title: CYP3A5*3 genotype associated with intrasubject pharmacokinetic variation toward tacrolimus in bioequivalence study.
abstract: Tacrolimus is metabolized by CYP3A and has highly variable pharmacokinetics. To study the factors contributing to this high variability in pharmacokinetics and to investigate the possibility of genotype-specific clinical applications, the effect of differing CYP3A5 genotypes on the intrasubject coefficients of variation for tacrolimus was investigated. Genotyping for CYP3A5*3 was performed in healthy volunteers who had previously participated in the pharmacokinetic study of 2 tacrolimus formulations with a 2 x 2 cross-over design. Intrasubject coefficients of variation calculated from analysis of variation in CYP3A5*1/*1+*1/*3 (n = 16) and CYP3A5*3/*3 (n = 13) groups were compared. The intrasubject CVs of AUClast and Cmax in the CYP3A5*3/*3 group were about 41.1% and 52.4% greater than those in the CYP3A5*1*1+*1/*3 group. The estimated total sample size for the bioequivalence study of tacrolimus with a 2 x 2 cross-over design was increased by 93.3% for AUClast (n = 30 versus 58) and 121.4% for Cmax (n = 28 versus 62) in the CYP3A5*3/*3 group compared with the CYP3A5*1/*1+*1/*3 group. The intraindividual variability of tacrolimus PK parameters may be associated with the CYP3A5 genotype. We propose that genotyping for CYP3A5 will provide a more efficient approach for bioequivalence designs and therapeutic drug monitoring.
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Jae
authors.initials: J
authors.lastname: Yong Chung
authors.forename: Yoon
authors.initials: Y
authors.lastname: Jung Lee
authors.forename: Seong
authors.initials: S
authors.lastname: Bok Jang
authors.forename: Lay
authors.initials: L
authors.lastname: Ahyoung Lim
authors.forename: Min
authors.initials: M
authors.lastname: Soo Park
authors.forename: Kyung
authors.initials: K
authors.lastname: Hwan Kim
mesh_terms: D019540:Area Under Curve; D044466:Asian People; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007723:Korea; D008297:Male; D016032:Randomized Controlled Trials as Topic; D016559:Tacrolimus / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus