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Naidoo P.,University of KwaZulu - Natal | Chetty V.V.,Novartis | Chetty M.,University of KwaZulu - Natal | Chetty M.,Simcyp Ltd A Certara Company
European Journal of Clinical Pharmacology | Year: 2014

Purpose: Differences in drug metabolism due to cytochrome P450 (CYP) polymorphisms may be significant enough to warrant different dosing strategies in carriers of specific cytochrome P450 (CYP) polymorphisms, especially for drugs with a narrow therapeutic index. The impact of such polymorphisms on drug plasma concentrations and the resulting dosing strategies are presented in this review, using the example of efavirenz (EFV). Methods: A structured literature search was performed to extract information pertaining to EFV metabolism and the influence of polymorphisms of CYP2B6, ethnicity, sex and drug interactions on plasma concentrations of EFV. The corresponding dosing strategies developed for carriers of specific CYP2B6 genotypes were also reviewed. Results: The polymorphic CYP2B6 enzyme, which is the major enzyme in the EFV metabolic pathway, is a key determinant for the significant inter-individual differences seen in EFV pharmacokinetics and pharmacodynamics (PKPD). Ethnic differences and the associated prevalence of CYP2B6 polymorphisms result in significant differences in the PKPD associated with a standard 600 mg per day dose of EFV, warranting dosage reduction in carriers of specific CYP2B6 polymorphisms. Drug interactions and auto-induction also influence EFV PKPD significantly. Conclusion: Using EFV as an example of a drug with a narrow therapeutic index and a high inter-patient variability in plasma concentrations corresponding to a standard dose of the drug, this review demonstrates how genotyping of the primary metabolising enzyme can be useful for appropriate dosage adjustments in individuals. However, other variables such as drug interactions and auto-induction may necessitate plasma concentration measurements as well, prior to personalising the dose. © 2014 Springer-Verlag. Source


Glinka A.,Jagiellonian University | Polak S.,Jagiellonian University | Polak S.,Simcyp Ltd A Certara Company
Computers in Biology and Medicine | Year: 2014

Background: Many drugs (belonging to different chemical groups) have the potential for QT interval prolongation associated with ionic channel blockade in the cardiomyocyte membrane. Due to the fact that this phenomenon is linked to a higher risk of TdP, the ability to predict its scale is one of the most important outcomes of cardiotoxicity assessment of new agents. Methods: With use of the Cardiac Safety Simulator (CSS), the effect of six antipsychotic drugs was predicted in silico. Separate simulations were carried out for each studied population taking the drug. The aim of this study was to predict both the mean values of delta QTc and the results range. To be able to observe individual variability after drug administration, each patient was randomly assigned to the individual drug concentration. Also, appropriate diversity in heart rate, plasma electrolytes concentrations, morphometric parameters of ventricular myocytes, and one common hERG polymorphism frequency in population were added. Results: Analyzing the results of simulation with Student[U+05F3]s t-test, in five of six cases, there were no statistically significant differences between observed and predicted mean values. The diversity of results in all populations studied, however, was not fully reconstructed. Discussion: The model was able to accurately reproduce the average effect of the drug on the length when the phenomenon is associated purely with blocking of ionic channels. Nevertheless, the problem of variability in the population and its effect on the QT interval requires further study. © 2014. Source


Rostami-Hodjegan A.,University of Manchester | Rostami-Hodjegan A.,Simcyp Ltd A Certara Company
Clinical Pharmacology and Therapeutics | Year: 2012

Classic pharmacokinetics (PK) rarely takes into account the full knowledge of physiology and biology of the human body. However, physiologically based PK (PBPK) is built mainly from drug-independent "system" information. PBPK is not a new concept, but it has shown a very rapid rise in recent years. This has been attributed to a greater connectivity to in vitro-in vivo extrapolation (IVIVE) techniques for predicting drug absorption, distribution, metabolism, and excretion (ADME) and their variability in humans. The marriage between PBPK and IVIVE under the overarching umbrella of "systems biology" has removed many constraints related to cutoff approaches on prediction of ADME. PBPK-IVIVE linked models have repeatedly shown their value in guiding decisions when predicting the effects of intrinsic and extrinsic factors on PK of drugs. A review of the achievements and shortcomings of the models might suggest better strategies in extending the success of PBPK-IVIVE to pharmacodynamics (PD) and drug safety. Source


Badee J.,University of Manchester | Achour B.,University of Manchester | Rostami-Hodjegan A.,University of Manchester | Rostami-Hodjegan A.,Simcyp Ltd A Certara Company | Galetin A.,University of Manchester
Drug Metabolism and Disposition | Year: 2015

Organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 transporters play an important role in hepatic drug disposition. Recently, an increasing number of studies have reported proteomic expression data for OATP transporters. However, systematic analysis and understanding of the actual differences in OATP expression between liver tissue and commonly used cellular systems is lacking. In the current study, meta-analysis was performed to assess the protein expression of OATP transporters reported in hepatocytes relative to liver tissue and to identify any potential correlations in transporter expression levels in the same individual. OATP1B1 was identified as the most abundant uptake transporter at 5.9 ± 8.3, 5.8 ± 3.3, and 4.2 ± 1.7 fmol/μg protein in liver tissue, sandwich-cultured human hepatocytes (SCHH), and cryopreserved suspended hepatocytes, respectively. The rank order in average expression in liver tissue and cellular systems was OATP1B1 > OATP1B3 ≈ OATP2B1. Abundance levels of the OATP transporters investigated were not significantly different between liver and cellular systems, with the exception of OATP2B1 expression in SCHH relative to liver tissue. Analysis of OATP1B1, OATP1B3, and OATP2B1 liver expression data in the same individuals (n = 86) identified weak (OATP1B1-OATP2B1) to moderately (OATP1B3-OATP2B1) significant correlations. A significant weak correlation was noted between OATP1B1 abundance and age of human donors, whereas expression of the OATPs investigated was independent of sex. Implications of the current analysis on the in vitro-in vivo extrapolation of transporter-mediated drug disposition using physiologically based pharmacokinetic models are discussed. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. Source


Abduljalil K.,Simcyp Ltd A Certara Company | Jamei M.,Simcyp Ltd A Certara Company | Rostami-Hodjegan A.,Simcyp Ltd A Certara Company | Rostami-Hodjegan A.,University of Manchester | Johnson T.N.,Simcyp Ltd A Certara Company
AAPS Journal | Year: 2014

Although both POPPK and physiologically based pharmacokinetic (PBPK) models can account for age and other covariates within a paediatric population, they generally do not account for real-time growth and maturation of the individuals through the time course of drug exposure; this may be significant in prolonged neonatal studies. The major objective of this study was to introduce age progression into a paediatric PBPK model, to allow for continuous updating of anatomical, physiological and biological processes in each individual subject over time. The Simcyp paediatric PBPK model simulator system parameters were reanalysed to assess the impact of re-defining the individual over the study period. A schedule for re-defining parameters within the Simcyp paediatric simulator, for each subject, over a prolonged study period, was devised to allow seamless prediction of pharmacokinetics (PK). The model was applied to predict concentration-time data from multiday studies on sildenafil and phenytoin performed in neonates. Among PBPK system parameters, CYP3A4 abundance was one of the fastest changing covariates and a 1-h re-sampling schedule was needed for babies below age 3.5 days in order to seamlessly predict PK (<5% change in abundance) with subject maturation. The re-sampling frequency decreased as age increased, reaching biweekly by 6 months of age. The PK of both sildenafil and phenytoin were predicted better at the end of a prolonged study period using the time varying vs fixed PBPK models. Paediatric PBPK models which account for time-varying system parameters during prolonged studies may provide more mechanistic PK predictions in neonates and infants. © 2014 American Association of Pharmaceutical Scientists. Source

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