Importance of patient selection when determining the significance of the CYP3A5 polymorphism in clinical trials

Foti, R.; Fisher, Megan

doi:10.1038/sj.tpj.6500286

Cited by 5 publications

(3 citation statements)

References 13 publications

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“…It fulfills the patient selection and design criteria proposed for determining the clinical significance of the CYP3A5 polymorphism. 39,40 The first major finding of this investigation was that CYP3A5 genotype and phenotype had no major influence on the plasma concentration-time profile, clearance, and most pharmacokinetic parameters for the CYP3A probe ALF, after i.v. or oral administration.…”

Section: Discussionmentioning

confidence: 92%

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Influence of CYP3A5 Genotype on the Pharmacokinetics and Pharmacodynamics of the Cytochrome P4503A Probes Alfentanil and Midazolam

Kharasch

Walker

Isoherranen

et al. 2007

Clin Pharmacol Ther

101

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The hepatic and first-pass cytochrome P4503A (CYP3A) probe alfentanil (ALF) is also metabolized in vitro by CYP3A5. Human hepatic microsomal ALF metabolism is higher in livers with at least one CYP3A5*1 allele and higher CYP3A5 protein content, compared with CYP3A5*3 homozygotes with little CYP3A5. The influence of CYP3A5 genotype on ALF pharmacokinetics and pharmacodynamics was studied, and compared to midazolam (MDZ), another CYP3A probe. Healthy volunteers (58 men, 41 women) were genotyped for CYP3A5 *1, *3, *6, and *7 alleles. They received intravenous MDZ then ALF, and oral MDZ and ALF the next day. Plasma MDZ and ALF concentrations were determined by mass spectrometry. Dark-adapted pupil diameters were determined coincident with blood sampling. In CYP3A5(*)3/(*)3 (n=62), (*)1/(*)3 (n=28), and (*)1/(*)1 (n=8) genotypes, systemic clearances of ALF were 4.6+/-1.8, 4.8+/-1.7, and 3.9+/-1.7 ml/kg/min and those of MDZ were 7.8+/-2.3, 7.7+/-2.3, and 6.0+/-1.4 ml/kg/min, respectively (not significant), and apparent oral clearances were 11.8+/-7.2, 13.3+/-6.1, and 12.6+/-8.2 ml/kg/min for ALF and 35.2+/-19.0, 36.4+/-15.7, and 29.4+/-9.3 ml/kg/min for MDZ (not significant). Clearances were not different between African Americans (n=25) and Whites (n=68), or between CYP3A5 genotypes within African Americans. ALF pharmacodynamics was not different between CYP3A5 genotypes. There was consistent concordance between ALF and MDZ, in clearances and extraction ratios. Thus, in a relatively large cohort of healthy subjects with constitutive CYP3A activity, CYP3A5 genotype had no effect on the systemic or apparent oral clearances, or pharmacodynamics, of the CYP3A probes ALF and MDZ, despite affecting their hepatic microsomal metabolism.

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Section: Discussionmentioning

confidence: 92%

“…and oral administration. It fulfills the patient selection and design criteria proposed for determining the clinical significance of the CYP3A5 polymorphism 39 , 40 …”

Section: Discussionmentioning

confidence: 99%

Influence of CYP3A5 Genotype on the Pharmacokinetics and Pharmacodynamics of the Cytochrome P4503A Probes Alfentanil and Midazolam

Kharasch

Walker

Isoherranen

et al. 2007

Clin Pharmacol Ther

101

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“…If the genetic variant results in absence of encoded protein, heterozygous subjects may readily demonstrate a phenotype that is measurably different to the phenotype exhibited by homozygous wild types. However, it has been argued that comparison of homozygous wild types and homozygous variants is likely to yield the greatest observed difference in drug exposures 38 . Foti and Fisher presented a valid case for this latter approach to appropriately investigate the influence of CYP3A5 polymorphisms on the pharmacokinetics of CYP3A substrates 38 …”

Section: What Is the Best Way To Design Studies That Ask Whether Polymentioning

confidence: 99%

So Many Studies, Too Few Subjects: Establishing Functional Relevance of Genetic Polymorphisms on Pharmacokinetics

Ja¹,

Johnson²,

Paulauskis³

et al. 2006

The Journal of Clinical Pharma

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Based on current literature, greater clarity in defining the magnitude of polymorphism effects on pharmacokinetics can be achieved by addressing key components of study design, including adequate subject numbers per study group. Convincing evidence of functional relevance exists for polymorphisms in genes such as CYP2D6 and UGT1A1, whereas the published evidence for similar effects for CYP3A5, OATP1B1, and ABCB1 is still emerging or equivocal. Polymorphism-associated differences in pharmacokinetic parameters were simulated to incorporate (1) the ratio of group mean parameter values for homozygous wild-type subjects versus homozygous variants, (2) pharmacokinetic variability, and (3) sample size needed to achieve 80% power, assuming 69% coefficient of variation. Subject selection by genotype and choice of probe substrate are also considered. Simulation results and literature examples are incorporated to define key recommendations for future investigations. This will allow for more definitive statements in publications regarding genotype influence on pharmacokinetics.

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Impact of the CYP3A5 genotype on midazolam pharmacokinetics and pharmacodynamics during intensive care sedation

Fromm

Schwilden

Bachmakov

et al. 2007

Eur J Clin Pharmacol

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Importance of patient selection when determining the significance of the CYP3A5 polymorphism in clinical trials

Cited by 5 publications

References 13 publications

Influence of CYP3A5 Genotype on the Pharmacokinetics and Pharmacodynamics of the Cytochrome P4503A Probes Alfentanil and Midazolam

Influence of CYP3A5 Genotype on the Pharmacokinetics and Pharmacodynamics of the Cytochrome P4503A Probes Alfentanil and Midazolam

So Many Studies, Too Few Subjects: Establishing Functional Relevance of Genetic Polymorphisms on Pharmacokinetics

Impact of the CYP3A5 genotype on midazolam pharmacokinetics and pharmacodynamics during intensive care sedation

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