Williams J Andrew, Johnson Keith, Paulauskis Joseph, Cook Jack
Pfizer Global Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
J Clin Pharmacol. 2006 Mar;46(3):258-64. doi: 10.1177/0091270005283463.
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.
基于当前文献，通过解决研究设计的关键要素，包括每个研究组足够的受试者数量，可以更清晰地界定基因多态性对药代动力学影响的程度。对于CYP2D6和UGT1A1等基因的多态性，存在功能相关性的确凿证据，而关于CYP3A5、OATP1B1和ABCB1类似效应的已发表证据仍在不断涌现或模棱两可。模拟了药代动力学参数中与多态性相关的差异，以纳入（1）纯合野生型受试者与纯合变体的组平均参数值之比，（2）药代动力学变异性，以及（3）假设变异系数为69%时达到80%检验效能所需的样本量。还考虑了根据基因型进行受试者选择和探针底物的选择。纳入模拟结果和文献实例以确定未来研究的关键建议。这将使出版物中关于基因型对药代动力学影响的表述更加明确。
