WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
A black‐box property of an artificial neural network (ANN) decreases the scientific confidence of the model, and making it difficult to utilize the ANN in the medical field. Moreover, difficulty in handling the time‐series data is a significant problem for applying the ANN for pharmacometrics study.
WHAT QUESTION DID THIS STUDY ADDRESS?
How can we apply the ANN for predicting the time‐series pharmacokinetics (PKs) , and confirm the scientific validity of the ANN model?
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Using the ANN in combination with a conventional compartment (ANN‐PK) model enabled to handle the time‐series PK data, and the predicting performance of the model was higher than that of the population PK model. Furthermore, we could evaluate the scientific validity of the ANN model by applying the Shapley additive explanations.
HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?
We expect that our study will contribute to develop the interpretable ANN model, which can predict the time‐series PKs, drug efficacies, and side effects with high prediction performance.
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Affiliation(s)
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Cited by Other Article(s) |
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1
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Elnaggar M, Hafez H, Abdallah A, Hamza M, Khalaf MM, El-Haddad A. Optimizing cyclosporine A dose post allogeneic hematopoietic stem cell transplantation in paediatric cancer patients. J Oncol Pharm Pract 2024; 30:983-991. [PMID: 37528663 DOI: 10.1177/10781552231192516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2023]
Abstract
BACKGROUND/OBJECTIVES Cyclosporine A (CSA) dosing has been complicated by considerable intra-patient and inter-patient variability in pharmacokinetics, which is affected by different factors. We aimed to assess the various factors that might affect the CSA dose and its plasma level. PATIENTS AND METHODS This retrospective study included paediatric cancer patients who underwent allogeneic hematopoietic stem cell transplant at the Children's Cancer Hospital Egypt 57357 from matched related donors with CSA as graft versus host disease prophylaxis. The CSA initial dose was 1.5 mg/kg IV Q12H. Then, it was titrated according to the level and drug toxicity. Cyclosporine A trough levels were assessed two to three times per week using the Emit 2000 cyclosporine-specific assay. Moreover, factors that may affect cyclosporine levels, such as age, sex, weight and the antifungal used, were analyzed to determine their effect on CSA plasma levels. RESULTS There were 119 patients included in the study. The median age was 10 years; and 43% of them used voriconazole as a prophylactic antifungal. The multivariate analysis revealed that female patients, those >9 years or on voriconazole reached the target level at low initial CSA doses. A higher probability (93%) of reaching the desired plasma level with doses 1.5 mg/kg IV Q12H was observed among patients >9 years, and on voriconazole. While those who were ≤9 years and not on voriconazole required doses >1.5 mg/kg IV Q12H, with an 89% probability of reaching the desired level. CONCLUSION This study suggests that the initial CSA dose should consider the patient's age and the antifungal used. Patients >9 years and/or on voriconazole may require lower initial CSA doses and could start with 1.5 mg/kg IV Q12H.
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Affiliation(s)
- Mennatallah Elnaggar
- Department of Clinical Pharmacy, Children Cancer Hospital Egypt 57357, Cairo, Egypt
| | - Hanafy Hafez
- Department of Pediatric Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
- Department of Pediatric Oncology, Children Cancer Hospital Egypt 57357, Cairo, Egypt
| | - Amr Abdallah
- Department of Pediatric Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
- Department of Pediatric Oncology, Children Cancer Hospital Egypt 57357, Cairo, Egypt
| | - Mahmoud Hamza
- Department of Clinical Research, Children Cancer hospital Egypt 57357, Cairo, Egypt
| | - Marwa M Khalaf
- Department of Pharmacology and Toxicology, Beni-Suef University, Beni-Suef, Egypt
| | - Alaa El-Haddad
- Department of Pediatric Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
- Department of Pediatric Oncology, Children Cancer Hospital Egypt 57357, Cairo, Egypt
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2
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Leclerc V, Ducher M, Ceraulo A, Bertrand Y, Bleyzac N. A Clinical Decision Support Tool to Find the Best Initial Intravenous Cyclosporine Regimen in Pediatric Hematopoietic Stem Cell Transplantation. J Clin Pharmacol 2021; 61:1485-1492. [PMID: 34105165 DOI: 10.1002/jcph.1924] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/04/2021] [Indexed: 12/20/2022]
Abstract
To optimize cyclosporine A (CsA) dosing regimen in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT), we aimed to provide clinicians with a validated decision support tool for determining the most suitable first dose of intravenous CsA. We used a 10-year monocentric data set of pediatric patients undergoing HSCT. Discretization of all variables was performed according to literature or thanks to algorithms using Shannon entropy (from information theory) or equal width intervals. The first 8 years were used to build the Bayesian network model. This model underwent a 10-fold cross-validation, and then a prospective validation with data of the last 2 years. There were 3.3% and 4.1% of missing values in the training and the validation data set, respectively. After prospective validation, the Tree-Augmented Naïve Bayesian network shows interesting prediction performances with an average area under the receiver operating characteristic curve of 0.804, 32.8% of misclassified patients, a true-positive rate of 0.672, and a false-positive rate of 0.285. This validated model allows good predictions to propose an optimized and personalized initial CsA dose for pediatric patients undergoing HSCT. The clinical impact of its use should be further evaluated.
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Affiliation(s)
- Vincent Leclerc
- Targeted Therapies in Oncology, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France.,Pharmacy Department, Hôpital Pierre Garraud, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France
| | - Michel Ducher
- Targeted Therapies in Oncology, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France.,Pharmacy Department, Hôpital Pierre Garraud, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France
| | - Antony Ceraulo
- Institute of Pediatric Hematology and Oncology (IHOPe), Hematology Unit, Hospices Civils de Lyon and Claude Bernard University, Lyon, France
| | - Yves Bertrand
- Institute of Pediatric Hematology and Oncology (IHOPe), Hematology Unit, Hospices Civils de Lyon and Claude Bernard University, Lyon, France
| | - Nathalie Bleyzac
- Targeted Therapies in Oncology, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France
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3
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Ogami C, Tsuji Y, Seki H, Kawano H, To H, Matsumoto Y, Hosono H. An artificial neural network-pharmacokinetic model and its interpretation using Shapley additive explanations. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2021; 10:760-768. [PMID: 33955705 PMCID: PMC8302242 DOI: 10.1002/psp4.12643] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/23/2021] [Accepted: 04/19/2021] [Indexed: 12/20/2022]
Abstract
We developed a method to apply artificial neural networks (ANNs) for predicting time‐series pharmacokinetics (PKs), and an interpretable the ANN‐PK model, which can explain the evidence of prediction by applying Shapley additive explanations (SHAP). A previous population PK (PopPK) model of cyclosporin A was used as the comparison model. The patients’ data were used for the ANN‐PK model input, and the output by ANN was the clearance (CL). The estimated CL value from the ANN were substituted into the one‐compartment with one‐order absorption model, the concentrations were calculated, and the parameters of ANN were updated by the back‐propagation method. Kernel SHAP was applied to the trained model and the SHAP value of each input was calculated. The root mean squared error for the PopPK model and the ANN‐PK model were 41.1 and 31.0 ng/ml, respectively. The goodness of fit plots for the ANN‐PK model represented more convergence to y = x compared with that for the PopPK model, with good model performance for the ANN‐PK model. The most influential factors on CL output were age and body weight from the evaluation using Kernel SHAP, and these factors were incorporated into the PopPK model as the significant covariates of CL. The ANN‐PK model could handle time‐series data and showed higher prediction accuracy then the conventional PopPK model, and the scientific validity for the model could be evaluated by applying SHAP.
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Study Highlights
- Chika Ogami
- Department of Medical Pharmaceutics, Graduate School of Medical and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.,Center for Pharmacist Education, School of Pharmacy, Nihon University, Chiba, Japan
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- Yasuhiro Tsuji
- Center for Pharmacist Education, School of Pharmacy, Nihon University, Chiba, Japan
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- Hiroto Seki
- Department of Computer Engineering, College of Science and Technology, Nihon University, Chiba, Japan
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- Hideaki Kawano
- Faculty of Engineering, Kyushu Institute of Technology, Fukuoka, Japan
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- Hideto To
- Department of Medical Pharmaceutics, Graduate School of Medical and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan
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- Yoshiaki Matsumoto
- Laboratory of Clinical Pharmacokinetics, School of Pharmacy, Nihon University, Chiba, Japan
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- Hiroyuki Hosono
- Department of Computer Engineering, College of Science and Technology, Nihon University, Chiba, Japan
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4
Chung EK, Yee J, Kim JY, Gwak HS. Low cyclosporine concentrations in children and time to acute graft versus host disease.
BMC Pediatr 2020;
20:206. [PMID:
32393210 PMCID:
PMC7212619 DOI:
10.1186/s12887-020-02125-6]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Accepted: 05/05/2020] [Indexed: 11/19/2022] Open
Abstract
Background
Achievement of target blood concentrations of cyclosporine (CsA) early after transplantation is known to be highly effective for reducing the incidence of acute graft versus host disease (aGVHD). However, no research has been conducted for predicting aGVHD occurrence with low CsA concentrations at different time periods. The objective of this study was to investigate the risk of aGVHD according to low CsA concentrations at lag days in children with allogenic hematopoietic stem cell transplantation (HSCT).
Methods
The records of 61 consecutive children who underwent allogeneic HSCT and received CsA as prophylaxis against aGVHD between May 2012 and March 2015 were retrospectively evaluated. The main outcome was any association between low CsA concentrations at lag days and aGVHD occurrence, which was examined for the first month after transplantation. Mean CsA concentrations at three lag periods were calculated: lag days 0–6, 7–13, and 14–20 before aGVHD occurrence.
Results
Patients whose mean CsA concentrations at lag days 0–6 did not reach the initial target concentration had 11.0-fold (95% confidence interval [CI]: 2.3–51.9) greater incidence of aGVHD. In addition, the AORs of low CsA concentrations at lag days 7–13 and 14–20 for developing aGVHD were 108.2 (95% CI: 7.7–1515.5) and 12.1 (95% CI: 1.1–138.1), respectively.
Conclusions
After low CsA concentrations are detected, careful attention needs to be paid to prevent aGVHD.
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Affiliation(s)
- Eun Kyung Chung
- Graduate School of Converging Clinical & Public Health, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Korea.,Department of Pharmacy, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul, 05535, Korea
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- Jeong Yee
- College of Pharmacy & Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Korea
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- Jae Youn Kim
- Department of Pharmacy, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul, 05535, Korea
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- Hye Sun Gwak
- Graduate School of Converging Clinical & Public Health, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Korea. .,College of Pharmacy & Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Korea.
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5
Yoon S, Yi S, Rhee SJ, Lee HA, Kim Y, Yu KS, Chung JY. Development of a physiologically-based pharmacokinetic model for cyclosporine in Asian children with renal impairment.
Transl Clin Pharmacol 2019;
27:107-114. [PMID:
32055591 PMCID:
PMC6989237 DOI:
10.12793/tcp.2019.27.3.107]
[Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/30/2019] [Accepted: 09/03/2019] [Indexed: 11/19/2022] Open
Abstract
This study aimed to assess the pharmacokinetics of cyclosporine A (CsA) in Asian children with renal impairment (RI) by developing a physiologically-based pharmacokinetic (PBPK) model with Simcyp Simulator. The PBPK model of Asian children with RI was developed by modifying the physiological parameters of the built-in population libraries in Simcyp Simulator. The ratio of healthy and RI populations was obtained for each parameter showing a difference between the populations. Each ratio was multiplied by the corresponding parameter in healthy Asian children. The model verification was performed with published data of Korean children with kidney disease given multiple CsA administrations. Simulations were performed with different combinations of ethnicity, age, and renal function to identify the net impact of each factor. The simulated results suggested that the effect of RI was higher in children than adults for both Caucasian and Asian. In conclusion, the constructed model adequately characterized CsA pharmacokinetics in Korean children with RI. Simulations with populations categorized by ethnicity, age, and renal function enabled to assess the net impact of each factor on specific populations.
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Affiliation(s)
- Sumin Yoon
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
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- Sojeong Yi
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
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- Su-Jin Rhee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
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- Hyun A Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
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- Yun Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
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- Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
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- Jae-Yong Chung
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam 13620, Republic of Korea
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6
Abstract
The field of pediatric solid-organ transplantation has significantly evolved since its beginnings in the early 20th century. As advancements have led to the development of innovative surgical techniques and novel medication regimens, transplantation has now become a routine practice leading to an increase in the rates of organ recipients worldwide. The care of pediatric solid-organ transplant recipients differs from adults in several areas not only due to technically challenging surgeries, but mostly due to the complexity of their immunosuppression management. Although there is large variation of pediatric immunosuppression regimens worldwide, the use of calcineurin inhibitors, either tacrolimus or cyclosporine, still forms the backbone of immunosuppression regimens after solid-organ transplantation. Both medications are relatively well tolerated but are known to have long-term side effects, especially nephrotoxicity and neurotoxicity. The goal of care in long-term pediatric survivors of solid-organ transplant now aims to safely minimize exposure to immunosuppression and to achieve long-term graft tolerance.
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Affiliation(s)
- Niviann M Blondet
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Seattle Children's Hospital and the University of Washington, Seattle, WA, USA.
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- Patrick J Healey
- Department of Pediatric Surgery, Division of Transplantation, Seattle Children's Hospital and the University of Washington, Seattle, WA, USA
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- Evelyn Hsu
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Seattle Children's Hospital and the University of Washington, Seattle, WA, USA
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7
Kim KS, Moon A, Kang HJ, Shin HY, Choi YH, Kim HS, Kim SG. Higher plasma bilirubin predicts veno-occlusive disease in early childhood undergoing hematopoietic stem cell transplantation with cyclosporine.
World J Transplant 2016;
6:403-410. [PMID:
27358786 PMCID:
PMC4919745 DOI:
10.5500/wjt.v6.i2.403]
[Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2016] [Revised: 02/15/2016] [Accepted: 03/18/2016] [Indexed: 02/05/2023] Open
Abstract
AIM: To analyze the association between plasma bilirubin levels and veno-occlusive disease (VOD) in non-adult patients undergoing hematopoietic stem cell transplantation (HSCT) during cyclosporine therapy.
METHODS: A total of 123 patients taking cyclosporine were evaluated using an electronic medical system at the Seoul National University Children’s Hospital from the years 2004 through 2011. Patients were grouped by age and analyzed for incidence and type of adverse drug reactions (ADRs) including VOD.
RESULTS: The HSCT patients were divided into three age groups: G#1 ≥ 18; 9 ≤ G#2 ≤ 17; and G#3 ≤ 8 years of age). The majority of transplant donor types were cord blood transplantations. Most prevalent ADRs represented acute graft-vs-host disease (aGVHD) and VOD. Although the incidences of aGVHD did not vary among the groups, the higher frequency ratios of VOD in G#3 suggested that an age of 8 or younger is a risk factor for developing VOD in HSCT patients. After cyclosporine therapy, the trough plasma concentrations of cyclosporine were lower in G#3 than in G#1, indicative of its increased clearance. Moreover, in G#3 only, a maximal total bilirubin level (BILmax) of ≥ 1.4 mg/dL correlated with VOD incidence after cyclosporine therapy.
CONCLUSION: HSCT patients 8 years of age or younger are more at risk for developing VOD, diagnosed as hyperbilirubinemia, tender hepatomegaly, and ascites/weight gain after cyclosporine therapy, which may be represented by a criterion of plasma BILmax being ≥ 1.4 mg/dL, suggestive of more sensitive VOD indication in this age group.
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8
Limited sampling strategies for estimating intravenous and oral cyclosporine area under the curve in pediatric hematopoietic stem cell transplantation.
Ther Drug Monit 2015;
37:198-205. [PMID:
25162214 DOI:
10.1097/ftd.0000000000000124]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND
The optimal monitoring strategy for cyclosporine (CsA) in pediatric hematopoietic stem cell transplantation (HSCT) patients remains unclear. Although there is a growing interest in the use of the area under the concentration-time curve (AUC), measurement of AUC in clinical settings is often impractical. The objective of this study was to identify and validate limited sampling strategies (LSSs) for the prediction of CsA AUC after intravenous (IV) and oral (PO) administration in this population.
METHODS
Sixty-eight pediatric patients who underwent HSCT and received CsA were investigated. Twelve-hour pharmacokinetic profiles (n = 138) performed per standard of care were collected. Weighted multiple linear regression was used to investigate all possible LSSs consisting of 4 or less concentration-time points. Their predictive performance was evaluated by leave one out cross validation and external validation by measuring the root mean squared relative error (RMSE%) and the 95th percentile of the absolute relative error (AE%). Values less than 20% were considered clinically acceptable.
RESULTS
Nine LSSs (4 IV and 5 PO) convenient for clinical application proved to have clinically acceptable performance. Notably, LSS based on C0, C2, and C4 was found to be accurate for estimation of CsA exposure after both IV and PO administration with the 95th percentile of AE% of 19.7% and 17.5%, respectively.
CONCLUSIONS
LSSs using 3 or 4 concentration-time points obtained within 4 hours postdose provide a convenient and reliable method to estimate CsA exposure in this population. These LSSs may facilitate future research aiming at better defining the relationship between AUC and clinical outcomes.
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9
Tafazoli A. Cyclosporine use in hematopoietic stem cell transplantation: pharmacokinetic approach.
Immunotherapy 2015;
7:811-36. [DOI:
10.2217/imt.15.47]
[Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Cyclosporine is one of the most vital agents in the process of successful allogeneic hematopoietic stem cell transplantation. Despite a long history and worldwide extent of cyclosporine use for prevention of graft versus host disease, currently there are lots of uncertainties about its optimal method of application to reach the best clinical outcome. A major portion of this problem stems from complicated cyclosporine pharmacokinetics. Study of cyclosporine pharmacokinetic behavior can significantly help recognition of its effectiveness and consequently, optimization of dosing, administration, monitoring and management of adverse effects. In this review, highly accredited but sparse scientific data are gathered in order to provide a better insight for preparation of practice guidelines and directing future studies for allogeneic hematopoietic cell recipients.
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Affiliation(s)
- Ali Tafazoli
- Clinical Pharmacy Department, School of Pharmacy, Shahid Beheshti University of Medical Sciences (SBMU), Vali-e-Asr Avenue, Niayesh Junction, PO Box: 14155/6153 Tehran, Iran
- Taleghani Bone Marrow Transplantation Center, Taleghani Hospital, Shahid Beheshti University of Medical Sciences (SBMU), Vali-e-Asr Avenue, Niayesh Junction, PO Box 14155/6153 Tehran, Iran
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10
Sarem S, Li J, Barriere O, Litalien C, Théorêt Y, Lapeyraque AL, Nekka F. Bayesian approach for the estimation of cyclosporine area under the curve using limited sampling strategies in pediatric hematopoietic stem cell transplantation.
Theor Biol Med Model 2014;
11:39. [PMID:
25192585 PMCID:
PMC4237955 DOI:
10.1186/1742-4682-11-39]
[Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 07/29/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND
The optimal marker for cyclosporine (CsA) monitoring in transplantation patients remains controversial. However, there is a growing interest in the use of the area under the concentration-time curve (AUC), particularly for cyclosporine dose adjustment in pediatric hematopoietic stem cell transplantation. In this paper, we develop Bayesian limited sampling strategies (B-LSS) for cyclosporine AUC estimation using population pharmacokinetic (Pop-PK) models and investigate related issues, with the aim to improve B-LSS prediction performance.
METHODS
Twenty five pediatric hematopoietic stem cell transplantation patients receiving intravenous and oral cyclosporine were investigated. Pop-PK analyses were carried out and the predictive performance of B-LSS was evaluated using the final Pop-PK model and several related ones. The performance of B-LSS when targeting different versions of AUC was also discussed.
RESULTS
A two-compartment structure model with a lag time and a combined additive and proportional error is retained. The final covariate model does not improve the B-LSS prediction performance. The best performing models for intravenous and oral cyclosporine are the structure ones with combined and additive error, respectively. Twelve B-LSS, consisting of 4 or less sampling points obtained within 4 hours post-dose, predict AUC with 95th percentile of the absolute values of relative prediction errors of 20% or less. Moreover, B-LSS perform better for the prediction of the 'underlying' AUC derived from the Pop-PK model estimated concentrations that exclude the residual errors, in comparison to their prediction of the observed AUC directly calculated using measured concentrations.
CONCLUSIONS
B-LSS can adequately estimate cyclosporine AUC. However, B-LSS performance is not perfectly in line with the standard Pop-PK model selection criteria; hence the final model might not be ideal for AUC prediction purpose. Therefore, for B-LSS application, Pop-PK model diagnostic criteria should additionally account for AUC prediction errors.
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Affiliation(s)
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- Fahima Nekka
- Faculty of Pharmacy, Université de Montréal, C,P, 6128, Succ, Centre-ville, H3C 3J7 Montreal, Canada.
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11
Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II.
J Am Acad Dermatol 2010;
63:949-72; quiz 973-4. [PMID:
21093660 DOI:
10.1016/j.jaad.2010.02.062]
[Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Revised: 02/01/2010] [Accepted: 02/08/2010] [Indexed: 01/11/2023]
Abstract
UNLABELLED
Cyclosporine is highly effective in the treatment of a multitude of dermatoses. Concern over its side effect profile has limited its use in dermatology. Adverse effects are, for the most part, dose dependent and related to duration of therapy. Using the recommended monitoring protocols results in a significant decrease in the incidence of cyclosporine-related toxicities. This article provides a comprehensive review of the pharmacokinetics of cyclosporine, potential drug interactions, adverse effects, and recommendations for monitoring in patients treated with cyclosporine. The use of cyclosporine in pregnancy and in the pediatric population is also addressed.
LEARNING OBJECTIVES
After completing this learning activity, participants should be familiar with the monitoring guidelines of cyclosporine, its contraindications, its possible drug interactions, its adverse effect profile, and its use in pregnancy and the childhood and adolescent populations.
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Affiliation(s)
- Caitriona Ryan
- Department of Dermatology at Baylor University Medical Center, Dallas, Texas 75246, USA
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12
Deeg HJ, Sandmaier BM. Who is fit for allogeneic transplantation?
Blood 2010;
116:4762-70. [PMID:
20702782 PMCID:
PMC3253743 DOI:
10.1182/blood-2010-07-259358]
[Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Accepted: 08/07/2010] [Indexed: 11/20/2022] Open
Abstract
The use of allogeneic hematopoietic cell transplantation (HCT) has expanded progressively, facilitated by the increasing availability of unrelated donors and cord blood, and the inclusion of older patients as transplantation candidates. Indications remain diagnosis-dependent. As novel nontransplantation modalities have been developed concurrently, many patients come to HCT only when no longer responding to such therapy. However, patients with refractory or advanced disease frequently relapse after HCT, even with high-dose conditioning, and more so with reduced-intensity regimens as used for patients of older age or with comorbid conditions. Thus, patients with high-risk malignancies who have substantial comorbidities or are of advanced age are at high risk of both relapse and nonrelapse mortality and should probably not be transplanted. Being in remission or at least having shown responsiveness to pre-HCT therapy is generally associated with increased transplantation success. In addition, to handle the stress associated with HCT, patients need a good social support system and a secure financial net. They must be well informed, not only about the transplantation process, but also about expected or potential post-HCT events, including graft-versus-host disease and delayed effects that may become manifest only years after HCT.
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Affiliation(s)
- H Joachim Deeg
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
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13
Abstract
The calcineurin inhibitors, cyclosporine (ciclosporin) [microemulsion] and tacrolimus, are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. For pediatric patients, both drugs should be dosed per body surface area, and pharmacokinetic monitoring is mandatory. While monitoring of the trough levels may suffice for tacrolimus, cyclosporine therapy that utilizes the microemulsion formulation requires additional monitoring (e.g. determination of 2-hour post-dose levels). In a well designed randomized study in children, as in studies in adults, there was no difference in short-term patient and graft survival with cyclosporine microemulsion and tacrolimus. However, tacrolimus was significantly more effective than cyclosporine microemulsion in preventing acute rejection after renal transplantation when used in conjunction with azathioprine and corticosteroids. With regard to long-term outcome, the difference in acute rejection episodes resulted in a better glomerular filtration rate at 1 year after transplantation and eventually in better graft survival 4 years after renal transplantation. Whether this difference persists when calcineurin inhibitors are used in combination with mycophenolate mofetil has not been determined. The prevalence of hypomagnesemia was higher in the tacrolimus group whereas hypertrichosis and gingival hyperplasia occurred more frequently in the cyclosporine group. In contrast with adults, the incidence of post-transplantation diabetes mellitus was not significantly different between tacrolimus- and cyclosporine-treated patients. There was also no difference with regard to post-transplantation lymphoproliferative disorder. Medication costs were similar, but in view of the lower rejection episodes and better long-term graft survival as well as the more favorable cosmetic side effect profile, tacrolimus may be preferable. The recommendation drawn from the available data is that both cyclosporine and tacrolimus can be used safely and effectively in children. We recommend that cyclosporine should be chosen when patients experience tacrolimus-related adverse events.
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Affiliation(s)
- Guido Filler
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
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14
Fujinaga S, Kaneko K, Muto T, Ohtomo Y, Murakami H, Yamashiro Y. Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome.
Arch Dis Child 2006;
91:666-70. [PMID:
16670120 PMCID:
PMC2083035 DOI:
10.1136/adc.2005.080960]
[Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND
Cyclosporine A (CsA) has been widely used in children with steroid dependent and steroid resistant nephrotic syndrome (NS) because of its efficacy in relieving these patients from systemic side effects of steroids. However, its long term use is controversial, since chronic CsA induced nephropathy (CsAN) may develop in a considerable number of patients.
AIMS AND METHODS
In order to clarify the risk factors for the development of CsAN, the clinical characteristics of children with steroid dependent or steroid resistant NS taking CsA (target blood trough levels 50-150 ng/ml) for more than six months, managed at a single centre, were retrospectively analysed.
RESULTS
Thirteen of 30 children (24 boys and 6 girls) taking CsA (mean duration 43 months, range 6-144) had CsAN defined as the presence of CsA associated arteriopathy with or without striped tubulointerstitial lesions. The multivariate analysis revealed that CsA treatment for more than 36 months and an age younger than 5 years at the start of CsA treatment were independent risk factors for the development of CsAN. The univariate analysis also showed that patients with CsAN had more frequent relapses during CsA treatment than those without CsAN.
CONCLUSION
An alternative treatment should be seriously considered after a 36 month administration of CsA in order to prevent CsAN. Data also suggest that CsA treatment in children younger than 5 years should be avoided if possible.
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Affiliation(s)
- S Fujinaga
- Division of Nephrology, Saitama Children's Medical Centre, 2100 Magome, Iwatsuki-ku, Saitama-shi 339 8551, Japan.
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15
Choi JS, Lee SH, Chung SJ, Yoo KH, Sung KW, Koo HH. Assessment of converting from intravenous to oral administration of cyclosporin A in pediatric allogeneic hematopoietic stem cell transplant recipients.
Bone Marrow Transplant 2006;
38:29-35. [PMID:
16715103 DOI:
10.1038/sj.bmt.1705402]
[Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
We studied the administration method during a transition period from continuous intravenous (i.v.) infusion to oral administration of cyclosporin A (CsA). Thirty-two pediatric hematopoietic stem cell transplant (HSCT) recipients, between the ages of 8 months and 15.6 years (median 7.1 years) participated in this study. The pharmacokinetic properties of CsA was evaluated during the transition period from i.v. to oral CsA. The daily oral dose of CsA was three times higher than the i.v. dose. Oral dosing began immediately after the continuous infusion was discontinued. Whole-blood CsA concentrations were measured by a monoclonal fluorescence polarization immunoassay (FPIA). The mean+/-s.d. value of bioavailability (F), maximum concentration (C(max)), half-life (t(1/2)) of CsA were 43.1+/-14.4%, 1135.3+/-340.6 ng/ml and 3.1+/-1.2 h, respectively. Mean clearance (CL)+/-s.d. was 480.9+/-103.7, 414.9+/-137.1 and 320+/-51.8 ml/h/kg in patients <20, 20-40 and >40 kg of body weight, respectively. The CsA CL of younger children was significantly greater than for older children (P=0.044). CsA trough levels were maintained within the therapeutic range throughout the transition period. Therefore, our findings suggest that the immediate administration of an oral formulation, after discontinuation of the continuous infusion, would be practical and effective for routine clinical use.
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Affiliation(s)
- J S Choi
- Division of Pharmaceutical Services, Samsung Medical Center, Seoul, Korea
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16
Björkman S. Prediction of Cytochrome P450-Mediated Hepatic Drug Clearance in Neonates, Infants and Children.
Clin Pharmacokinet 2006;
45:1-11. [PMID:
16430308 DOI:
10.2165/00003088-200645010-00001]
[Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Correct dosing of drugs in neonates, infants and children is hampered by a general lack of knowledge about drug disposition in this population. Suggested methods to improve our knowledge without performing conventional full-scale investigations include population pharmacokinetic studies, allometric scaling of drug disposition according to bodyweight and in silico prediction of pharmacokinetics. The last method entails scaling of pharmacokinetic parameters according to age-dependent changes in drug absorption and elimination capacity, plasma protein binding and physiological characteristics of the subjects. Maturation (or ontogeny) of the drug-metabolising part of the cytochrome P450 (CYP) enzyme system is thus an important factor in the calculations for most drugs. The aim of this commentary is to test and critically examine the proposed methods to estimate hepatic clearance (CL) as a function of age (0-20 years), with CYP3A-mediated metabolism as the case in point. Midazolam and alfentanil were used as model drugs. Allometric scaling failed to predict the CL of midazolam and alfentanil in neonates. Calculations using in vitro findings on CYP maturation gave better estimates for neonates but very divergent ones for older infants and children. This was chiefly due to very different data on CYP3A4/5 ontogeny in three published studies. In the age range where full adult CYP activity per gram of liver could be assumed, allometric scaling and in silico predictions gave similar results. These predictions were also in approximate agreement with clinical data.The findings with the two model drugs can very probably be generalised to most drugs cleared by CYP-dependent hepatic metabolism. Allometric scaling accounts for development of body size and function but not for the fact that the drug-metabolising capacity of the liver is generally low at birth. The crucial question in the prediction of CL is thus when the activity of the applicable CYP isoform(s) attains adult levels. There are still not enough data on this, particularly when different studies even on the same CYP isoform have given very divergent results. It may also be pointed out that CYP ontogeny is an area where we have at least some information. There are several other important developmental changes about which we know practically nothing. Thus, while allometric scaling is generally unreliable for prediction in neonates and infants, the alternative method of in silico prediction can at present be used only to obtain tentative initial estimates of drug CL. Neither of the methods can be used as a substitute for actual clinical studies.
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Affiliation(s)
- Sven Björkman
- Hospital Pharmacy, Malmö University Hospital, Malmö, Sweden.
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17
Fujinaga S, Kaneko K, Takada M, Ohtomo Y, Akashi S, Yamashiro Y. Preprandial C2 monitoring of cyclosporine treatment in children with nephrotic syndrome.
Pediatr Nephrol 2005;
20:1359-60. [PMID:
15918005 DOI:
10.1007/s00467-005-1932-7]
[Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2005] [Accepted: 02/15/2005] [Indexed: 10/25/2022]
Affiliation(s)
- Shuichiro Fujinaga
- Division of Nephrology, Saitama Children's Medical Center, Shuichiro 2100, Magome Iwatsuki City, Saitama 339, 8551 Iwatsuki, Japan.
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18
Fife DJ, Maibach HI. Gender Differences in the Pharmacokinetics of Oral Dermatologic Medications.
ACTA ACUST UNITED AC 2004. [DOI:
10.1081/cus-120030169]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
19
Nagamura F, Takahashi T, Takeuchi M, Iseki T, Ooi J, Tomonari A, Uchimaru K, Takahashi S, Tojo A, Tani K, Asano S. Effect of cyclophosphamide on serum cyclosporine levels at the conditioning of hematopoietic stem cell transplantation.
Bone Marrow Transplant 2003;
32:1051-8. [PMID:
14625575 DOI:
10.1038/sj.bmt.1704259]
[Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We retrospectively analyzed the factors that affect serum cyclosporine (CsA) concentrations up to day 14 after allogeneic hematopoietic stem cell transplantation (HSCT). In all, 103 transplant recipients who received MTX and CsA for acute GVHD prophylaxis were analyzed. No significant relationships between serum CsA concentrations and gender, age, serum creatinine levels, AST/ALT levels, or antibiotic/fluconazole administration were found by comparing median CsA concentrations or by using longitudinal or regression multivariate analyses. However, the mean of the median serum CsA concentration in patients (n=54) receiving the regimen containing cyclophosphamide (CY) (149.7 ng/ml; 95% confidence interval (CI): 132.1-167.4) was significantly (P<0.0001) lower than that in patients (n=49) receiving the non-CY regimen (217.3 ng/ml; 95% CI: 198.9-235.6). Longitudinal analysis and regression multivariate analysis showed that only administration of CY had a significant effect on the serum CsA concentration. Our results suggest that administration of CY during conditioning can reduce the effects on serum CsA concentrations during the 2 weeks following HSCT. The mechanism of this effect is not clear, but it may be due to the autoinduction of CY.
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Affiliation(s)
- F Nagamura
- Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
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20
Alloway RR, Isaacs R, Lake K, Hoyer P, First R, Helderman H, Bunnapradist S, Leichtman A, Bennett MW, Tejani A, Takemoto SK. Report of the American Society of Transplantation conference on immunosuppressive drugs and the use of generic immunosuppressants.
Am J Transplant 2003;
3:1211-5. [PMID:
14510694 DOI:
10.1046/j.1600-6143.2003.00212.x]
[Citation(s) in RCA: 84] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Considerable economic and health-related costs are associated with the life-long maintenance immunosuppressive therapy required to prevent transplant rejection. Generic medications have the potential of providing equivalent therapeutic efficacy at a lower economic cost. In 2001, the American Society of Transplantation invited experts to review the data and issues associated with the approval and use of generic immunosuppressants. A summary of that meeting is reported here. The generic medication approval process has been in effect for more than 30 years. All marketed generic cyclosporin formulations have met FDA criteria demonstrating bioequivalence in healthy subjects, and some were also tested in transplant recipients. Most participants agreed that generic narrow therapeutic index immunosuppressive agents provide adequate de novo immunosuppression in low-risk transplant recipients. However, some participants expressed concern regarding the currently unquantified risk that may be associated with switching immunosuppressive agents under uncontrolled circumstances. There was broad agreement among the participants that generic medications should be clearly labeled and distinguishable from innovator drugs, and that patients should be educated to inform their physicians of any switch to or among generic alternatives. There was also strong support in favor of requiring studies to demonstrate bioequivalence in potentially at-risk patient populations, specifically African-Americans and pediatric patients.
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Affiliation(s)
- Rita R Alloway
- University of Cincinnati, College of Medicine, Cincinnati OH, USA
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21
Abstract
In transplantation the risk of acute rejection decreases with recipient age. This is clearly illustrated in transplantation of a non-vascularised tissue, such as the cornea. In vascularised transplants, such as kidneys, acute rejection decreases with recipient age, but the phenomenon is obscured by the fact that chronic allograft nephropathy increases with age, and is further confounded by increased death from infectious disease and drug-related causes. The underlying cellular mechanisms responsible for this weakening of rejection are discussed, as is defective signal transduction leading to decreased activation of cells and decreased resistance to immunosuppressive drugs. This supports a view that less intensive immunosuppressive drug therapy is desirable in elderly recipients. Although pharmacokinetic studies are documented, there are no routine assays to measure efficacy of these drugs in individual patients. In summary, the decline in acute rejection with increasing recipient age may be due both to immunosenescence and decreased resistance to immunosuppressive drugs. Future assays to test these mechanisms could be used to tailor therapy to individual needs.
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Affiliation(s)
- Benjamin A Bradley
- University of Bristol Department of Transplantation Sciences, Paul O'Gorman Lifeline Centre, Southmead Hospital, UK.
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22
del Mar Fernández De Gatta M, Santos-Buelga D, Domínguez-Gil A, García MJ. Immunosuppressive therapy for paediatric transplant patients: pharmacokinetic considerations.
Clin Pharmacokinet 2002;
41:115-35. [PMID:
11888332 DOI:
10.2165/00003088-200241020-00004]
[Citation(s) in RCA: 68] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Immunosuppressive therapy in paediatric transplant recipients is changing as a consequence of the increasing number of available immunosuppressive agents. Generic and other new formulations are now emerging onto the market, clinical experience is growing, and it is expected that clinicians should tailor immunosuppressive protocols to individual patients by optimising dosages and drugs according to the maturation and clinical status of the child. Most information about the clinical pharmacokinetics of immunosuppressive drugs in paediatrics is centred on cyclosporin, tacrolimus and mycophenolate mofetil in renal and liver transplant recipients; data regarding other immunosuppressants and transplant types are limited. Although the clinical pharmacokinetics of these drugs in paediatric transplant recipients are still under investigation, it is evident that the pharmacokinetic parameters observed in adults may not be applicable to children, especially in younger age groups. In general, patients younger than 5 years old show higher clearance rates irrespective of the organ transplanted or drug used. Another important factor that frequently affects clearance in this patient population is the post-transplant time. In accordance with these findings, and in contrast with the usual under-dosage in children, the need for higher dosages in younger recipients and during the early post-transplant period seems evident. To achieve the best compromise between prevention of rejection and toxicity, dosage individualisation is required and this can be achieved through therapeutic drug monitoring (TDM). This approach is particularly useful to ensure the cost-effective management of paediatric transplant recipients in whom the pharmacokinetic behaviour, target concentrations for clinical use and optimal dosage strategies of a particular drug may not yet be well defined. Although TDM may be a tool for improving immunosuppressive therapy, there is little information concerning its positive contribution to clinical events, including outcomes, for paediatric patients. Substantial information to support the use of TDM exists for cyclosporin and, to a lesser extent, for tacrolimus, but a diversity of options affects their implementation in the clinical setting. The role of TDM in therapy with mycophenolate mofetil and sirolimus has yet to be defined regarding both methods and clinical indications. Pharmacodynamic monitoring appears more suited to other immunosuppressants such as azathioprine, corticosteroids and monoclonal or polyclonal antibodies. If coupled with pharmacokinetic measurements, such monitoring would allow earlier and more precise optimisation of therapy. Very few population pharmacokinetic studies have been carried out in paediatric transplant patients. This type of study is needed so that techniques such as Bayesian forecasting can be applied to optimise immunosuppressive therapy in paediatric transplant patients.
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23
Schultz KR, Nevill TJ, Balshaw RF, Toze CL, Corr T, Currie CJ, Strong DK, Keown PA. Effect of gastrointestinal inflammation and age on the pharmacokinetics of oral microemulsion cyclosporin A in the first month after bone marrow transplantation.
Bone Marrow Transplant 2000;
26:545-51. [PMID:
11019845 DOI:
10.1038/sj.bmt.1702545]
[Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Cyclosporin A (CsA) absorption is highly variable in BMT patients. Neoral, a new microemulsion formulation of CsA, permits increased absorption with less variable pharmacokinetic parameters in non-BMT patients. We evaluated the pharmacokinetics of CsA after BMT in patients received microemulsion CsA. Two oral doses of 3mg/kg were given 48 h apart between 14 and 28 days after allogeneic BMT in 20 adults, and one dose in seven children, while subjects were receiving a continuous i.v. infusion of CsA. Whole blood samples were taken throughout the dosing interval to calculate the incremental CsA exposure using maximum concentration (Cmax), time to Cmax (tmax), concentration at 12 h after the dose (C12), the area under the concentration-time curve (AUC), and to establish inter- and intra-patient pharmacokinetic variability. Drug exposure was substantially lower in children than adults, with an AUC of 861+/-805 vs 2629+/-1487 micromg x h/l (P = 0.001), respectively, and absorption was delayed and diminished in both groups by comparison with solid organ recipients. Intra-patient variability in adults for AUC was high at 0.59+/-0.34, while inter-patient variability, measured as the coefficient of variation (c.v.), was 0.55 for the first and 0.54 for the second dose. In adults, gastrointestinal (GI) inflammation due to either mucositis or GVHD resulted in a higher AUC of 3077+/-1551 microg x h/l compared to 1795+/-973 microg x h/l (P = 0.02), and a similar trend was observed in children. AUC seemed little affected by the CsA formulation (liquid or capsule), or co-administration with liquids or food. Trough (12 h) CsA levels correlated poorly with incremental AUC. Sparse sample modeling of the AUC using two-point predictors taken at 2.5 and 5 h after dosing accurately approximated AUC in adults (r2 = 0.94), while 1.5 and 5 h was superior in children (r2 = 0.98). These data suggest that 12 h postdose trough measurements of CsA may not be the most appropriate way to evaluate CsA blood concentrations in order to establish therapeutic efficacy in BMT patients. Based on this study, the dose of microemulsion CsA should be adjusted based on recipient age, and the presence of GI inflammation secondary to mucositis or GVHD. These data would suggest that sparse sampling at time points earlier than the trough more accurately reflects the AUC and may correlate more closely with therapeutic efficacy early post-BMT.
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Affiliation(s)
- K R Schultz
- Department of Pediatrics, University of British Columbia and British Columbia's Children's Hospital, Vancouver, Canada
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24
Abstract
This review and critical analysis of current trends of immunosuppression management in pediatric transplantation provides evidence and support for the continued role of Neoral as an indispensable part of immunosuppressive protocols. CyA formulation influences clinical outcomes such as acute rejection, as confirmed by two studies. The CyA microemulsion formulation provides more reliable and effective absorption. An advanced TDM strategy to determine CyA bioavailability can improve the effectiveness and safety of immunosuppression in de novo liver transplant patients. especially in the younger de novo patient. Neoral is an indispensable part of combination protocols in pediatric transplantation.
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Affiliation(s)
- S Dunn
- Transplantation and Surgery, St Christopher's Hospital for Children, Philadelphia, Pennsylvania 19134, USA
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25
Diav-Citrin O, Ratnapalan S, Grouhi M, Roifman C, Koren G. Medication errors in paediatrics: a case report and systematic review of risk factors.
Paediatr Drugs 2000;
2:239-42. [PMID:
10937473 DOI:
10.2165/00128072-200002030-00007]
[Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- O Diav-Citrin
- Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Ontario, Canada
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26
Abstract
In this review I have attempted to summarize gender differences in pharmacokinetics involving the cytochrome P450 (CYP) isozymes of young and mature adults, excluding the effects of the menstrual cycle, use of oral contraceptives and pregnancy. Sex differences in drug metabolism and elimination are mainly related to steroid hormone levels. CYP3A4, responsible for the metabolism of over 50% of therapeutic drugs, exhibits higher activity in women than in men. Nonetheless, the absence of a sex difference has been reported by some workers. The activity of several other CYP (CYP2C19, CYP2D6, CYP2E1) isozymes and the conjugation (glucuronidation) activity involved in drug metabolism may be higher in men than in women. Drug metabolism in women is affected by sex-specific factors (menopause, pregnancy and menstruation) in addition to the cigarette smoking, drug ingestion and alcohol consumption that are more commonly observed factors in men. Furthermore, they are affected by physiological factors such as drug absorption, protein binding and elimination. Thus, careful attention should be paid to the side-effects and toxicity arising from sex differences in drug metabolism in clinical situations. Although there are specific ethical considerations regarding carrying out drug trials in women, the relationship between the side-effects and toxicity that may be influenced by hormones during drug metabolism and drug treatment needs further study.
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Affiliation(s)
- E Tanaka
- Institute of Community Medicine, University of Tsukuba, Japan
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27
Lin Y, Anderson GD, Kantor E, Ojemann LM, Wilensky AJ. Differences in the urinary excretion of 6-beta-hydroxycortisol/cortisol between Asian and Caucasian women.
J Clin Pharmacol 1999;
39:578-82. [PMID:
10354961 DOI:
10.1177/00912709922008182]
[Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The urinary ratio of 6-beta-hydroxycortisol/cortisol has been used as a noninvasive probe for human cytochrome P450 3A4 isoforms (CYP3A4). Ethnic-related differences in the ratio have not been evaluated. The aim of this study was to determine if there are differences in the ratio between Asian and Caucasian women over a menstrual cycle. First-morning urine samples were collected every other day starting from the second day of menstruation for a complete menstrual cycle from 15 Asians and 16 Caucasian women who were 18 to 40 years old, healthy, nonsmoking, and alcohol and drug free, including oral contraceptives. Urine concentrations of 6-beta-hydroxycortisol and cortisol were measured by high-pressure liquid chromatography (HPLC). For statistical analysis, three phases of the menstrual cycle were evaluated: menstruation (days 1-4), follicular or postmenstruation (days 6-10), and the luteal phase (days 21-24) based on the average menstrual cycle (28 days). Statistical analysis was performed by an independent sample t-test using the Bonferroni correction for repeated measures. Large intersubject and intrasubject variations of the 6-beta-hydroxycortisol/cortisol ratios were observed during the menstrual cycles in both ethnic groups. Asian women had a statistically significant lower ratio than Caucasian women did for all three phases of the menstrual cycle: 2.2 +/- 1.1 versus 5.1 +/- 3.5, 2.1 +/- 1.1 versus 6.0 +/- 4.9, and 2.8 +/- 1.6 versus 5.6 +/- 3.0 for the menstruation, follicular, and luteal phases, respectively. The two- to threefold lower 6-beta-hydroxycortisol/cortisol ratios in Asian women suggest that Asian women may have a lower CYP3A activity compared with Caucasian women. Differences in ethnicity may mask potential gender-related effects if ethnic background is not evaluated as a contributing factor.
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Affiliation(s)
- Y Lin
- Department of Pharmacy, School of Pharmacy, University of Washington, Seattle 98195, USA
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28
Guidelines for immunosuppression management and monitoring after transplantation in children.
Transplant Rev (Orlando) 1999. [DOI:
10.1016/s0955-470x(99)80050-0]
[Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
29
Akhlaghi F, Ashley J, Keogh A, Brown K. Cyclosporine plasma unbound fraction in heart and lung transplantation recipients.
Ther Drug Monit 1999;
21:8-16. [PMID:
10051049 DOI:
10.1097/00007691-199902000-00003]
[Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
To investigate the variability in the unbound fraction (fu) of cyclosporine in recipients of heart, heart-lung, and lung transplantation, cyclosporine fu was determined ex vivo in plasma by equilibrium dialysis. In a retrospective study, 260 samples of plasma (one to seven per patient) were obtained from 89 heart (86%), lung (9%), and heart-lung (5%) transplant patients. The unbound fraction (x100) of cyclosporine ranged from 0.52% to 3.94%, with an overall mean of 1.53%+/-0.375% (SD). The mean percentage unbound for individual patients ranged from 0.71% to 1.98%, giving a 2.8-fold interpatient variation. In heart transplant recipients (66 patients), the values of fu were significantly lower (p < 0.01) during more severe rejection episodes, which required antirejection treatment (endomycardial biopsy result of grade 3a and higher) than in the absence of rejection (grade 0) or during grade la rejections. The value of fu did not vary with organ transplanted (p = 0.35) or etiology of organ failure (p = 0.32). Cyclosporine fu was negatively correlated with the age of the patient (r = -0.18, p < 0.05). Correlations were not observed between fu and blood biochemical and cytologic indices. However, fu was significantly lower (p < 0.01) in hypercholesterolemic transplant recipients (1.37+/-0.52%) than in normocholesterolemic patients (1.60+/-0.63%). Administration of simvastatin resulted in a significant increase in the mean fu from 1.40+/-0.09%) to 1.82+/-0.13% (paired t test, n = 13; p < 0.01). In patients who received ketoconazole, fu was not different from controls. These findings suggest that the level of cyclosporine fu may be an important determinant of immunosuppressive activity of cyclosporine. Moreover, the variation in fu could be strongly related to the concentration of serum lipoproteins; interpretation of the results of cyclosporine monitoring thus requires consideration of the lipidemic status of the patient.
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Affiliation(s)
- F Akhlaghi
- Department of Pharmacy, University of Sydney, Australia
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30
Gorski JC, Jones DR, Haehner-Daniels BD, Hamman MA, O'Mara EM, Hall SD. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin.
Clin Pharmacol Ther 1998;
64:133-43. [PMID:
9728893 DOI:
10.1016/s0009-9236(98)90146-1]
[Citation(s) in RCA: 282] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE
To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin.
METHODS
On day 1, 16 volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3-midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by gas chromatography-mass spectrometry.
RESULTS
There was no significant (p > 0.05) difference in the urinary excretion of 1'-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 +/- 1.0 versus 1.0 +/- 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 +/- 0.1 versus 0.44 +/- 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 +/- 9 L/hr to 10 +/- 3 L/hr occurred after clarithromycin administration. Oral midazolam availability was significantly increased from 0.31 +/- 0.1 to 0.75 +/- 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability were significantly increased from 0.42 +/- 0.2 to 0.83 +/- 0.2 and from 0.74 +/- 0.1 to 0.90 +/- 0.04, respectively. A significant correlation was observed between intestinal and oral availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or intestinal availability and the relative increase in hepatic or intestinal availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05).
CONCLUSION
These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first-pass extraction of high-affinity CYP3A substrates such as midazolam is primarily a function of intestinal enzyme activity.
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Affiliation(s)
- J C Gorski
- Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Memorial Hospital, Indianapolis 46202-2879, USA
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31
Georgouras KE, Zagarella SS, Cains GD, Brown PJ. Systemic treatment of severe psoriasis.
Australas J Dermatol 1997;
38:171-80; quiz 181-2. [PMID:
9431708 DOI:
10.1111/j.1440-0960.1997.tb01690.x]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Severe psoriasis presents a difficult therapeutic challenge. Some modalities such as synthetic retinoids, phototherapy and methotrexate have been available for many years and need reappraisal, cyclosporin has only recently become available and requires careful administration. In this article we focus on the therapeutic modalities available to the dermatologist in Australia.
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32
Charlebois JE, Lum BL, Cooney GF, Mochon M, Kaiser BA. Comparison and validation of limited sampling equations for cyclosporine area-under-the-curve monitoring calculations in pediatric renal transplant recipients.
Ther Drug Monit 1997;
19:277-80. [PMID:
9200767 DOI:
10.1097/00007691-199706000-00006]
[Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Therapeutic monitoring of cyclosporine (CsA) by using area-under-the-concentration-time-curve (AUC) values in renal transplant recipients has been previously demonstrated to predict posttransplant clinical outcome. Two previous studies also reported that limited sampling equations could accurately determine the AUC of CsA using one to six blood concentration determinations in adults. The purpose of this study was to validate the accuracy of these equations in a pediatric population. In 18 pediatric patients who received renal allografts, three limited sampling equations, which used one, four, or five concentration time points, accurately estimated CsA AUC when compared with an actual 7- to 9-point curve. An equation that used a single concentration time point at 5 hours was unbiased and provided the best precision in calculating a 12-hour interval AUC. This equation had a mean absolute percentage error of 5.8% (95% confidence interval, 3.3 to 8.3). Equations using four or five concentration time points were found to provide estimates of AUC for a 24-hour interval AUC, with less than 10% error. These findings suggest that limited sampling models using as few as one to four concentration time points provide accurate estimations of CsA AUC in pediatric patients. The use of these limited sampling models provides the clinical advantage of lower blood sampling requirements and reduced costs associated with the monitoring of cyclosporine.
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Affiliation(s)
- J E Charlebois
- Department of Clinical pharmacy, School of Pharmacy, University of the Pacific, Stockton, California, USA
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33
Abstract
Cyclosporin is an essential component of the antirejection drug protocol used in the long term management of paediatric organ transplant recipients. This article looks at the pharmacokinetics of cyclosporin in paediatric kidney, heart, liver and bone marrow transplant recipients and critically evaluates its relationship to pharmacokinetic data in adult transplant recipients. There are limited data on the pharmacokinetics of cyclosporin in paediatric transplant recipients (14 publications provide the database) as compared with the adult transplant population. Study design, analytical methodology and age ranges of the individuals differ between studies, making comparative interpretation of pharmacokinetic data difficult. However, significant trends are noteworthy and these may influence dose administration guidelines and therapeutic monitoring standards for cyclosporin in the paediatric organ transplant recipient. The bioavailability of the oral formulations of cyclosporin is highly variable as with the adult population, but there appears to be a correlation between cyclosporin bioavailability and age with both the traditional oral formulation (Sandimmun) and the new microemulsion formulation (Neoral) in young liver transplant patients. Bowel length, presystemic metabolism in the gut wall, type of transplant and time since transplant are contributing factors in the variation of bioavailability patterns in paediatric transplant patients. The volume of distribution of cyclosporin does not appear to differ between paediatric and adult transplant recipients, but systemic clearance is comparatively higher in the paediatric population. In general, paediatric patients require higher doses of cyclosporin to achieve target blood concentrations of the drug which are equivalent to the values used in the adult population. Younger patients (less than 8 years of age) may be managed more effectively with a 3 times daily administration schedule rather than the twice daily schedule which is universally used for cyclosporin in the transplant population. The comparatively higher doses and more frequent administration schedule used in paediatric transplant recipients are the consequence of age-related differences in bioavailability and the possibility of increased metabolic clearance of the drug in younger patients.
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Affiliation(s)
- G F Cooney
- Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA.
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34
Zaki I, Emerson R, Allen BR. Treatment of severe atopic dermatitis in childhood with cyclosporin.
Br J Dermatol 1996;
135 Suppl 48:21-4. [PMID:
8881900 DOI:
10.1111/j.1365-2133.1996.tb00705.x]
[Citation(s) in RCA: 50] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Cyclosporin has been shown to be effective in the treatment of adult atopic dermatitis, but there are no clinical trials evaluating its use in childhood. Atopic dermatitis is more common in children and the severe form can be associated with considerable morbidity. We report on 18 children with severe refractory atopic dermatitis who have been treated with cyclosporin on an open basis. The drug was given at an initial daily dose of 5 or 6 mg/kg and in some patients the dose was reduced according to response. Sixteen patients showed a good or excellent response to treatment, one a moderate response and one patient failed to improve. The treatment was well tolerated and there were no significant changes in serum creatinine or blood pressure. Long remission after withdrawal of treatment was seen in some patients, although most relapsed within a few weeks. We suggest that cyclosporin is an effective and safe short-term treatment for severe atopic dermatitis in childhood.
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Affiliation(s)
- I Zaki
- Department of Dermatology, University Hospital, Nottingham, U.K
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35
Mochon M, Cooney G, Lum B, Caputo GC, Dunn S, Goldsmith B, Baluarte HJ, Polinsky MS, Kaiser BA. Pharmacokinetics of cyclosporine after renal transplant in children.
J Clin Pharmacol 1996;
36:580-6. [PMID:
8844439 DOI:
10.1002/j.1552-4604.1996.tb04221.x]
[Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The pharmacokinetics of cyclosporine and the relationship between blood levels and average drug concentration were prospectively evaluated in 18 children 1 month after renal transplantation. All children had normal renal function and no hepatic or gastrointestinal dysfunction. Cyclosporine was administered after an overnight fast, and serial blood samples were drawn over a 24-hour period. Analysis of cyclosporine levels was performed by means of monoclonal radio immunoassay on whole blood. Children were divided into three age groups for comparison: 2-5 years, 5-10 years, and > 10 years. There were no differences between age groups in serum protein, serum lipids, or hemoglobin levels, or in the pharmacokinetic parameters of cyclosporine except as follows: significant differences were noted in cyclosporine dose based on body weight, apparent steady-state volume of distribution, and apparent blood clearance, with the youngest children (2-5) requiring higher doses, a relative greater distribution, and exhibiting more rapid drug clearance than those > 10 years of age. In addition, we observed diurnal variation in trough levels, with morning levels (0 hr) significantly higher than those obtained in the evening (12 hours after administration of cyclosporine). Trough levels demonstrated a fair correlation with area under the concentration-time curve (AUC) and average concentration (Cav), but an abbreviated kinetic profile using cyclosporine levels 1 and 3.5 hours after administration accurately predicted AUC.
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Affiliation(s)
- M Mochon
- Department of Pediatrics, St. Christopher's Hospital for Children, Philadelphia, Pennsylvania 19134, USA
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36
Abstract
There is growing awareness that the underrepresentation of women in clinical trials and in particular in phase I studies may lead to incorrect handling of drugs. Despite the fact that investigations are not informed in a systematic way, there are a number of examples showing pharmacokinetic differences between gender. From the data actually presented, it can be concluded that the activity of CYP 3A4 activity as measured by elimination in vivo is higher in women compared to men. CYP isoenzymes other than CYP 3A4 seem to be more active in men than in woman, as are conjugation reactions, such as glucuronidation. The influence of changing hormonal levels during the lifetime of a woman has been looked at in some drugs but deserves further systematic investigation. The use of oral contraceptives can interfere with the metabolism of many drugs whereas, in pregnancy, the elimination of antiepileptics is increased which, without dose adjustment, leads to an increased number of seizures. The impacts of hormonal replacement therapy (HRT) on the pharmacokinetics of concomitantly given drugs is an important issue, as HRT is increasingly used, but more research is needed in this field.
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Affiliation(s)
- C H Gleiter
- Department of Clinical Pharmacology, University of Göttingen, Germany
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37
Borel JF, Baumann G, Chapman I, Donatsch P, Fahr A, Mueller EA, Vigouret JM. In vivo pharmacological effects of ciclosporin and some analogues.
ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 1996;
35:115-246. [PMID:
8920206 DOI:
10.1016/s1054-3589(08)60276-8]
[Citation(s) in RCA: 95] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- J F Borel
- Sandoz Pharma AG, Preclinical Research Division, Basel Switzerland
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38
González-Manzano R, Cid J, Brugarolas A, Piasecki CC. Cyclosporin A and doxorubicin-ifosfamide in resistant solid tumours: a phase I and an immunological study.
Br J Cancer 1995;
72:1294-9. [PMID:
7577485 PMCID:
PMC2033951 DOI:
10.1038/bjc.1995.503]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
In order to test whether circumvention of clinical resistance can be obtained in common solid tumours by targeting different drug resistance mechanisms, a phase I clinical and immunological study was designed. The purpose of the study was to determine the dose of cyclosporin A (CsA), in combination with doxorubicin (DOX) and ifosfamide (IFX), needed to achieve steady-state whole-blood levels of 2000 ng ml-1 and the associated toxicity of this combination. Treatment consisted of CsA 5 mg kg-1 as a 2 h loading infusion, followed by a CsA 3 day continuous infusion (c.i.) (days 1-3) at doses that were escalated from 10 to 18 mg kg-1 day-1. Chemotherapy consisted of DOX 55 mg m-2 by i.v. 24 h c.i. (day 2) and IFX 2 g m-2 i.v. over 1 h on days 1 and 3. Treatments were repeated every 4 weeks. Eighteen patients with previously treated resistant solid tumours received 39 cycles. Mean steady-state CsA levels > or = 2000 ng ml-1 were reached at 5 mg kg-1 loading dose followed by a 3 day c.i. of 16 mg kg-1 day-1 or greater. Haematological toxicity was greater than expected for the same chemotherapy alone. One patient died of intracranial haemorrhage due to severe thrombopenia. Other observed toxicities were: asymptomatic hyperbilirubinaemia (46% cycles), mild nephrotoxicity (20% cycles), hypomagnesaemia (72% cycles), mild increase in body weight (100% cycles), hypertension (15% cycles) and headache (15% cycles). Overall the toxicity was acceptable and manageable. No alterations in absolute lymphocyte number, the lymphocyte subsets studied (CD3, CD4, CD8, CD19) or CD4/CD8 ratio were observed in patients receiving more than one treatment cycle, although there were significant and non-uniform variations in the values of the different lymphocyte subsets studied when pre- and post-treatment values were compared. There was also a significant increase in the CD4/CD8 ratio. Tumour regressions were observed in two patients (epidermoid carcinoma of the cervix and Ewing's sarcoma). The CsA dose recommended for phase II trials is a 5 mg kg-1 loading dose followed by a 3-day c.i. of 16 mg kg-1 day-1 simultaneously with DOX and IFX at the doses administered in this study.
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Affiliation(s)
- R González-Manzano
- Department of Oncology, Clinica Universitaria of Navarra, Pamplona, Spain
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39
Sketris I, Yatscoff R, Keown P, Canafax DM, First MR, Holt DW, Schroeder TJ, Wright M. Optimizing the use of cyclosporine in renal transplantation.
Clin Biochem 1995;
28:195-211. [PMID:
7554239 DOI:
10.1016/0009-9120(95)91341-y]
[Citation(s) in RCA: 36] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVE
To review the existing data on the use of cyclosporine (CsA) in kidney transplantation, particularly with respect to therapeutic drug monitoring.
DATA SOURCES
A literature search was conducted of applicable articles related to therapeutic drug monitoring of cyclosporine in renal transplantation. Previous consensus guidelines were examined. Discussions on issues related to this topic convened in Toronto, ON, on June 15-16, 1994.
DATA SYNTHESIS
The literature was analyzed to examine patient factors and drug interactions affecting CsA concentrations, the effect of CsA concentrations on patient outcome, current methods of analysis, pharmacodynamic monitoring, and new immunosuppressants.
CONCLUSIONS
CsA has improved the success of kidney transplantation, reducing the incidence and severity of acute rejection and improving short-term patient and graft survival. The rate of graft loss after the first year (primarily due to chronic rejection) has remained largely unchanged. Sandimmune Neoral offers promise due to its better bioavailability and limited dependence on bile flow for absorption. Long-term studies are underway to determine its effectiveness and safety. Indications for therapeutic drug monitoring for CsA are provided.
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Affiliation(s)
- I Sketris
- College of Pharmacy, Dalhousie University, Halifax, NS
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40
Holt DW, Johnston A, Roberts NB, Tredger JM, Trull AK. Methodological and clinical aspects of cyclosporin monitoring: report of the Association of Clinical Biochemists task force.
Ann Clin Biochem 1994;
31 ( Pt 5):420-46. [PMID:
7832569 DOI:
10.1177/000456329403100503]
[Citation(s) in RCA: 52] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- D W Holt
- Analytical Unit, St George's Hospital Medical School, London, UK
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41
Jacqz-Aigrain E, Montes C, Brun P, Loirat C. Cyclosporine pharmacokinetics in nephrotic and kidney-transplanted children.
Eur J Clin Pharmacol 1994;
47:61-5. [PMID:
7988626 DOI:
10.1007/bf00193480]
[Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The pharmacokinetic parameters of cyclosporine (CsA) were determined in 23 kidney transplant recipients and 19 children with nephrotic syndrome, after intravenous and oral administration. The mean bioavailability was 39%, blood clearance was 0.55 l.h-1.kg-1 and volume of distribution at steady-state was 2.77 l.kg-1. The absorption profile was monophasic (67%), biphasic (29%) or poor (4%). The maximum blood concentration of CsA was significantly higher in children with a monophasic profile than in children with a biphasic profile (550 vs 380 ng.ml-1). Blood clearance was significantly higher in the transplant recipients than in the patients with nephrotic syndrome (0.65 vs 0.43 l.h-1.kg-1. Although age, haematocrit, creatinine clearance, serum albumin and cholesterol differed between the two groups, only haematocrit and creatinine clearance were significantly (negatively) correlated with CsA clearance.
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Affiliation(s)
- E Jacqz-Aigrain
- Department of Clinical Pharmacology, Hôpital Robert Debrè, Paris, France
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42
Crocker JF, Renton KW, LeVatte TL, McLellan DH. The interaction of the calcium channel blockers verapamil and nifedipine with cyclosporin A in pediatric renal transplant patients.
Pediatr Nephrol 1994;
8:408-11. [PMID:
7947026 DOI:
10.1007/bf00856514]
[Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The elimination of cyclosporin A was assessed in eight pediatric renal transplant patients who received calcium channel blockers concomitantly with their immunosuppressive therapy. In three children, verapamil decreased the rate of elimination of cyclosporin A. In five children who received nifedipine, cyclosporin A elimination was also impaired, which contrasts with the reports in adult patients indicating that this calcium channel blocker has no effect on cyclosporin A elimination. When both calcium channel blockers were used on separate occasions in the same patient, nifedipine was less potent than verapamil in depressing cyclosporin A elimination. Although the number of subjects studied is small, these results likely indicate that nifedipine, as well as other calcium channel blocking drugs, must be used with caution in pediatric renal transplant patients.
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Affiliation(s)
- J F Crocker
- Department of Pediatrics, Dalhousie University, IWK Hospital, Nova Scotia, Canada
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43
Chan HS, DeBoer G, Thorner PS, Haddad G, Gallie BL, Ling V. Multidrug Resistance: Clinical Opportunities in Diagnosis and Circumvention.
Hematol Oncol Clin North Am 1994. [DOI:
10.1016/s0889-8588(18)30178-3]
[Citation(s) in RCA: 17] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
44
Whipple JK, Lewis KS, Weitman SD, Ausman RK, Bourne DW, Andrews W, Adams MB, Sasse EA, Quebbeman EJ. Pharmacokinetic evaluation of a new oral cyclosporine formulation.
Pharmacotherapy 1994;
14:105-10. [PMID:
8159594 DOI:
10.1002/j.1875-9114.1994.tb02794.x]
[Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
STUDY OBJECTIVE
To compare the pharmacokinetics of a new oral cyclosporine preparation with those of cyclosporine solution diluted in Isocal and the intravenous formulation.
DESIGN
Randomized, crossover trial.
SETTING
Tertiary care referral center.
PATIENTS
Seven pediatric liver transplant recipients who were receiving oral cyclosporine as part of their immunosuppressive regimen. All patients completed the study.
INTERVENTIONS
Pharmacokinetic studies were performed with the intravenous and oral dosage forms. Patients received one dose of intravenous cyclosporine, and then were randomized to receive their usual oral cyclosporine dose incorporated into a chocolate wafer or mixed with Isocal. After a minimum of 3 days, the alternative preparation was administered. Serial cyclosporine blood samples were collected at predetermined intervals for 12 hours after the third dose for each regimen. Concentrations were determined by high-performance liquid chromatography. The data for the three dosage forms were fit simultaneously with a two-compartment model.
MEASUREMENTS AND MAIN RESULTS
No difference was seen in F, ka, Cmax, and tmax between the two oral cyclosporine preparations (p > 0.05). No new rejection episodes occurred during the study period.
CONCLUSIONS
We conclude there is no difference in the bioavailability of the oral solution and the chocolate formulation. We believe the new preparation may increase patient compliance and ensure administration of a complete dose compared with the currently marketed solution.
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Affiliation(s)
- J K Whipple
- Department of General Surgery, Medical College of Wisconsin, Milwaukee 53226
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45
Abstract
Cyclosporin is a powerful immunosuppressive drug used in transplantation medicine and to treat autoimmune diseases. It is a lipophilic molecule, with its bioavailability dependent on food, bile and other interacting factors. Cyclosporin is extensively metabolised in the liver by the cytochrome P450 3A system, which is subject to considerable interindividual variation. Distribution of cyclosporin depends not only on physicochemical characteristics, but also on biological carriers such as lipoproteins and erythrocytes in blood. Cyclophilin, a binding protein for cyclosporin, influences distribution of cyclosporin in the body. Despite its lipophilicity, cyclosporin does not appear in the brain. The distribution of metabolites in the body can differ from that of cyclosporin itself. Elimination of the drug is mainly via the bile as metabolites, other routes not being very important. Pharmacokinetic parameters of cyclosporin are highly variable and depend on factors such as age, the physical condition of the patient, type of organ transplant or comedication. Renal side effects of cyclosporin are dose-related, but the influence of the dosage regimen has not been thoroughly investigated. An important factor in the reported variability is the different analytical methods used. Following the recommendations of recent consensus documents to monitor blood concentrations, this source of variability may diminish in the future. Several metabolites are reported as having less immunosuppressive activity than the parent drug. Metabolites with renal side effects have been reported. These and other effects of metabolites have not been clearly defined in the literature, presumably because of the highly variable activity of cyclosporin-metabolising liver enzymes and the paucity of data available on metabolite pharmacokinetics. The therapeutic range and dosage of cyclosporin are therefore highly dependent on many individual parameters in patients. Dosages of less than 5 mg/kg/day, however, rarely cause renal side effects. Further studies to correlate the clinical pharmacokinetics of metabolites with their activity and adverse effects are needed.
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Affiliation(s)
- A Fahr
- Sandoz Pharma Ltd, Basel, Switzerland
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46
Chan HS, Thorner PS, Haddad G, DeBoer G, Gallie BL, Ling V. Multidrug resistance in cancers of childhood: clinical relevance and circumvention.
ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 1993;
24:157-97. [PMID:
8504063 DOI:
10.1016/s1054-3589(08)60937-0]
[Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Affiliation(s)
- H S Chan
- Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
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47
Bertin L, Rey E, Pons G, Mathiot JL, Richard MO, Chrétien P, Saint-Maurice C, Moran C, Ginisty D, Olive G. Pharmacokinetics of tiaprofenic acid in children after a single oral dose.
Eur J Clin Pharmacol 1991;
41:251-3. [PMID:
1748142 DOI:
10.1007/bf00315438]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Twelve healthy children in three age groups anaesthetized for minor surgery were given a single oral dose of tiaprofenic acid (3 mg.kg-1) (TA). Seven blood samples and zero to 8 and 8 to 24 h urines were collected. TA concentrations in plasma and urine were measured by HPLC. No significant difference was found between the age groups in the kinetic parameters of TA and no correlation was found between these parameters and age: tmax = 2.12 h, Cmax = 8.78 mg.l-1, AUC(0----8 h) 33.9 mg.h.l-1, AUC = 39.3 mg.h.l-1, t1/2 = 2.35 h, Vt = 0.319 l.kg-1, CL = 0.094 l.h-1.kg-1. Renal clearance was 14 ml.h-1.kg-1.33% of the TA dose was recovered in the 24 h urine, 48% of which was conjugated, whereas in adults, TA is only found in urine as conjugates. The apparent plasma clearance was significantly higher (56%) than in 12 healthy adults given 1.5 mg.kg-1 TA. Volume of distribution and t1/2 did not significantly differ between children and adults. Since no relationship has been established between plasma TA and either efficacy or toxicity, a different dose regimen cannot be recommended in 3-11 year-old children from that in adults.
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Affiliation(s)
- L Bertin
- Département de Pharmacologie Clinique Périnatale et Pédiatrique, Hôpital Saint-Vincent de Paul, Paris, France
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48
Hoyer PF, Brodehl J, Ehrich JH, Offner G. Practical aspects in the use of cyclosporin in paediatric nephrology.
Pediatr Nephrol 1991;
5:630-8. [PMID:
1911153 DOI:
10.1007/bf00856658]
[Citation(s) in RCA: 43] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Many factors must be considered for the effective and safe use of cyclosporin A (CsA) in paediatric nephrology. Detailed knowledge of the variable bioavailability, tissue distribution, and metabolism, as well as causes which lead to their alteration are necessary. Factors which affect the activity of the mixed function oxidase system cytochrome P-450 must be considered, i.e. liver dysfunction and many drugs. Precise knowledge of the CsA determination method and the spectrum of metabolites is essential. In children with renal transplants, a body surface area-related dose will better meet the dose requirements than a body weight related-dose. For drug level monitoring whole blood rather than plasma should be used, and the parent drug level should be the main determinant; elevated metabolite levels may be important in suspected nephrotoxicity or liver dysfunction. Pharmacokinetic profiles are necessary to discover absorption problems or increased CsA clearance rates which necessitate shorter dosing intervals. In children with steroid-dependent minimal change nephrotic syndrome, remission without steroids is maintained as long as CsA is given. The appropriate starting dosage is 150 mg/m2 per day; trough level monitoring is mandatory to prevent nephrotoxicity and to confirm adequate immunosuppressive drug levels which should be 80-160 ng/ml (parent drug level). Although the benefit of CsA has been reported in some cases of lupus erythematosus, its use should be restricted to severe cases only until its efficacy and safety has been confirmed in controlled trials.
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Affiliation(s)
- P F Hoyer
- Department of Paediatric Nephrology and Metabolic Diseases, Children's Hospital, Medical School Hannover, Federal Republic of Germany
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49
Hoppu K, Koskimies O, Holmberg C, Hirvisalo EL. Pharmacokinetically determined cyclosporine dosage in young children.
Pediatr Nephrol 1991;
5:1-4. [PMID:
2025515 DOI:
10.1007/bf00852828]
[Citation(s) in RCA: 40] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
To account for the individual variability in cyclosporine pharmacokinetics and the non-existence of dosing recommendations in young children, we studied the pharmacokinetics of cyclosporine before renal transplantation in ten children aged 1.1-2.5 years, to determine the appropriate individual dose. Our aim was to reach a steady-state cyclosporine blood level of 200-300 micrograms/l, 8 h after a dose in the first days after renal transplantation. Cyclosporine was given as a single oral dose (10 mg/kg) or as a 4-h i.v. infusion (3 mg/kg), and the blood concentration was determined for 24 h by a specific monoclonal radioimmunoassay. The mean terminal cyclosporine half-life (t1/2) was 9.3 h (range 2.8-20.4), blood clearance 10.8 ml/min per kilogram (range 6.8-22.7) and volume of distribution 2.8 l/kg (range 1.4-4.7). The bioavailability of oral cyclosporine was low; the mean amount absorbed was 21.8% of the administered dose (range 11-35). The mean calculated dose needed to attain the intended predose blood cyclosporine level of 200-300 micrograms/l at steady-state was 5 mg/kg per day for i.v. and 21 mg/kg per day for oral administration. In view of the short t1/2, we used three doses/day. The validity of the predicted doses is shown by the mean cyclosporine doses used during the first 10 days after transplantation, which were 93.5% of the calculated oral and 96.6% of the calculated i.v. doses. The observed mean cyclosporine concentration during the same period was 196 micrograms/l.
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Affiliation(s)
- K Hoppu
- Children's Hospital, Helsinki, Finland
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50
Affiliation(s)
- S J Phelps
- Department of Clinical Pharmacy, University of Tennessee, Memphis 38163
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