly high mortality. This study describes the case of an immunocompetent 42-year-old man with a history of intravenous drug use and hepatitis C who developed multiple Aspergillus lesions in the cerebellum. Despite neurosurgery and antifungal therapy with amphotericin B, he had a protracted hospital course with multiple complications, eventually developing cognitive and motor impairment due to progressive cerebellar lesions. After transfer to hospice and palliative care service, oral itraconazole was escalated to 1600 mg/day with the hope of palliating headache, nausea, and cognitive impairment. Remarkably, the patient stabilized and improved over time. After 14 months, this unprecedented high-dose regimen was discontinued, and the patient was discharged home with only mild cerebellar motor impairment.
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Affiliation(s)
- Akilesh Palanisamy
- Laguna Honda Hospice & Palliative Care Service, Laguna Honda Hospital, San Francisco, California, USA
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Goldman JL, Abdel-Rahman SM. Pharmacokinetic considerations in treating invasive pediatric fungal infections. Expert Opin Drug Metab Toxicol 2016; 12:645-55. [PMID: 27111148 DOI: 10.1080/17425255.2016.1181752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Despite the increased availability of systemic antifungal agents in recent years, the management of invasive fungal disease is still associated with significant morbidity and mortality. Knowledge of a drug's pharmacokinetic behavior is critical for optimizing existing treatment strategies. AREAS COVERED This review examines the pharmacokinetics of the major drug classes used to treat invasive mycoses including the echinocandins, imidazoles, triazoles, nucleoside analogs, and polyenes. It examines the mechanisms behind dose-exposure profiles that differ in children as compared with adults and explores the utility of pharmacogenetic testing and therapeutic drug monitoring. EXPERT OPINION Lifesaving medical advances for oncologic and autoimmune conditions have resulted in a significant increase in the frequency of opportunistic fungal infections. Owing to the high rate of treatment failures observed when managing invasive fungal infections, strategies to optimize antifungal therapy are critical when caring for these complex patients. Opportunities to maximize positive outcomes include dose refinement based on age or genetic status, formulation selection, co-administration of interacting medications, and administration with regard to food. The application of therapeutic drug monitoring for dose individualization is a valuable strategy to achieve pharmacodynamic targets.
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Affiliation(s)
- Jennifer L Goldman
- a Department of Pediatrics , UMKC School of Medicine , Kansas City , MO , USA.,b Drug Safety Service Children's Mercy Hospital , Kansas City , MO , USA.,c Antimicrobial Stewardship Program Children's Mercy Hospital , Kansas City , MO , USA.,d Divisions Pediatric Infectious Diseases & Clinical Pharmacology , Toxicology, and Therapeutic Innovation Children's Mercy Hospital , Kansas City , MO , USA
| | - Susan M Abdel-Rahman
- a Department of Pediatrics , UMKC School of Medicine , Kansas City , MO , USA.,d Divisions Pediatric Infectious Diseases & Clinical Pharmacology , Toxicology, and Therapeutic Innovation Children's Mercy Hospital , Kansas City , MO , USA
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Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Reboli AC, Schuster MG, Vazquez JA, Walsh TJ, Zaoutis TE, Sobel JD. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62:e1-50. [PMID: 26679628 PMCID: PMC4725385 DOI: 10.1093/cid/civ933] [Citation(s) in RCA: 2133] [Impact Index Per Article: 237.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 11/02/2015] [Indexed: 02/06/2023] Open
Abstract
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
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Affiliation(s)
| | - Carol A Kauffman
- Veterans Affairs Ann Arbor Healthcare System and University of Michigan Medical School, Ann Arbor
| | | | | | - Kieren A Marr
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | | | | | | | - Thomas J Walsh
- Weill Cornell Medical Center and Cornell University, New York, New York
| | | | - Jack D Sobel
- Harper University Hospital and Wayne State University, Detroit, Michigan
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Abstract
Invasive candidiasis is a collective term that refers to a group of infectious syndromes caused by a variety of species of Candida, 5 of which cause most cases. Candidemia is the most commonly recognized syndrome associated with invasive candidiasis. Certain conditions may influence the likelihood for one species versus another in a specific clinical scenario, and this can have important implications for selection of antifungal therapy and the duration of treatment. Molecular diagnostic technology plays an ever-increasing role as an adjunct to traditional culture-based diagnostics, offering significant potential toward improvement in patient care.
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Affiliation(s)
- Todd P McCarty
- University of Alabama at Birmingham, 1900 University Boulevard, 229 THT, Birmingham, AL 35294-0006, USA
| | - Peter G Pappas
- University of Alabama at Birmingham, 1900 University Boulevard, 229 THT, Birmingham, AL 35294-0006, USA.
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Fadke J, Desai J, Thakkar H. Formulation Development of Spherical Crystal Agglomerates of Itraconazole for Preparation of Directly Compressible Tablets with Enhanced Bioavailability. AAPS PharmSciTech 2015; 16:1434-44. [PMID: 25991065 DOI: 10.1208/s12249-015-0332-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Accepted: 05/08/2015] [Indexed: 01/02/2023] Open
Abstract
The objective of the present work was to formulate tablet dosage form of itraconazole with enhanced bioavailability. Spherical crystal agglomerates (SCA) of itraconazole prepared by quasi emulsification solvent diffusion method using Soluplus and polyethylene glycol 4000 (PEG 4000) showed increased solubility (540 μg/ml) in 0.1 N hydrochloric acid as compared to pure drug (12 μg/ml). A Fourier transform infrared (FTIR) study indicated compatibility of drug with the excipients. The developed SCA were spherical with smooth surface having an average size of 412 μm. The significantly improved micromeritic properties compared to the plain drug suggested its suitability for direct compression. The antifungal activity of itraconazole was retained in the SCA form as evidenced from the results of the disc diffusion method. The optimized SCA formulation could be easily compressed into tablet with desirable characteristics of hardness (5 kg/cm(2)) and disintegration time (6.3 min). The in vitro dissolution studies showed significant difference in the dissolution profiles of pure drug (21%) and SCA formulation (85%) which was even greater than that of marketed preparation (75%). In vivo pharmacokinetic showed significant enhancement in C max and AUC0-t with relative bioavailability of 225%. The SCA formulation seems to be promising for enhancement of oral bioavailability of itraconazole.
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Chau MM, Kong DCM, van Hal SJ, Urbancic K, Trubiano JA, Cassumbhoy M, Wilkes J, Cooper CM, Roberts JA, Marriott DJE, Worth LJ. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Intern Med J 2015; 44:1364-88. [PMID: 25482746 DOI: 10.1111/imj.12600] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Antifungal agents may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy. These risks may be minimised by clinical assessment, laboratory monitoring, avoidance of particular drug combinations and dose modification. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. Therapeutic drug monitoring (TDM) of antifungal agents is warranted, especially where non-compliance, non-linear pharmacokinetics, inadequate absorption, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Recommended indications for voriconazole and posaconazole TDM in the clinical management of haematology patients are provided. With emerging knowledge regarding the impact of pharmacogenomics upon metabolism of azole agents (particularly voriconazole), potential applications of pharmacogenomic evaluation to clinical practice are proposed.
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Affiliation(s)
- M M Chau
- Pharmacy Department, The Royal Melbourne Hospital, Melbourne Health, Parkville, Victoria
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Population pharmacokinetic modeling of itraconazole and hydroxyitraconazole for oral SUBA-itraconazole and sporanox capsule formulations in healthy subjects in fed and fasted states. Antimicrob Agents Chemother 2015; 59:5681-96. [PMID: 26149987 DOI: 10.1128/aac.00973-15] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 06/28/2015] [Indexed: 01/21/2023] Open
Abstract
Itraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies.
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Sjögren E, Abrahamsson B, Augustijns P, Becker D, Bolger MB, Brewster M, Brouwers J, Flanagan T, Harwood M, Heinen C, Holm R, Juretschke HP, Kubbinga M, Lindahl A, Lukacova V, Münster U, Neuhoff S, Nguyen MA, Peer AV, Reppas C, Hodjegan AR, Tannergren C, Weitschies W, Wilson C, Zane P, Lennernäs H, Langguth P. In vivo methods for drug absorption – Comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects. Eur J Pharm Sci 2014; 57:99-151. [PMID: 24637348 DOI: 10.1016/j.ejps.2014.02.010] [Citation(s) in RCA: 196] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 02/15/2014] [Accepted: 02/17/2014] [Indexed: 01/11/2023]
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Jambhekar SS, Breen PJ. Drug dissolution: significance of physicochemical properties and physiological conditions. Drug Discov Today 2013; 18:1173-84. [DOI: 10.1016/j.drudis.2013.08.013] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Revised: 08/01/2013] [Accepted: 08/19/2013] [Indexed: 11/24/2022]
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Kim JY, Rhee YS, Park CW, Ha JM, Park ES. Preparation and evaluation of dual-mode floating gastroretentive tablets containing itraconazole. Drug Deliv 2013; 21:519-29. [DOI: 10.3109/10717544.2013.853212] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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