Cabaleiro Teresa, Ochoa Dolores, Román Manuel, Moreno Isabel, López-Rodríguez Rosario, Novalbos Jesús, Abad-Santos Francisco
Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
Basic Clin Pharmacol Toxicol. 2015 Feb;116(2):124-8. doi: 10.1111/bcpt.12286. Epub 2014 Jul 25.
Within-subject coefficient of variation (CVw ) plays a decisive role in the determination of sample size in bioequivalence clinical trials. Highly variable drugs may require the participation of a large number of subjects. The aim of this study was to investigate whether gender and polymorphisms in CYP2D6 affect the CVw of risperidone. Two single-dose, two-period crossover studies of risperidone (n = 70) were reanalysed to calculate CVw for AUCt and Cmax . Subjects were classified into four different CYP2D6 phenotype groups [poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM)]. The effect of gender was evaluated in EM and IM. CVw was lower in PM (13.3% for AUCt and 10.9% for Cmax ) and UM (17.4% and 8.7%) than in EM (28.7% and 34.7%) and IM (33.2% and 27.3%). Variability was slightly lower in women (27.9% for AUCt and 25.7% for Cmax ) than in men (33.3% and 37.2%, respectively). Genetic polymorphisms affect within-subject variability more than gender and could considerably affect sample size calculation. Therefore, subjects participating in bioequivalence trials should be genotyped.
受试者内变异系数（CVw）在生物等效性临床试验的样本量确定中起决定性作用。高变异性药物可能需要大量受试者参与。本研究的目的是调查性别和CYP2D6基因多态性是否会影响利培酮的CVw。对两项利培酮单剂量、两周期交叉研究（n = 70）重新进行分析，以计算AUCt和Cmax的CVw。受试者被分为四个不同的CYP2D6表型组[慢代谢者（PM）、中间代谢者（IM）、快代谢者（EM）和超快代谢者（UM）]。在EM和IM中评估了性别的影响。PM组（AUCt为13.3%，Cmax为10.9%）和UM组（分别为17.4%和8.7%）的CVw低于EM组（分别为28.7%和34.7%）和IM组（分别为33.2%和27.3%）。女性的变异性（AUCt为27.9%，Cmax为25.7%）略低于男性（分别为33.3%和37.2%）。基因多态性对受试者内变异性的影响大于性别，并且可能会显著影响样本量计算。因此，参与生物等效性试验的受试者应进行基因分型。
