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Moliya P, Singh A, Singh N, Kumar V, Sohal A. Insights into gastrointestinal manifestation of human immunodeficiency virus: A narrative review. World J Virol 2025; 14:99249. [PMID: 40134843 PMCID: PMC11612874 DOI: 10.5501/wjv.v14.i1.99249] [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: 07/18/2024] [Revised: 10/15/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
Human immunodeficiency virus (HIV) modifies CD4-positive cells, resulting in immunodeficiency and a wide range of gastrointestinal (GI) manifestations. The burden of HIV-related GI illnesses has significantly evolved with the widespread use of antiretroviral therapy (ART). While ART has effectively reduced the occurrence of opportunistic infections, it has led to an increase in therapy-related GI illnesses. Common esophageal conditions in HIV patients include gastroesophageal reflux disease, idiopathic esophageal ulcers, herpes simplex virus, cytomegalovirus (CMV), and candidal esophagitis. Kaposi's sarcoma, a hallmark of acquired immunodeficiency syndrome, may affect the entire GI system. Gastritis and peptic ulcer disease are also frequently seen in patients with HIV. Diarrhea, often linked to both opportunistic infections and ART, requires careful evaluation. Bloody diarrhea, often a sign of colitis caused by bacterial infections such as Shigella or Clostridium difficile, is prevalent. Small bowel lymphoma, although rare, is increasing in prevalence. Anorectal disorders, including proctitis, fissures, and anal squamous cell carcinoma, are particularly relevant in homosexual men, underlining the importance of timely diagnosis. This review comprehensively explores the epidemiology, pathogenesis, and treatment considerations for the various GI disorders associated with HIV, highlighting the importance of accurate diagnosis and effective treatment to improve outcomes for HIV-infected patients.
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Affiliation(s)
- Pratiksha Moliya
- Department of Transplant Hepatology, University of Nebraska Medical Center, Omaha, NE 69198, United States
| | - Anmol Singh
- Department of Medicine, Tristar Centennial Medical Center, Nashville, TN 37203, United States
| | - Navdeep Singh
- Department of Medicine, Government Medical College, Amritsar 143001, Punjab, India
| | - Vikash Kumar
- Department of Gastroenterology and Hepatology, Creighton University School of Medicine, Phoenix, AZ 85012, United States
| | - Aalam Sohal
- Department of Gastroenterology and Hepatology, Creighton University School of Medicine, Phoenix, AZ 85012, United States
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Zhang CX, Arnold SLM. Potential and challenges in application of physiologically based pharmacokinetic modeling in predicting diarrheal disease impact on oral drug pharmacokinetics. Drug Metab Dispos 2025; 53:100014. [PMID: 39884815 DOI: 10.1124/dmd.122.000964] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/03/2023] [Accepted: 08/31/2023] [Indexed: 09/17/2023] Open
Abstract
Physiologically based pharmacokinetic (PBPK) modeling is a physiologically relevant approach that integrates drug-specific and system parameters to generate pharmacokinetic predictions for target populations. It has gained immense popularity for drug-drug interaction, organ impairment, and special population studies over the past 2 decades. However, an application of PBPK modeling with great potential remains rather overlooked-prediction of diarrheal disease impact on oral drug pharmacokinetics. Oral drug absorption is a complex process involving the interplay between physicochemical characteristics of the drug and physiological conditions in the gastrointestinal tract. Diarrhea, a condition common to numerous diseases impacting many worldwide, is associated with physiological changes in many processes critical to oral drug absorption. In this Minireview, we outline key processes governing oral drug absorption, provide a high-level overview of key parameters for modeling oral drug absorption in PBPK models, examine how diarrheal diseases may impact these processes based on literature findings, illustrate the clinical relevance of diarrheal disease impact on oral drug absorption, and discuss the potential and challenges of applying PBPK modeling in predicting disease impacts. SIGNIFICANCE STATEMENT: Pathophysiological changes resulting from diarrheal diseases can alter important factors governing oral drug absorption, contributing to suboptimal drug exposure and treatment failure. Physiologically based pharmacokinetic (PBPK) modeling is an in silico approach that has been increasingly adopted for drug-drug interaction potential, organ impairment, and special population assessment. This Minireview highlights the potential and challenges of using physiologically based pharmacokinetic modeling as a tool to improve our understanding of how diarrheal diseases impact oral drug pharmacokinetics.
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Affiliation(s)
- Cindy X Zhang
- Department of Pharmaceutics, University of Washington, Seattle, Washington
| | - Samuel L M Arnold
- Department of Pharmaceutics, University of Washington, Seattle, Washington.
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Wu D, Liu J, Paragas EM, Yadav J, Aliwarga T, Heimbach T, Escotet-Espinoza MS. Assessing and mitigating pH-mediated DDI risks in drug development - formulation approaches and clinical considerations. Drug Metab Rev 2024:1-20. [PMID: 38700278 DOI: 10.1080/03602532.2024.2345632] [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: 11/28/2023] [Accepted: 04/10/2024] [Indexed: 05/05/2024]
Abstract
pH-mediated drug-drug interactions (DDI) is a prevalent DDI in drug development, especially for weak base compounds with highly pH-dependent solubility. FDA has released a guidance on the evaluation of pH-mediated DDI assessments using in vitro testing and clinical studies. Currently, there is no common practice of ways of testing across the academia and industry. The development of biopredictive method and physiologically-based biopharmaceutics modeling (PBBM) approaches to assess acid-reducing agent (ARA)-DDI have been proven with accurate prediction and could decrease drug development burden, inform clinical design and potentially waive clinical studies. Formulation strategies and careful clinical design could help mitigate the pH-mediated DDI to avoid more clinical studies and label restrictions, ultimately benefiting the patient. In this review paper, a detailed introduction on biorelevant dissolution testing, preclinical and clinical study requirement and PBPK modeling approaches to assess ARA-DDI are described. An improved decision tree for pH-mediated DDI is proposed. Potential mitigations including clinical or formulation strategies are discussed.
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Affiliation(s)
- Di Wu
- Pharmaceutical Sciences & Clinical Supply, Merck & Co., Inc, Rahway, NJ, USA
| | - Jiaying Liu
- Pharmaceutical Sciences & Clinical Supply, Merck & Co., Inc, Rahway, NJ, USA
| | - Erickson M Paragas
- Pharmacokinetics and Drug Metabolism Department, Amgen Research, South San Francisco, CA, USA
| | - Jaydeep Yadav
- Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc, Boston, MA, USA
| | - Theresa Aliwarga
- Pharmacokinetics and Drug Metabolism Department, Amgen Research, South San Francisco, CA, USA
| | - Tycho Heimbach
- Pharmaceutical Sciences & Clinical Supply, Merck & Co., Inc, Rahway, NJ, USA
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Franco YL, Da Silva L, Charbe N, Kinvig H, Kim S, Cristofoletti R. Integrating Forward and Reverse Translation in PBPK Modeling to Predict Food Effect on Oral Absorption of Weakly Basic Drugs. Pharm Res 2023; 40:405-418. [PMID: 36788156 DOI: 10.1007/s11095-023-03478-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/28/2023] [Indexed: 02/16/2023]
Abstract
INTRODUCTION Ketoconazole and posaconazole are two weakly basic broad-spectrum antifungals classified as Biopharmaceutics Classification System class II drugs, indicating that they are highly permeable, but exhibit poor solubility. As a result, oral bioavailability and clinical efficacy can be impacted by the formulation performance in the gastrointestinal system. In this work, we have leveraged in vitro biopharmaceutics and clinical data available in the literature to build physiologically based pharmacokinetic (PBPK) models for ketoconazole and posaconazole, to determine the suitability of forward in vitro-in vivo translation for characterization of in vivo drug precipitation, and to predict food effect. METHODS A stepwise modeling approach was utilized to derive key parameters related to absorption, such as drug solubility, dissolution, and precipitation kinetics from in vitro data. These parameters were then integrated into PBPK models for the simulation of ketoconazole and posaconazole plasma concentrations in the fasted and fed states. RESULTS Forward in vitro-in vivo translation of intestinal precipitation kinetics for both model drugs resulted in poor predictions of PK profiles. Therefore, a reverse translation approach was applied, based on limited fitting of precipitation-related parameters to clinical data. Subsequent simulations for ketoconazole and posaconazole demonstrated that fasted and fed state PK profiles for both drugs were adequately recapitulated. CONCLUSION The two examples presented in this paper show how middle-out modeling approaches can be used to predict the magnitude and direction of food effects provided the model is verified on fasted state PK data.
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Affiliation(s)
- Yesenia L Franco
- Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL, USA
| | - Lais Da Silva
- Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL, USA
| | - Nitin Charbe
- Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL, USA
| | - Hannah Kinvig
- Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL, USA
| | - Soyoung Kim
- Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL, USA
| | - Rodrigo Cristofoletti
- Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL, USA.
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Lee TH, Chan A, Bryan W, Park L, Hashem M, Townsend M, Moylan C, Britt R, Choi S, Naggie S. Proton pump inhibitor usage reduces sustained viral response rates for veterans with HIV/HCV coinfection on ledipasvir/sofosbuvir: a real-world study from a multicentre VA cohort. J Viral Hepat 2021; 28:630-636. [PMID: 33378562 PMCID: PMC8054484 DOI: 10.1111/jvh.13462] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 10/04/2020] [Accepted: 12/07/2020] [Indexed: 01/20/2023]
Abstract
Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased sustained viral response rate (SVR) in patients taking ledipasvir/sofosbuvir (LDV/SOF). The relationship between PPI usage and SVR is less clear in patients with HIV/HCV coinfection, where concomitant antiretrovirals may result in more complex drug interactions. This retrospective study evaluates the effects of acid suppression medications (PPI or H2 -receptor antagonist [H2 B]) use and SVR rates in patients with HIV/HCV or HCV and taking LDV/SOF in a large multicentre veteran cohort. Patients in the Veterans Affairs Health Care System who received LDV/SOF ± ribavirin from 10/10/2014 to 12/31/2015 were included. The odds ratios (OR) of PPI or H2 B use for SVR were adjusted for clinical factors and with inverse probability of treatment weighting for non-random treatment selection for acid suppression medication use. There were 9703 veterans included in our final analysis. After adjustment of other clinical factors, PPI use is associated with a lower SVR in the overall cohort (95.0% vs. 96.1%, OR: 0.86, 95% CI: 0.74-0.99, p = .03, number needed to harm 90.9) and HIV/HCV coinfection subgroup (93.4% vs. 96.9%, OR: 0.47, 95% CI: 0.26-0.85, p = .01, number needed to harm 28.6). This present study reveals PPI use is associated with reduced SVR after LDV/SOF treatment, with a more significant impact in the subgroup of patients with HIV/HCV coinfection. Precautions need to be taken when using PPI and LDV/SOF in this group of patients.
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Affiliation(s)
- Tzu-Hao Lee
- Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA,Durham Veterans Affairs Health Care System, Durham, NC, USA
| | - Austin Chan
- Department of Medicine, Morehouse School of Medicine, Atlanta, GA, USA
| | - William Bryan
- Durham Veterans Affairs Health Care System, Durham, NC, USA
| | - Lawrence Park
- Durham Veterans Affairs Health Care System, Durham, NC, USA,Division of infectious diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Mohamed Hashem
- Durham Veterans Affairs Health Care System, Durham, NC, USA
| | - Mary Townsend
- Durham Veterans Affairs Health Care System, Durham, NC, USA
| | - Cynthia Moylan
- Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA,Durham Veterans Affairs Health Care System, Durham, NC, USA
| | - Rachel Britt
- Durham Veterans Affairs Health Care System, Durham, NC, USA
| | - Steve Choi
- Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA,Durham Veterans Affairs Health Care System, Durham, NC, USA
| | - Susanna Naggie
- Durham Veterans Affairs Health Care System, Durham, NC, USA,Division of infectious diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
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SahBandar IN, Chew GM, Corley MJ, Pang APS, Tsai N, Hanks N, Khadka VS, Klatt NR, Hensley-McBain T, Somsouk M, Vujkovic-Cvijin I, Chow DC, Shikuma CM, Ndhlovu LC. Changes in gastrointestinal microbial communities influence HIV-specific CD8+ T-cell responsiveness to immune checkpoint blockade. AIDS 2020; 34:1451-1460. [PMID: 32675558 PMCID: PMC7371239 DOI: 10.1097/qad.0000000000002557] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES The aim of this study was to examine the relationship between gut microbial communities in HIV-infected individuals on suppressive antiretroviral therapy (cART), and the peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo immune checkpoint blockade (ICB). DESIGN Thirty-four HIV-seropositive, 10 HIV-seronegative and 12 HIV-seropositive receiving faecal microbiota transplant (FMT) participants were included. Gut microbial communities, peripheral and gut associated negative checkpoint receptors (NCRs) and peripheral effector functions were assessed. METHODS Bacterial 16s rRNA sequencing for gut microbiome study and flow-based assays for peripheral and gut NCR and their cognate ligand expression, including peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo anti-PD-L1 and anti-TIGIT ICB were performed. RESULTS Fusobacteria abundance was significantly higher in HIV-infected donors compared to uninfected controls. In HIV-infected participants receiving Fusobacteria-free FMT, Fusobacteria persisted up to 24 weeks in stool post FMT. PD-1 TIGIT and their ligands were expanded in mucosal vs. peripheral T cells and dendritic cells, respectively. PD-L1 and TIGIT blockade significantly increased the magnitude of peripheral anti-HIV-Gag-specific CD8 T-cell responses. Higher gut Fusobacteria abundance was associated with lower magnitude of peripheral IFN-γ+ HIV-Gag-specific CD8 T-cell responses following ICB. CONCLUSION The gut colonization of Fusobacteria in HIV infection is persistent and may influence anti-HIV T-cell immunity to PD-1 or TIGIT blockade. Strategies modulating Fusobacteria colonization may elicit a favourable mucosal immune landscape to enhance the efficacy of ICB for HIV cure.
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Affiliation(s)
| | - Glen M Chew
- Department of Tropical Medicine
- Hawaii Center for AIDS
| | | | | | | | | | - Vedbar S Khadka
- Department of Biostatistics and Quantitative Health Science, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii
| | - Nichole R Klatt
- Department of Pharmaceutics, University of Washington, Seattle, Washington
| | | | - Ma Somsouk
- Division of Gastroenterology, Department of Medicine, Zuckerberg San Francisco General Hospital, University of California, San Francisco, California
| | - Ivan Vujkovic-Cvijin
- Metaorganism Immunity Section, National Institute of Allergy & Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA
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Stader F, Courlet P, Kinvig H, Battegay M, Decosterd LA, Penny MA, Siccardi M, Marzolini C. Effect of ageing on antiretroviral drug pharmacokinetics using clinical data combined with modelling and simulation. Br J Clin Pharmacol 2020; 87:458-470. [PMID: 32470203 DOI: 10.1111/bcp.14402] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 05/04/2020] [Accepted: 05/18/2020] [Indexed: 12/19/2022] Open
Abstract
AIMS The impact of ageing on antiretroviral pharmacokinetics remains uncertain, leading to missing dosing recommendations for elderly people living with human immunodeficiency virus (HIV: PLWH). The objective of this study was to investigate whether ageing leads to clinically relevant pharmacokinetic changes of antiretrovirals that would support a dose adjustment based on the age of the treated PLWH. METHODS Plasma concentrations for 10 first-line antiretrovirals were obtained in PLWH ≥55 years, participating in the Swiss HIV Cohort Study, and used to proof the predictive performance of our physiologically based pharmacokinetic (PBPK) model. The verified PBPK model predicted the continuous effect of ageing on HIV drug pharmacokinetics across adulthood (20-99 years). The impact of ethnicity on age-related pharmacokinetic changes between whites and other races was statistically analysed. RESULTS Clinically observed concentration-time profiles of all investigated antiretrovirals were generally within the 95% confidence interval of the PBPK simulations, demonstrating the predictive power of the modelling approach used. The predicted decline in drug clearance drove age-related pharmacokinetic changes of antiretrovirals, resulting in a maximal 70% [95% confidence interval: 40%, 120%] increase in antiretrovirals exposure across adulthood. Peak concentration, time to peak concentration and apparent volume of distribution were predicted to be unaltered by ageing. There was no statistically significant difference of age-related pharmacokinetic changes between studied ethnicities. CONCLUSION Dose adjustment for antiretrovirals based on the age of male and female PLWH is a priori not necessary in the absence of severe comorbidities considering the large safety margin of the current first-line HIV treatments.
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Affiliation(s)
- Felix Stader
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,Swiss Tropical and Public Health Institute, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Perrine Courlet
- Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Hannah Kinvig
- Department of Molecular and Clinical Pharmacology Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Manuel Battegay
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Laurent A Decosterd
- Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Melissa A Penny
- Swiss Tropical and Public Health Institute, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Marco Siccardi
- Department of Molecular and Clinical Pharmacology Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Catia Marzolini
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
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Kayamba V, Shibemba A, Zyambo K, Heimburger DC, Morgan D, Kelly P. HIV related hypochlorhydria does not appear to respond to anti-retroviral therapy in Zambian adults: a case control study. Pan Afr Med J 2018; 31:128. [PMID: 31037188 PMCID: PMC6462371 DOI: 10.11604/pamj.2018.31.128.11850] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 06/16/2018] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION Human Immunodeficiency Virus (HIV) infection is associated with hypochlorhydria but the mechanism is unknown. The objective of this study was to determine effects of anti-retroviral therapy (ART) on gastric physiology as measured by validated markers. METHODS We studied HIV infected individuals who were either ART-naïve or on treatment with undetectable viral loads. We measured H.pylori IgG antibodies, pepsinogen (PG) 1 and 2 levels and fasting gastrin-17 using Biohit GastroPanel®. Gastric antral biopsies and juice were obtained for histology and pH respectively. Also included were historical data from HIV negative participants (n = 72) in a previous study, for reference. RESULTS We enrolled 84 HIV positive individuals with a median age 42 years (IQR 37-40 years). 55(66%) were female, 32(38%) were ART naïve, and 52(62%) were on ART. Hypochlorhydria (pH>4) was present in 48(57%) of the HIV positive and 18(25%) of the HIV negative individuals (OR 4: 95% CI 1.9-8.5, P<0.001) with no significant effect of ART (OR 0.9: 95% CI 0.3-2.3, P = 0.82). Hypochlorhydria was not associated with the serological detection of corpus atrophy using low PG 1:2 ratio (OR 2.1: 95% CI 0.5-10.2, P = 0.37) or GastroPanel® algorithm, (OR 0.7: 95% CI 0.01-60.1, P = 1.0). ART reduced the frequency of low PG 1:2 ratio (P = 0.001), but not the histological detection in the antrum of atrophy or non-atrophic gastritis. CONCLUSION ART use is associated with reduced serological evidence of corpus atrophy but has no effect on fasting pH, supporting earlier data that suggest that the mechanism of HIV-associated hypochlorhydria is multifactorial.
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Affiliation(s)
- Violet Kayamba
- Tropical Gastroenterology & Nutrition Group, Department of Internal Medicine, University of Zambia School of Medicine, Nationalist Road, Lusaka, Zambia
| | - Aaron Shibemba
- Cancer Diseases Hospital, Pathology section, Nationalist Road, Lusaka, Zambia
| | - Kanekwa Zyambo
- Tropical Gastroenterology & Nutrition Group, Department of Internal Medicine, University of Zambia School of Medicine, Nationalist Road, Lusaka, Zambia
| | - Douglas Corbett Heimburger
- Vanderbilt Institute of Global Health, Vanderbilt Medical Center, 2525 West End Avenue, Suite 750, Nashville, 37203, Tennessee, USA
| | - Douglas Morgan
- Vanderbilt Institute of Global Health, Vanderbilt Medical Center, 2525 West End Avenue, Suite 750, Nashville, 37203, Tennessee, USA
| | - Paul Kelly
- Tropical Gastroenterology & Nutrition Group, Department of Internal Medicine, University of Zambia School of Medicine, Nationalist Road, Lusaka, Zambia
- Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
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Chen YM, Rodríguez-Hornedo N. Cocrystals Mitigate Negative Effects of High pH on Solubility and Dissolution of a Basic Drug. CRYSTAL GROWTH & DESIGN 2018; 18:1358-1366. [PMID: 30505243 PMCID: PMC6261521 DOI: 10.1021/acs.cgd.7b01206] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Weakly basic drugs are predisposed to order of magnitude decreases in solubility and dissolution as pH increases from 1 to 7 along the gastrointestinal tract. Such behavior is known to be detrimental to drug absorption. The work presented here shows how cocrystals of basic drugs with acidic coformers can mitigate these negative effects. Cocrystals of ketoconazole (KTZ) with adipic, fumaric, and succinic acids exhibit a parabolic solubility dependence on pH such that with increasing pH, solubility decreases, reaches a minimum, and increases. Cocrystals exhibit pHmax values between 3.6 and 3.8, above which they generate supersaturation with respect to drug. Cocrystal supersaturation index (SA), defined as Scocrystal/Sdrug, changes from 1 (pHmax) to 10-30 (pH 5) to 800 - 3,000 (pH 6.5). SA represents the driving force for cocrystal conversion to the less soluble drug during dissolution. SA is not expected to be equal to the observed supersaturation, but it is of great value to classify cocrystals in terms of their risk of conversion. Cocrystal dissolution behavior was analyzed in terms of Cmax, σmax (maximum KTZ concentration and supersaturation), AUCdiss (KTZ concentration area under the curve during dissolution-precipitation), and SA. The three cocrystals studied achieved σmax values between 5 and 15 and sustained supersaturation for 1 to 3 h, resulting in AUCdiss advantage over drug in the range of 2 to 12. SA values as high as 800 were associated with enhanced drug exposure. SA of 3,000 led to limited exposure, very rapid conversion, and no measurable supersaturation. Since cocrystals may be more soluble than needed and/or too soluble to be developed, there is great value in recognizing the relationship between supersaturation threshold, cocrystal solubility, and SA. This becomes more important as cocrystal SA is dependent on pH and other environmental conditions.
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Affiliation(s)
- Yitian M Chen
- Department of Pharmaceutical Sciences, University of Michigan Ann Arbor, Michigan 48109-1065, United States
| | - Naír Rodríguez-Hornedo
- Department of Pharmaceutical Sciences, University of Michigan Ann Arbor, Michigan 48109-1065, United States
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10
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Faber KP, Wu HF, Yago MR, Xu X, Kadiyala P, Frassetto LA, Benet LZ. Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir Absorption. Pharm Res 2016; 34:619-628. [PMID: 28028768 DOI: 10.1007/s11095-016-2090-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 12/19/2016] [Indexed: 02/01/2023]
Abstract
PURPOSE Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria. METHODS In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule. RESULTS Pretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax (p < 0.01) and AUC0-last (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir Cmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmax and 12% of AUClast lost due to rabeprazole. CONCLUSIONS The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.
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Affiliation(s)
- Kathleen Panter Faber
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 533 Parnassus Ave., Room U-68, San Francisco, CA, 94143-0912, USA
| | - Hsin-Fang Wu
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 533 Parnassus Ave., Room U-68, San Francisco, CA, 94143-0912, USA
| | - Marc R Yago
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 533 Parnassus Ave., Room U-68, San Francisco, CA, 94143-0912, USA
| | - Xiaohui Xu
- Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, New Jersey, USA
| | | | - Lynda A Frassetto
- Department of Medicine University of California San Francisco, San Francisco, California, USA
- Clinical Research Center, University of California San Francisco, San Francisco, California, USA
| | - Leslie Z Benet
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 533 Parnassus Ave., Room U-68, San Francisco, CA, 94143-0912, USA.
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Geraghty J, Thumbs A, Kankwatira A, Andrews T, Moore A, Malamba R, Mtunthama N, Hellberg K, Kalongolera L, O’Toole P, Varro A, Pritchard DM, Gordon M. Helicobacter pylori, HIV and Gastric Hypochlorhydria in the Malawian Population. PLoS One 2015; 10:e0132043. [PMID: 26244370 PMCID: PMC4526546 DOI: 10.1371/journal.pone.0132043] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 06/09/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND HIV and Helicobacter pylori are common chronic infections in sub-Saharan Africa. Both conditions can predispose to gastric hypochlorhydria that may be a risk factor for enteric infections and reduced drug absorption. We have investigated to what extent HIV and H. pylori infections are associated with hypochlorhydria in a Malawian cohort of patients undergoing endoscopy. METHODS 104 sequential symptomatic adults referred for gastroscopy at Queen Elizabeth Central Hospital, Blantyre, Malawi, had blood taken for rapid HIV testing and fasting serum gastrin analysis. Gastric fluid was aspirated for pH testing, and gastric biopsies were taken. RESULTS After 9/104 HIV-infected patients who were already established on anti-retroviral therapy were excluded, 17/95 (25.0%) were seropositive for untreated HIV, and 68/95 (71.6%) patients were H. pylori positive by histology. Hypochlorhydria (fasting gastric pH>4.0) was present in 55.8% (53/95) of patients. H. pylori infection was significantly associated with hypochlorhydria (OR 2.91, [1.02-7.75], p=0.046). While single infection with HIV was not significantly independently associated with hypochlorhydria. H. pylori and HIV co-infection was more strongly associated with hypochlorhydria (OR 6.25, [1.33-29.43], p=0.020) than either infection alone, suggesting an additive effect of co-infection. HIV infection was associated with higher serum gastrin levels (91.3 pM vs. 53.1 pM, p=0.040), while H. pylori infection was not (63.1 pM vs. 55.1 pM, p=0.610). Irrespective of H. pylori and HIV status, most patients (>90%) exhibited pangastritis. Only three patients had histological evidence of gastric atrophy, of which only one was HIV-infected. CONCLUSION H. pylori infection was associated with fasting hypochlorhydria, while HIV was not independently associated. HIV and H. pylori co-infection, however, was more strongly associated with hypochlorhydria than H. pylori infection alone. The mechanism of this apparent additive effect between HIV and H. pylori remains unclear, but appears to be related to chronic pangastritis rather than gastric atrophy, and associated with hypergastrinaemia in HIV-infected individuals.
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Affiliation(s)
- Joe Geraghty
- Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
- Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, United Kingdom
| | | | - Anstead Kankwatira
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, PO Box 30096, Blantyre 3, Malawi
- Department of Medicine, College of Medicine, Blantyre, Malawi
| | - Tim Andrews
- Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom
| | - Andrew Moore
- Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
- Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, United Kingdom
| | - Rose Malamba
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, PO Box 30096, Blantyre 3, Malawi
| | - Neema Mtunthama
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, PO Box 30096, Blantyre 3, Malawi
| | - Kai Hellberg
- Department of Surgery, College of Medicine, Blantyre, Malawi
| | | | - Paul O’Toole
- Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, United Kingdom
| | - Andrea Varro
- Department of Cellular and Molecular Physiology, University of Liverpool, United Kingdom
| | - D. Mark Pritchard
- Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
- Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, United Kingdom
| | - Melita Gordon
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, PO Box 30096, Blantyre 3, Malawi
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
- Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, United Kingdom
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12
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Development of self emulsifying drug delivery system of itraconazole for oral delivery: formulation and pharmacokinetic consideration. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2015. [DOI: 10.1007/s40005-015-0172-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Lewis JM, Stott KE, Monnery D, Seden K, Beeching NJ, Chaponda M, Khoo S, Beadsworth MBJ. Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: experience from a large HIV-positive cohort. Int J STD AIDS 2015; 27:105-9. [PMID: 25721922 DOI: 10.1177/0956462415574632] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Accepted: 02/01/2015] [Indexed: 11/17/2022]
Abstract
Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid-reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety.
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Affiliation(s)
- J M Lewis
- Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Prescott Street, Liverpool, UK
| | - K E Stott
- Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Prescott Street, Liverpool, UK
| | - D Monnery
- Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Prescott Street, Liverpool, UK
| | - K Seden
- Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, UK
| | - N J Beeching
- Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Prescott Street, Liverpool, UK
| | - M Chaponda
- Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Prescott Street, Liverpool, UK
| | - S Khoo
- Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Prescott Street, Liverpool, UK Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, UK
| | - M B J Beadsworth
- Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Prescott Street, Liverpool, UK
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14
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Meng Q, Dong T, Chen X, Tong B, Qian X, Che J, Cheng Y. Pharmacokinetics of sifuvirtide in treatment-naive and treatment-experienced HIV-infected patients. J Pharm Sci 2014; 103:4038-4047. [PMID: 25291974 DOI: 10.1002/jps.24174] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 08/21/2014] [Accepted: 08/21/2014] [Indexed: 11/06/2022]
Abstract
The pharmacokinetics assessment in two clinical studies of sifuvirtide (a novel HIV fusion inhibitor) was first reported in Chinese HIV patients. Nineteen treatment-naive HIV patients were treated with s.c.(subcutaneous injection) sifuvirtide [10 or 20 mg q.d.(quaque die)] for 28 days in study 1, and eight treatment-experienced HIV patients were treated with s.c. sifuvirtide (20 mg q.d.) in combination with HAART drugs (lamivudine, didanosine, and Kaletra) for 168 days in study 2. In study 1, T1/2 was 17.8 ± 3.7 h for 10 mg group and 39.0 ± 3.5 h for 20 mg group; the mean Cmax of last dose was 498 ± 54 ng/mL for 10 mg group and 897 ± 136 ng/mL for 20 mg group. In study 2, T1/2 was 6.71 ± 2.17 h in treatment-experienced patients. Cmax was 765 ± 288 ng/mL after last 168th dosage. Sifuvirtide showed improved clinical pharmacokinetics characteristics compared with Enfuvirtide, and showed very different pharmacokinetic characteristics between treatment-naive and treatment-experienced patients. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:4038-4047, 2014.
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Affiliation(s)
- Qingfang Meng
- School of Life Science, Beijing Institute of Technology, Beijing 100081, People's Republic of China; Lab of Drug Metabolism and Pharmacokineticsm, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, People's Republic of China
| | - Tianhao Dong
- FusoGen Pharmaceuticals, Inc, Tianjin 300308, People's Republic of China
| | - Xin Chen
- FusoGen Pharmaceuticals, Inc, Tianjin 300308, People's Republic of China
| | - Baohui Tong
- Lab of Drug Metabolism and Pharmacokineticsm, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, People's Republic of China
| | - Xiaohong Qian
- School of Life Science, Beijing Institute of Technology, Beijing 100081, People's Republic of China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, People's Republic of China
| | - Jinjing Che
- Lab of Drug Metabolism and Pharmacokineticsm, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, People's Republic of China.
| | - Yuanguo Cheng
- Lab of Drug Metabolism and Pharmacokineticsm, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, People's Republic of China
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15
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Lahner E, Virili C, Santaguida MG, Annibale B, Centanni M. Helicobacter pylori infection and drugs malabsorption. World J Gastroenterol 2014; 20:10331-10337. [PMID: 25132749 PMCID: PMC4130840 DOI: 10.3748/wjg.v20.i30.10331] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 01/24/2014] [Accepted: 04/27/2014] [Indexed: 02/06/2023] Open
Abstract
Drug absorption represents an important factor affecting the efficacy of oral drug treatment. Gastric secretion and motility seem to be critical for drug absorption. A causal relationship between impaired absorption of orally administered drugs and Helicobacter pylori (H. pylori) infection has been proposed. Associations have been reported between poor bioavailability of l-thyroxine and l-dopa and H. pylori infection. According to the Maastricht Florence Consensus Report on the management of H. pylori infection, H. pylori treatment improves the bioavailability of both these drugs, whereas the direct clinical benefits to patients still await to be established. Less strong seems the association between H. pylori infection and other drugs malabsorption, such as delavirdine and ketoconazole. The exact mechanisms forming the basis of the relationship between H. pylori infection and impaired drugs absorption and/or bioavailability are not fully elucidated. H. pylori infection may trigger a chronic inflammation of the gastric mucosa, and impaired gastric acid secretion often follows. The reduction of acid secretion closely relates with the wideness and the severity of the damage and may affect drug absorption. This minireview focuses on the evidence of H. pylori infection associated with impaired drug absorption.
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16
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Abdollahi A, Shoar S, Jafari S, Emadi-Kochak H. Seroprevalence of helicobacter pylori in human immunodeficiency virus-positive Patients and it's correlation with CD4(+) Lymphocyte Count. Niger Med J 2014; 55:67-72. [PMID: 24970974 PMCID: PMC4071667 DOI: 10.4103/0300-1652.128176] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background: This study assessed the seroprevalence of Helicobacter pylori antibodies among Iranian patients with human immunodeficiency virus (HIV) infection. It also examines whether anti H. pylori seroprevalence was associated with the severity of the HIV infection or the antiretroviral treatment. Material and Methods: A total of 114 HIV-infected patients and 114 age and sex-matched controls, without symptoms referable to upper gastrointestinal tract were recruited. Blood samples were obtained from all subjects. Serum IgG and IgA against H. pylori measured using the enzyme-linked immunosorbent assay (ELISA). Results: The rate of anti H. pylori IgG seropositivity was 57.9% in HIV-infected patients and 28.95% in controls (P < 0.001), while the rate of IgA seropositivity was 2.64% in HIV patients and 31.57% in controls (P < 0.001). Although there was an increasing trend of higher IgG and IgA titre by increasing CD4 cell count in HIV-positive patients, it was not reach statistical significance. There was no statistical difference in the serology of anti H. pylori IgG and IgA between patients receiving antiretroviral therapy comparing untreated HIV patients. Conclusions: This study showed higher seroprevalence of H. pylori IgG along with lower seroprevalence of H. pylori IgA in HIV-positive patients compared matched controls.
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Affiliation(s)
- Alireza Abdollahi
- Associate Professor of Pathology, Central Laboratory, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Shoar
- Associate Professor of Pathology, Central Laboratory, Tehran University of Medical Sciences, Tehran, Iran ; Laboratory Assistant, Student Scientific Research Center, Central Laboratory, Tehran University of Medical Sciences, Tehran, Iran
| | - Siroos Jafari
- Associate Professor of Infectious Diseases, Infectious Diseases Department, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Emadi-Kochak
- Associate Professor of Infectious Diseases, Infectious Diseases Department, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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Kis O, Walmsley SL, Bendayan R. In Vitro and In Situ Evaluation of pH-Dependence of Atazanavir Intestinal Permeability and Interactions with Acid-Reducing Agents. Pharm Res 2014; 31:2404-19. [DOI: 10.1007/s11095-014-1336-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 02/08/2014] [Indexed: 12/12/2022]
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19
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Crauwels HM, van Heeswijk RP, Buelens A, Stevens M, Boven K, Hoetelmans RM. Impact of Food and Different Meal Types on the Pharmacokinetics of Rilpivirine. J Clin Pharmacol 2013; 53:834-40. [DOI: 10.1002/jcph.107] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Accepted: 04/27/2013] [Indexed: 11/10/2022]
Affiliation(s)
| | | | | | | | - Katia Boven
- Janssen Infectious Diseases BVBA; Beerse; Belgium
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20
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Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol 2013; 11:483-90. [PMID: 23270866 DOI: 10.1016/j.cgh.2012.12.011] [Citation(s) in RCA: 244] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 11/14/2012] [Accepted: 12/07/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Use of proton pump inhibitors (PPIs) could predispose individuals to small intestinal bacterial overgrowth (SIBO) by altering the intraluminal environment and bacterial flora. There is controversy regarding the risk of SIBO among PPI users because of conflicting results from prior studies. A systematic review and meta-analysis were performed to evaluate the association between PPI use and SIBO, using objective clinical outcome measures. METHODS Clinical studies comparing SIBO risk among adult users of PPIs vs nonusers were identified in MEDLINE/PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and the National Institutes of Health Clinical Trials databases through July 2012. Two reviewers independently extracted data on study characteristics and outcomes. The primary metameter was the odds ratio (OR) of SIBO among PPI users vs nonusers. Subgroup analyses were performed to examine the influence of study characteristics, such as SIBO diagnostic modality, on study outcome. RESULTS Eleven studies (n = 3134) met inclusion criteria. The pooled OR of SIBO in PPI users vs nonusers was 2.282 (95% confidence interval [CI], 1.238-4.205). No significant single large study or temporal effect was seen. Subgroup analysis revealed an association between SIBO and PPI use in studies that used duodenal or jejunal aspirate cultures to diagnose SIBO (OR, 7.587; 95% CI, 1.805-31.894), but no relationship was found between SIBO and PPI use in studies that used the glucose hydrogen breath test (OR, 1.93; 95% CI, 0.69-5.42). Funnel plot analysis identified 4 outlying studies, indicating the possible presence of publication bias. CONCLUSIONS PPI use statistically was associated with SIBO risk, but only when the diagnosis was made by a highly accurate test (duodenal or jejunal aspirate culture). Differences in study results could arise from the use of different tests to diagnose SIBO.
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Affiliation(s)
- Wai-Kit Lo
- Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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21
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Zhu L, Persson A, Mahnke L, Eley T, Li T, Xu X, Agarwala S, Dragone J, Bertz R. Effect of Low-Dose Omeprazole (20 mg Daily) on the Pharmacokinetics of Multiple-Dose Atazanavir With Ritonavir in Healthy Subjects. J Clin Pharmacol 2013; 51:368-77. [DOI: 10.1177/0091270010367651] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Persson EC, Shiels MS, Dawsey SM, Bhatia K, Anderson LA, Engels EA. Retracted: Increased risk of stomach and esophageal malignancies in people with AIDS. Gastroenterology 2012; 143:943-950.e2. [PMID: 22796240 PMCID: PMC4236003 DOI: 10.1053/j.gastro.2012.07.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Revised: 06/21/2012] [Accepted: 07/10/2012] [Indexed: 02/06/2023]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and Authors. The authors recently discovered two programming errors that affected the results in their article on the epidemiology of esophageal and stomach cancers in human immunodeficiency virus infected people. As a result of these errors, the standardized incidence ratios (SIRs) were too high. The corrected SIRs are all lower than the authors reported, and the corrected SIR for stomach cancer is no longer significantly elevated. These errors affect Tables 2-5 in the paper. Because the new findings alter the conclusions, the editors and authors have jointly made the decision to retract the paper. The authors would like to express their sincere regret at the errors in their initial report and any inconvenience or confusion that they created. The corrected results may be obtained by contacting the corresponding author, Dr. Eric A. Engels, by email at engelse@exchange.nih.gov.
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Affiliation(s)
- E Christina Persson
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20852-7234, USA.
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Abstract
It is estimated that by 2015 more than half of all HIV-infected individuals in the United States will be 50 years of age or older. As this population ages, the frequency of non-AIDS related comorbidities increases, which includes cardiovascular, metabolic, gastrointestinal, genitourinary and psychiatric disorders. As a result, medical management of the aging HIV population can be complicated by polypharmacy and higher pill burden, leading to poorer antiretroviral therapy (ART) adherence. Adherence to ART is generally better in older populations when compared to younger populations; however, cognitive impairment in elderly patients can impair adherence, leading to worse treatment outcomes. Practical monitoring tools can improve adherence and increase rates of viral load suppression. Several antiretroviral drugs exhibit inhibitory and/or inducing effects on cytochrome P450 isoenzymes, which are responsible for the metabolism of many medications used for the treatment of comorbidities in the aging HIV population. The combination of ART with polypharmacy significantly increases the chance of potentially serious drug-drug interactions (DDIs), which can lead to drug toxicity, poorer ART adherence, loss of efficacy of the coadministered medication, or virologic breakthrough. Increasing clinicians awareness of common DDIs and the use of DDI programs can prevent coadministration of potentially harmful combinations in elderly HIV-infected individuals. Well designed ART adherence interventions and DDI studies are needed in the elderly HIV population.
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Wang X, Boffito M, Zhang J, Chung E, Zhu L, Wu Y, Patterson K, Kashuba A, Tebas P, Child M, Mahnke L, Bertz R. Effects of the H2-receptor antagonist famotidine on the pharmacokinetics of atazanavir-ritonavir with or without tenofovir in HIV-infected patients. AIDS Patient Care STDS 2011; 25:509-15. [PMID: 21770762 DOI: 10.1089/apc.2011.0113] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Significant pharmacokinetic interactions can result between acid-suppressing agents and some protease inhibitors (PIs) in the management of HIV infection. In healthy subjects, famotidine, an H(2)-receptor antagonist, reduces exposures of atazanavir by 4-28% at doses of 20-40 mg twice daily. This study evaluated the effect of famotidine 20-40 mg twice daily on the pharmacokinetics of atazanavir/ritonavir 300/100 mg once daily with and without tenofovir disoproxil fumarate (TDF) 300 mg in HIV-infected patients (n=40; 87.5% male; mean age 42, range 26-63 years; 55% white). Coadministration of famotidine 40 mg and atazanavir/ritonavir to HIV-infected patients reduced exposures of atazanavir by approximately 20%. This is comparable to reductions seen in HIV-uninfected subjects. Coadministration of famotidine 20 mg had less impact on atazanavir exposures, with no reduction of atazanavir geometric mean plasma concentration at 24 h postdose (C(min)). In the presence of TDF, administration of famotidine 20-40 mg twice daily 2 h after and 10 h before atazanavir/ritonavir reduced exposures of atazanavir by 19-25%. However, all individual atazanavir C(min) values remained at least five-fold above the population mean protein-binding adjusted 90% maximum effect (EC(90)) against wild-type HIV (14 ng/mL). No viral load rebound was observed at end of study. The results confirmed that coadministration of an H(2)-receptor antagonist with atazanavir/ritonavir in HIV-infected patients resulted in similar magnitude of reductions in atazanavir exposures as in healthy subjects. This supports the current dose recommendations for coadministration of an H(2)-receptor antagonist with atazanavir/ritonavir.
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Affiliation(s)
- Xiaodong Wang
- Bristol-Myers Squibb, Research and Development, Princeton, New Jersey
| | | | - Jenny Zhang
- Bristol-Myers Squibb, Research and Development, Princeton, New Jersey
| | - Ellen Chung
- Bristol-Myers Squibb, Research and Development, Princeton, New Jersey
| | - Li Zhu
- Bristol-Myers Squibb, Research and Development, Princeton, New Jersey
| | - Yaoshi Wu
- Bristol-Myers Squibb, Research and Development, Princeton, New Jersey
| | | | - Angela Kashuba
- University of North Carolina, Chapel Hill, North Carolina
| | - Pablo Tebas
- University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael Child
- Bristol-Myers Squibb, Research and Development, Princeton, New Jersey
| | - Lisa Mahnke
- Bristol-Myers Squibb, Research and Development, Princeton, New Jersey
| | - Richard Bertz
- Bristol-Myers Squibb, Research and Development, Princeton, New Jersey
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Mukonzo JK, Nanzigu S, Rekić D, Waako P, Röshammar D, Ashton M, Ogwal-Okeng J, Gustafsson LL, Aklillu E. HIV/AIDS Patients Display Lower Relative Bioavailability of Efavirenz than Healthy Subjects. Clin Pharmacokinet 2011; 50:531-40. [DOI: 10.2165/11592660-000000000-00000] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics. Bone Marrow Transplant 2011; 47:881-94. [DOI: 10.1038/bmt.2011.146] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Saberi P, Ranatunga DK, Quesenberry CP, Silverberg MJ. Clinical implications of the nelfinavir-proton pump inhibitor drug interaction in patients with human immunodeficiency virus. Pharmacotherapy 2011; 31:253-61. [PMID: 21361735 PMCID: PMC3091502 DOI: 10.1592/phco.31.3.253] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
STUDY OBJECTIVE To determine if the concomitant use of nelfinavir and proton pump inhibitors (PPIs) in patients with human immunodeficiency virus (HIV) infection results in the loss of virologic control. DESIGN Retrospective cohort study. DATA SOURCE Pharmacy, laboratory, and administrative databases of a large integrated health care system in northern California. PATIENTS A total of 1147 HIV-positive adults who started nelfinavir therapy between November 1, 1998, and June 20, 2003; within this cohort, 141 patients (12.3%) were also prescribed PPIs. MEASUREMENTS AND MAIN RESULTS The effects on two virologic outcomes--achievement of undetectable HIV viral load and subsequent virologic rebound--were compared between patients receiving nelfinavir alone and those receiving nelfinavir with PPIs. Cox proportional hazards models were used, with adjustments for age, sex, race, HIV risk factors, hepatitis B or C coinfection, and other concurrent drugs known to affect the metabolism of nelfinavir. The use of PPIs had little effect on the ability to achieve an undetectable HIV viral load (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.58-1.19, p=0.29), but there was an approximate 50% increased risk of virologic rebound with the concurrent use of PPIs (adjusted HR 1.53, 95% CI 1.06-2.19, p=0.02). Short-term use of PPIs (defined as within 30 days of initial PPI dispensation) was not associated with increased risk of virologic rebound (HR 1.07, 95% CI 0.26-4.41, p=0.93) compared with no use of PPIs. CONCLUSION Use of PPIs should be minimized or avoided in patients who have attained an undetectable HIV viral load while taking a nelfinavir-based antiretroviral regimen. However, concomitant use of these drugs may be acceptable for indications where PPIs are required for fewer than 30 days.
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Affiliation(s)
- Parya Saberi
- Department of Medicine, University of California-San Francisco, San Francisco, California 94105, USA.
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Liptrott NJ, Owen A. The role of cytokines in the regulation of drug disposition: extended functional pleiotropism? Expert Opin Drug Metab Toxicol 2011; 7:341-52. [PMID: 21299442 DOI: 10.1517/17425255.2011.553600] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Drug disposition, metabolism and drug-drug interactions are important considerations for most drugs. Cytokines are integral to the successful resolution of many diseases. Data are emerging on a role for cytokines in regulation of the expression and activity of drug transporters and drug metabolising enzymes. Investigation of the interaction between pharmacological and immunological responses is key to understanding the complex relationships involved in patient response to therapy. AREAS COVERED Evidence detailing the ability of cytokines to regulate drug disposition and metabolism is reviewed in the context of different cell and tissue types. The literature search undertaken provides an overview of the current understanding of the interrelationship between pharmacological and immunological factors which may influence successful drug therapy. EXPERT OPINION Dysregulation of cytokines and cytokine networks is a hallmark of a number of diseases such as HIV and cancer. The mechanisms by which the immune system can influence drug disposition are relatively understudied but recent work has highlighted the necessity for examining its impact on pharmacokinetics and pharmacodynamics. A more comprehensive approach in clinical studies will allow better determination of the impact of cytokines on drug disposition. In addition, determining the mechanisms that underpin the differential effects of cytokines across different cell types will clarify the responses reported in these studies.
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Affiliation(s)
- Neill James Liptrott
- NIHR Biomedical Research Centre for Microbial Disease, Royal Liverpool & Broadgreen University Hospitals Trust, Liverpool, UK
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Fialho ABC, Braga-Neto MB, Guerra EJC, Fialho AMN, Fernandes KC, Sun JLM, Takeda CFV, Silva CIS, Queiroz DMM, Braga LLBC. Low prevalence of H. pylori infection in HIV-positive patients in the northeast of Brazil. BMC Gastroenterol 2011; 11:13. [PMID: 21333017 PMCID: PMC3055236 DOI: 10.1186/1471-230x-11-13] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2010] [Accepted: 02/19/2011] [Indexed: 01/07/2023] Open
Abstract
Background This study conducted in Northeastern Brazil, evaluated the prevalence of H. pylori infection and the presence of gastritis in HIV-infected patients. Methods There were included 113 HIV-positive and 141 age-matched HIV-negative patients, who underwent upper gastrointestinal endoscopy for dyspeptic symptoms. H. pylori status was evaluated by urease test and histology. Results The prevalence of H. pylori infection was significantly lower (p < 0.001) in HIV-infected (37.2%) than in uninfected (75.2%) patients. There were no significant differences between H. pylori status and gender, age, HIV viral load, antiretroviral therapy and the use of antibiotics. A lower prevalence of H. pylori was observed among patients with T CD4 cell count below 200/mm3; however, it was not significant. Chronic active antral gastritis was observed in 87.6% of the HIV-infected patients and in 780.4% of the control group (p = 0.11). H. pylori infection was significantly associated with chronic active gastritis in the antrum in both groups, but it was not associated with corpus chronic active gastritis in the HIV-infected patients. Conclusion We demonstrated that the prevalence of H. pylori was significantly lower in HIV-positive patients compared with HIV-negative ones. However, corpus gastritis was frequently observed in the HIV-positive patients, pointing to different mechanisms than H. pylori infection in the genesis of the lesion.
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Affiliation(s)
- Andréa B C Fialho
- Clinical Research Unity - Department of Internal Medicine - Federal University of Ceará, Fortaleza, Ceará, Brazil
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Achenbach CJ, Darin KM, Murphy RL, Katlama C. Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults. Future Virol 2011; 6:157-177. [PMID: 21731578 PMCID: PMC3127229 DOI: 10.2217/fvl.10.89] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In the past 15 years, improvements in the management of HIV infection have dramatically reduced morbidity and mortality. Similarly, rapid advances in antiretroviral medications have resulted in the possibility of life-long therapy with simple and tolerable regimens. Protease inhibitors have been important medications in regimens of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is once-daily-administered atazanavir, pharmacologically boosted with ritonavir (atazanavir/r). Clinical studies and practice have shown these drugs, in combination with other antiretroviral agents, to be potent, safe and easy to use in a variety of settings. Atazanavir/r has minimal short-term toxicity, including benign bilirubin elevation, and has less potential for long-term complications of hyperlipidemia and insulin resistance compared with other protease inhibitors. A high genetic barrier to resistance and a favorable resistance profile make it an excellent option for initial HIV treatment or as the first drug utilized in the protease inhibitors class. Atazanavir/r is also currently being studied in novel treatment strategies, including combinations with new classes of antiretrovirals to assess nucleoside reverse transcriptase inhibitor-sparing regimens. In this article we review atazanavir/r as a treatment for HIV infection and discuss the latest information on its pharmacology, efficacy and toxicity.
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Affiliation(s)
- Chad J Achenbach
- Feinberg School of Medicine & Center for Global Health, Northwestern University, Chicago, USA
| | - Kristin M Darin
- Feinberg School of Medicine & Center for Global Health, Northwestern University, Chicago, USA
| | - Robert L Murphy
- Feinberg School of Medicine & Center for Global Health, Northwestern University, Chicago, USA
- Université Pierre et Marie Curie, Paris, France
| | - Christine Katlama
- Université Pierre et Marie Curie, Paris, France
- Service de Maladies Infectieuses et Tropicales, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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Bae SK, Park SJ, Shim EJ, Mun JH, Kim EY, Shin JG, Shon JH. Increased oral bioavailability of itraconazole and its active metabolite, 7-hydroxyitraconazole, when coadministered with a vitamin C beverage in healthy participants. J Clin Pharmacol 2010; 51:444-51. [PMID: 20400647 DOI: 10.1177/0091270010365557] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Soo Kyung Bae
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, 633-165, Gaegum-Dong, Busanjin-Gu, Busan, 614-735, South Korea
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Overton ET, Tschampa JM, Klebert M, Royal M, Rodriguez M, Spitz T, Kim G, Mondy KE, Acosta EP. The effect of acid reduction with a proton pump inhibitor on the pharmacokinetics of lopinavir or ritonavir in HIV-infected patients on lopinavir/ritonavir-based therapy. J Clin Pharmacol 2010; 50:1050-5. [PMID: 20147613 DOI: 10.1177/0091270009357431] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Edgar T Overton
- Washington University School of Medicine, 660 S Euclid Ave, Box 8051, St. Louis, MO 63110, USA.
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Jetter A, Fätkenheuer G, Frank D, Klaassen T, Seeringer A, Doroshyenko O, Kirchheiner J, Hein W, Schömig E, Fuhr U, Wyen C. Do activities of cytochrome P450 (CYP)3A, CYP2D6 and P-glycoprotein differ between healthy volunteers and HIV-infected patients? Antivir Ther 2010; 15:975-83. [DOI: 10.3851/imp1648] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Zhu L, Butterton J, Persson A, Stonier M, Comisar W, Panebianco D, Breidinger S, Zhang J, Bertz R. Pharmacokinetics and safety of twice-daily atazanavir 300 mg and raltegravir 400 mg in healthy individuals. Antivir Ther 2010; 15:1107-14. [DOI: 10.3851/imp1673] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Dicks LMT, Fraser T, ten Doeschate K, van Reenen CA. Lactic acid bacteria population in children diagnosed with human immunodeficiency virus. J Paediatr Child Health 2009; 45:567-72. [PMID: 19751380 DOI: 10.1111/j.1440-1754.2009.01566.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIM To determine the effect of trimethoprim/sulphamethoxazole treatment on the natural population of lactic acid bacteria in the intestinal tract and to determine if any of the strains developed resistance to antibiotics. METHODS Lactic acid bacteria were isolated from stool samples of 100 children. The isolates were identified based on biochemical characteristics and DNA profiles obtained from polymerase chain reaction with genus- and species-specific primers. Resistance to sulphamethoxazole, streptomycin, compound sulphonamides, chloramphenicol and vancomycin was tested using the paper-disk method. RESULTS The lactic acid bacteria were identified as Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus paracasei, Lactobacillus pentosus, Lactobacillus rhamnosus, Leuconostoc mesenteroides subsp. mesenteroides, Enterococcus spp. and Weissella spp. Lactobacillus plantarum and Bifidobacterium spp. were not isolated. All strains, except two, were sensitive to chloramphenicol and streptomycin. Thirty-five percent of the isolates were resistant to vancomycin, 50% to compound sulphonamides and 66% to sulphamethoxazole. CONCLUSION Treatment with trimethoprim/sulphamethoxazole repressed a large number of lactic acid bacteria normally present in the intestinal tract of children. A number of strains were resistant to sulphamethoxazole and may be used as probiotics to correct the imbalance in lactic acid bacteria.
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Affiliation(s)
- Leon M T Dicks
- Department of Microbiology, University of Stellenbosch, Stellenbosch, South Africa.
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Dickinson L, Boffito M, Back D, Waters L, Else L, Davies G, Khoo S, Pozniak A, Aarons L. Population pharmacokinetics of ritonavir-boosted atazanavir in HIV-infected patients and healthy volunteers. J Antimicrob Chemother 2009; 63:1233-43. [PMID: 19329800 PMCID: PMC2680345 DOI: 10.1093/jac/dkp102] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Objectives The aim of this study was to develop and validate a population pharmacokinetic model to: (i) describe ritonavir-boosted atazanavir concentrations (300/100 mg once daily) and identify important covariates; and (ii) evaluate the predictive performance of the model for lower, unlicensed atazanavir doses (150 and 200 mg once daily) boosted with ritonavir (100 mg once daily). Methods Non-linear mixed effects modelling was applied to determine atazanavir pharmacokinetic parameters, inter-individual variability (IIV) and residual error. Covariates potentially related to atazanavir pharmacokinetics were explored. The final model was assessed by means of a visual predictive check for 300/100, 200/100 and 150/100 mg once daily. Results Forty-six individuals were included (30 HIV-infected). A one-compartment model with first-order absorption and lag-time best described the data. Final estimates of apparent oral clearance (CL/F), volume of distribution (V/F) and absorption rate constant [relative standard error (%) and IIV (%)] were 7.7 L/h (5, 29), 103 L (13, 48) and 3.4 h−1 (34, 154); a lag-time of 0.96 h (1) was determined. Ritonavir area under the curve (AUC0–24) was the only significant covariate. Overall, 94%–97% of observed concentrations were within the 95% prediction intervals for all three regimens. Conclusions A population pharmacokinetic model for ritonavir-boosted atazanavir has been developed and validated. Ritonavir AUC0–24 was significantly associated with atazanavir CL/F. The model was used to investigate other, particularly lower, ritonavir-boosted atazanavir dosing strategies.
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Affiliation(s)
- Laura Dickinson
- NIHR Biomedical Research Centre, Royal Liverpool and Broadgreen University Hospital Trust, UK.
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Werneck-Silva AL, Prado IB. Role of upper endoscopy in diagnosing opportunistic infections in human immunodeficiency virus-infected patients. World J Gastroenterol 2009; 15:1050-6. [PMID: 19266596 PMCID: PMC2655189 DOI: 10.3748/wjg.15.1050] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Highly active antiretroviral therapy (HAART) has dramatically decreased opportunistic infections (OIs) in human immunodeficiency virus (HIV)-infected patients. However, gastrointestinal disease continues to account for a high proportion of presenting symptoms in these patients. Gastrointestinal symptoms in treated patients who respond to therapy are more likely to the result of drug-induced complications than OI. Endoscopic evaluation of the gastrointestinal tract remains a cornerstone of diagnosis, especially in patients with advanced immunodeficiency, who are at risk for OI. The peripheral blood CD4 lymphocyte count helps to predict the risk of an OI, with the highest risk seen in HIV-infected patients with low CD4 count (< 200 cells/mm3). This review provides an update of the role of endoscopy in diagnosing OI in the upper gastrointestinal tract in HIV-infected patients in the era of HAART.
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Lahner E, Annibale B, Delle Fave G. Systematic review: Helicobacter pylori infection and impaired drug absorption. Aliment Pharmacol Ther 2009; 29:379-386. [PMID: 19053985 DOI: 10.1111/j.1365-2036.2008.03906.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Impaired acid secretion may affect drug absorption and may be consequent to corporal Helicobacter pylori-gastritis, which may affect the absorption of orally administered drugs. AIM To focus on the evidence of impaired drug absorption associated with H. pylori infection. METHODS Data sources were the systematic search of MEDLINE/EMBASE/SCOPUS databases (1980-April 2008) for English articles using the keywords: drug malabsorption/absorption, stomach, Helicobacter pylori, gastritis, gastric acid, gastric pH, hypochlorhydria, gastric hypoacidity. Study selection was made from 2099 retrieved articles, five studies were identified. Data were extracted from selected papers, investigated drugs, study type, main features of subjects, study design, intervention type and results were extracted. RESULTS In all, five studies investigated impaired absorption of l-dopa, thyroxine and delavirdine in H. pylori infection. Eradication treatment led to 21-54% increase in l-dopa in Parkinson's disease. Thyroxine requirement was higher in hypochlorhydric goitre with H. pylori-gastritis and thyrotropin levels decreased by 94% after treatment. In H. pylori- and HIV-positive hypochlorhydric subjects, delavirdine absorption increased by 57% with orange juice administration and by 150% after eradication. CONCLUSIONS A plausible mechanism of impaired drug absorption is decreased acid secretion in H. pylori-gastritis patients. Helicobacter pylori infection and hypochlorhydria should be considered in prescribing drugs the absorption of which is potentially affected by intragastric pH.
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Affiliation(s)
- E Lahner
- Digestive and Liver Disease Unit, 2nd Medical School, University La Sapienza, Rome, Italy
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Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, Owen A. The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC. Br J Pharmacol 2009; 156:497-508. [PMID: 19154420 PMCID: PMC2697671 DOI: 10.1111/j.1476-5381.2008.00050.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Revised: 09/22/2008] [Accepted: 10/03/2008] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND PURPOSE The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC. EXPERIMENTAL APPROACH Human PBMC were incubated with cytokines for 48 h. ATP-binding cassette (ABC)B1, ABCC1, ABCC2, CYP2B6, CYP3A4, CXCR4 and CCR5 expression were measured by quantitative polymerase chain reaction and flow cytometry at 0, 4, 8, 24 and 48 h. Enzyme activity was assessed using fluorescent probes. KEY RESULTS We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 +/- 11961) and protein (% control 200 +/- 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-gamma (IFNgamma) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFNgamma respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r(2) = 0.545). CONCLUSIONS AND IMPLICATIONS These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells.
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Affiliation(s)
- N J Liptrott
- Department of Pharmacology and Therapeutics, The University of Liverpool, UK.
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Werneck-Silva AL, Prado IB. Gastroduodenal opportunistic infections and dyspepsia in HIV-infected patients in the era of Highly Active Antiretroviral Therapy. J Gastroenterol Hepatol 2009; 24:135-9. [PMID: 19054257 DOI: 10.1111/j.1440-1746.2008.05700.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Dyspeptic symptoms are frequently reported by human immunodefficiency virus (HIV)-infected patients under highly active antiretroviral therapy. Whether opportunistic infections are a cause of dyspepsia is still unknown. In this study we prospectively compare the prevalence of gastrointestinal opportunistic infections in dyspeptic versus non-dyspeptic HIV-infected patients with advanced immunodeficiency. PATIENTS AND METHODS Six hundred and ninety HIV-infected patients under highly active antiretroviral therapy underwent esophagogastroduodenoscopy with mucosal biopsies from the stomach and duodenum. Group 1: 500 patients (161 women, 339 men; mean age 38.8 years; mean CD4 count 154.3 cells/mm(3) with dyspeptic symptoms such as epigastric pain, nausea, vomiting and fullness. Group 2: 190 patients (169 men, 21 women; mean age 40.7 years; mean CD4 count 171.6 cell/mm(3)) with no dyspeptic symptoms. RESULTS Group 1: Gastrointestinal opportunistic infections were observed in eight (1.6%), and non-opportunistic parasites in two (0.4%), patients. They were: Cytomegalovirus (four patients), Cryptosporidium sp. (two patients), Schistosoma mansoni sp. (one patient), Strongyloides stercoralis (one patient) and Giardia sp. (two patients). In five patients esophagogastroduodenoscopy showed no mucosal lesions. Group 2: Giardia sp. was detected in two patients (1.1%: P = 0.07947). CONCLUSION Gastrointestinal opportunistic infections were shown in a small number of HIV-infected patients under highly active antiretroviral therapy with advanced immunodeficiency. Although gastrointestinal opportunistic infections were detected exclusively in the dyspeptic patient group, they could not be related to these symptoms, since the number of infected patients was not statistically significant. To correctly diagnose opportunistic infections, multiple biopsy specimens may be necessary even from normal-appearing mucosa.
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Abstract
Small intestinal bacterial overgrowth (SIBO) syndrome is characterized in its florid form by diarrhoea and weight loss. The most common underlying factors are dysmotility, small intestinal obstruction, blind or afferent loops. Small intestinal bacterial overgrowth can be diagnosed by: 1) culture of jejunum aspirate for bacterial counts, 2) 14C-D-xylose breath testing, 3) non-invasive hydrogen breath testing using glucose or lactulose or 4) 14C-glycocholic acid breath testing. The treatment usually consists of the eradication of bacterial overgrowth with repeated course of antimicrobials, correction of associated nutritional deficiencies and, when possible, correction of the underlying predisposing conditions.
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Affiliation(s)
- S V Rana
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Differences in the pharmacokinetics of protease inhibitors between healthy volunteers and HIV-infected persons. Curr Opin HIV AIDS 2008; 3:296-305. [DOI: 10.1097/coh.0b013e3282f82bf1] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Otani H, Inoue K, Shiota T, Suzuki Y, Nomura S, Harada Y, Ishibashi H, Abe S, Uchida K, Yamaguchi H, Torii S. [Pharmacological, pharmacokinetic, and clinical profile of itraconazole oral solution (ITRIZOLE Oral Solution 1%)]. Nihon Yakurigaku Zasshi 2007; 130:69-76. [PMID: 17634684 DOI: 10.1254/fpj.130.69] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
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McCabe SM, Smith PF, Ma Q, Morse GD. Drug interactions between proton pump inhibitors and antiretroviral drugs. Expert Opin Drug Metab Toxicol 2007; 3:197-207. [PMID: 17428151 DOI: 10.1517/17425255.3.2.197] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Gastroesophageal reflux disease and other related symptoms are common comorbidities for HIV-infected patients. Therefore, concurrent use of proton pump inhibitors and antiretrovirals is a common practice in the clinical setting. However, this practice may alter antiretroviral pharmacokinetics and lead to treatment failure due to inadequate drug exposure. Clinician awareness of these complex interactions is essential for optimal HIV management. This review summarizes the current knowledge on the interactions between proton pump inhibitors and antiretrovirals, and makes recommendations for the coadministration of proton pump inhibitors.
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Affiliation(s)
- Sarah M McCabe
- Associate Dean, Clinical Education and Research, University of Buffalo, Department of Pharmacy Practice, 317 Hochstetter Hall, Buffalo, NY 14260, USA
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Guiard-Schmid JB, Poirier JM, Bonnard P, Meynard JL, Slama L, Lukiana T, Jaillon P, Pialoux G. Proton pump inhibitors do not reduce atazanavir concentrations in HIV-infected patients treated with ritonavir-boosted atazanavir. AIDS 2005; 19:1937-8. [PMID: 16227815 DOI: 10.1097/01.aids.0000189565.87600.4d] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Guarino A, Bruzzese E, De Marco G, Buccigrossi V. Management of gastrointestinal disorders in children with HIV infection. Paediatr Drugs 2005; 6:347-62. [PMID: 15612836 DOI: 10.2165/00148581-200406060-00003] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
A double scenario characterizes the epidemiology of HIV infection in children. In countries where highly active antiretroviral therapy (HAART) is available, the pattern of HIV infection is evolving into that of a chronic disease, for which control strictly depends on patients' adherence to treatment. In developing countries with no or limited access to HAART, AIDS is rapidly expanding and is loaded with a high fatality ratio, due to the combined effects of malnutrition and opportunistic infections. The digestive tract is a target of the disease in both settings. Opportunistic infections play a major role in children with severe immune impairment, with Cryptosporidium parvum being the leading agent of severe diarrhea. Several therapeutic approaches are effective in reducing fecal output, but the eradication of the parasite is rarely obtained. Other opportunistic infections may induce severe and protracted diarrhea, including atypical mycobacteria and cytomegalovirus. Diagnosis of diarrhea should be individually tailored based on presenting symptoms and risk factors. A stepwise approach is effective in limiting patient discomfort and minimizing the costs of investigations, starting with microbiologic investigation and proceeding with endoscopy and histology. Aggressive treatment of infectious diarrhea is required in severely immunocompromised children. However, antiretroviral therapy prevents the development of severe cryptosporidiosis. The liver and pancreas are also target organs in HIV infection, although functional failure is rare. The digestive-absorptive functions are impaired, with steatorrhea, nutrient malabsorption, and increased permeability occurring in 20-70% of children. Intestinal dysfunction contributes to growth failure and further immune derangement, leading to wasting, the terminal stage of AIDS. Nutritional management is crucial in HIV-infected children and is based on aggressive nutritional rehabilitation through enteral or parenteral routes and micronutrient supplementation.HIV may play a direct enteropathogenic role and is implicated in both diarrhea and intestinal dysfunction. This explains the efficacy of antiretroviral therapy in inducing remission of diarrhea and restoring intestinal function. Gastrointestinal side effects of antiretroviral drugs are increasingly observed; they are often mild and transient. Severe reactions are rare but require the withdrawal of drugs. In conclusion, severe enteric infections and intestinal dysfunction characterize the intestinal involvement of HIV infection. This is more common in, but not limited to, children who do not receive effective antiretroviral therapy. Diagnostic approaches include microbiologic and morphologic examinations and assessment of digestive processes, but immunologic and virologic data should be also carefully considered. Treatment is based upon specific anti-infectious drugs, antiretroviral therapy, and nutritional rehabilitation.
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Affiliation(s)
- Alfredo Guarino
- Department of Pediatrics, University Federico II, Naples, Italy.
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DePestel DD, Kazanjian PH, Cinti SK, Kauffman CA, Carver PL. Magnitude and duration of elevated gastric pH in patients infected with human immunodeficiency virus after administration of chewable, dispersible, buffered didanosine tablets. Pharmacotherapy 2004; 24:1539-45. [PMID: 15537559 DOI: 10.1592/phco.24.16.1539.50959] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
STUDY OBJECTIVES To test the hypothesis that gastric pH would be elevated above pH 3.0 for at least 2 hours after administration of chewable, dispersible, buffered didanosine tablets. Doses tested were 200 mg (two 100-mg tablets) and 400 mg (two 200-mg tablets). We also sought to compare these doses with regard to maximum gastric pH (pHmax), time to pHmax (TpH-max), time that gastric pH exceeds 3.0 (TpH>3), and area under the gastric pH versus time curve for pH greater than 3.0 (AUCT>pH 3). DESIGN Prospective, parallel-group, dose-comparison, gastric pH study. SETTING General Clinical Research Center, University of Michigan Hospitals, Ann Arbor, Michigan. PATIENTS Nineteen patients infected with human immunodeficiency virus, aged 30-62 years, and receiving long-term didanosine therapy. INTERVENTION Patients underwent continuous gastric pH monitoring, using the Heidelberg capsule radiotelemetric pH monitoring device. After documentation of a fasting baseline gastric pH below 3.0, patients were given 180 ml of water (control phase), and gastric pH was allowed to return to baseline. After administration of a single, oral dose of didanosine 200 mg or 400 mg with 180 ml of water, gastric pH was recorded until pH remained below 3.0 for 10 minutes. MEASUREMENTS AND MAIN RESULTS A mean pHmax of 8.6 (range 6.3-9.5) was achieved with a TpH-max of 4.1 minutes (range 1-12.0 min). Mean TpH>3 was 24.9 minutes (range 15-55 min), with an AUCT>pH 3 of 2.6 pH x min(-1) (range 1.2-6.9 pH x min(-1)). The two doses of didanosine tested did not differ significantly in mean gastric pH parameters. CONCLUSIONS After administration of chewable, dispersible, buffered didanosine tablets, 200 or 400 mg, the mean duration of elevated gastric pH (TpH>3) was less than 30 minutes, with a range of 15-55 minutes. Characterization of the magnitude and duration of elevated gastric pH may allow for earlier administration of other pH-sensitive drugs. The short duration of elevated gastric pH may help explain the wide variability in didanosine bioavailability observed clinically.
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Affiliation(s)
- Daryl D DePestel
- Department of Clinical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
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Abstract
Cyclodextrins are cyclic oligomers of glucose that can form water-soluble inclusion complexes with small molecules and portions of large compounds. These biocompatible, cyclic oligosaccharides do not elicit immune responses and have low toxicities in animals and humans. Cyclodextrins are used in pharmaceutical applications for numerous purposes, including improving the bioavailability of drugs. Current cyclodextrin-based therapeutics are described and possible future applications discussed. Cyclodextrin-containing polymers are reviewed and their use in drug delivery presented. Of specific interest is the use of cyclodextrin-containing polymers to provide unique capabilities for the delivery of nucleic acids.
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Affiliation(s)
- Mark E Davis
- Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
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50
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Courtney R, Radwanski E, Lim J, Laughlin M. Pharmacokinetics of posaconazole coadministered with antacid in fasting or nonfasting healthy men. Antimicrob Agents Chemother 2004; 48:804-8. [PMID: 14982768 PMCID: PMC353067 DOI: 10.1128/aac.48.3.804-808.2004] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Posaconazole is a potent broad-spectrum azole antifungal agent in clinical development for the treatment of invasive fungal infections. This study evaluated the potential for a pH-dependent pharmacokinetic interaction between posaconazole and an antacid (Mylanta), under fasting and nonfasting conditions. Twelve men completed this randomized, four-period crossover, single-dose study. Subjects received 200 mg of posaconazole following a 10-h fast, with 20 ml of Mylanta and a 10-h fast, with 20 ml of Mylanta and a high-fat breakfast, and with a high-fat breakfast alone. Antacid coadministration had no statistically significant effects on posaconazole bioavailability under fasting or nonfasting conditions. In the fasting state, antacid slightly increased the relative oral bioavailability of posaconazole by 15% (P = 0.296); in the nonfasting state, antacid decreased the relative bioavailability of posaconazole by 12% (P = 0.352). Food increased the relative oral bioavailability of posaconazole by 400% (P = 0.001). In conclusion, the effect of antacid on posaconazole exposure in the fasting or nonfasting state was small and is not considered clinically significant.
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Affiliation(s)
- Rachel Courtney
- Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
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