Prediction of the Effects of Genetic Polymorphism on the Pharmacokinetics of CYP2C9 Substrates from In Vitro Data

Kusama, Makiko; Maeda, Kazuya; Chiba, Koji; Aoyama, Akinori; Sugiyama, Yuichi

doi:10.1007/s11095-008-9781-2

Cited by 38 publications

(40 citation statements)

References 90 publications

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“…It appears that expressed CYP2B6 protein may be superior to HLMs in IVIVE, especially for the prediction in individuals with reduced-function alleles. However, variable successes were obtained using data from expressed cytochrome P450s, e.g., CYP2C9 (Dickinson et al, 2007a;Kusama et al, 2009), CYP2D6 (Dickinson et al, 2007b), and CYP2B6 (Siccardi et al, 2012). Therefore, the selection of a relevant in vitro system may be dependent on the specific cytochrome P450 isoform and variant allele studied.…”

Section: Discussionmentioning

confidence: 99%

CYP2B6 Pharmacogenetics–Based In Vitro–In Vivo Extrapolation of Efavirenz Clearance by Physiologically Based Pharmacokinetic Modeling

Quinney

Guo

et al. 2013

Drug Metab Dispos

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Efavirenz is mainly cleared by CYP2B6. The CYP2B6*6 allele is associated with lower efavirenz clearance. Efavirenz clearance was predictable using in vitro data for carriers of the CYP2B6*1/*1 genotype, but the prediction in carriers of the CYP2B6*6 allele was poor. To test the hypothesis that incorporation of mechanism of reduced efavirenz metabolism by the CYP2B6*6 allele can predict the genetic effect on efavirenz pharmacokinetics, in vitro-in vivo extrapolation of efavirenz clearance was performed by physiologically based pharmacokinetic modeling (Simcyp Simulator; Simcyp Ltd., Sheffield, UK) using data obtained from expressed CYP2B6.1 and CYP2B6.6 as well as human liver microsomes (HLMs) with CYP2B6*1/*1, *1/*6, and *6/*6 genotypes. Simulated pharmacokinetics of a single 600-mg oral dose of efavirenz for individuals with each genotype was compared with data observed in healthy subjects genotyped for the CYP2B6*6 allele (n = 20). Efavirenz clearance for carriers of the CYP2B6*1/*1 genotype was predicted reasonably well using HLM data, but the clearance in carriers of the CYP2B6*6 allele was underpredicted using both expressed and HLM systems. Improved prediction of efavirenz clearance was obtained from expressed CYP2B6 after recalculating intersystem extrapolation factors for CYP2B6.1 and CYP2B6.6 based on in vitro intrinsic clearance of bupropion 4-hydroxylation. These findings suggest that genetic effect on both CYP2B6 protein expression and catalytic efficiency needs to be taken into account for the prediction of pharmacokinetics in individuals carrying the CYP2B6*6/*6 genotype. Expressed CYP2B6 proteins may be a reliable in vitro system to predict effect of the CYP2B6*6 allele on the metabolism of CYP2B6 substrates.

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Section: Discussionmentioning

confidence: 99%

CYP2B6 Pharmacogenetics–Based In Vitro–In Vivo Extrapolation of Efavirenz Clearance by Physiologically Based Pharmacokinetic Modeling

Quinney

Guo

et al. 2013

Drug Metab Dispos

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“…[3][4][5][6][7][8] The presence of polymorphic alleles of CYP2C9 decreases the S-warfarin metabolic rate resulting in increased levels of Swarfarin which in turn leads to lower doses of warfarin required to produce the therapeutic response without any bleeding risk. 6,9,10 The reported studies have demonstrated that VKORC1 and CYP2C9 gene variants together with demographic factors account for 50% to 60% variance in warfarin dose requirement. [10][11][12][13] Different dosing algorithms have been constructed from data including demographic factors along with the frequencies of common CYP2C9 and VKORC1 genotypes in their populations.…”

Section: Introductionmentioning

confidence: 99%

Frequency of Common CYP2C9 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population

Qayyum

Najmi

Mansoor

et al. 2016

Clin Appl Thromb Hemost

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Polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9) gene result in interindividual variability in warfarin dose requirement. There is a need for characterization of genotype frequency distribution in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common CYP2C9 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations. Single blood sample was collected after informed consent. Genomic DNA was extracted, and genotype analysis for CYP2C9*2 and CYP2C9*3 polymorphisms was done by polymerase chain reaction-restriction fragment length polymorphism assay. A number of samples were also analyzed by direct DNA sequencing for validation of the results. Data were analyzed using SPSS version 20. Genotype frequency distribution of CYP2C9*2 and CYP2C9*3 was found to be different from other populations. Of these 2 polymorphisms, CYP2C9*2 did not demonstrate significant effect on warfarin dose requirement, whereas CYP2C9*3 did show significant effect ( P value = .012). It is concluded that there is a need to study genotype frequency distribution and their effect on warfarin dose variability among different populations due to diversity in outcome.

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“…For example, variability imposed by allelic variants of CYP2C9 with decreased catalytic activity can be addressed in both Caucasian and Asian populations based on successful IVIVE (32,176). By linking the PK model that incorporates genetic variability in CYP2C9 to an indirect pharmacodynamic model of the anticoagulant effect of S-warfarin, Dickinson et al (177) were able to assess the power of published pharmacogenetic studies to show differences between the genotypes in both kinetics and clinical response.…”

Section: Prediction Of the Effects Of Geneticsmentioning

confidence: 99%

Physiologically-Based Pharmacokinetics in Drug Development and Regulatory Science

Rowland

Peck

Tucker

2011

Annu. Rev. Pharmacol. Toxicol.

588

442

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The application of physiologically-based pharmacokinetic (PBPK) modeling is coming of age in drug development and regulation, reflecting significant advances over the past 10 years in the predictability of key pharmacokinetic (PK) parameters from human in vitro data and in the availability of dedicated software platforms and associated databases. Specific advances and contemporary challenges with respect to predicting the processes of drug clearance, distribution, and absorption are reviewed, together with the ability to anticipate the quantitative extent of PK-based drug-drug interactions and the impact of age, genetics, disease, and formulation. The value of this capability in selecting and designing appropriate clinical studies, its implications for resource-sparing techniques, and a more holistic view of the application of PK across the preclinical/clinical divide are considered. Finally, some attention is given to the positioning of PBPK within the drug development and approval paradigm and its future application in truly personalized medicine.

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Prediction of the Effects of Genetic Polymorphism on the Pharmacokinetics of CYP2C9 Substrates from In Vitro Data

Abstract: This theoretical method well estimated the quantitative changes in pharmacokinetics of CYP2C9 substrates in subjects with mutated alleles of CYP2C9. This can be applied to drug development even from the early clinical phases.

Cited by 38 publications

References 90 publications

CYP2B6 Pharmacogenetics–Based In Vitro–In Vivo Extrapolation of Efavirenz Clearance by Physiologically Based Pharmacokinetic Modeling

CYP2B6 Pharmacogenetics–Based In Vitro–In Vivo Extrapolation of Efavirenz Clearance by Physiologically Based Pharmacokinetic Modeling

Frequency of Common CYP2C9 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population

Physiologically-Based Pharmacokinetics in Drug Development and Regulatory Science

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