Modelling of Atorvastatin Pharmacokinetics in relation to SLCO1B1 genotype and Simulations for Bioequivalence Study
Jae Yong Chung (1,2), Sung Kweon Cho (1), Eun Sil Oh (2), Kyungsoo Park (1,2), Min Soo Park (2,3)
(1) Dept. of Pharmacology, Yonsei University College of Medicine, Seoul, Korea. (2) Dept. of Clinical Pharmacology, Yonsei University Severance Hospital, Seoul, Korea. (3) Dept. of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
Objectives: The pharmacokinetics of atorvastatin is affected by SLCO1B1 genotype and highly variable. This study aimed to assess atorvastatin pharmacokinetic profile and variability in relation to SLCO1B1 genotype by population pharmacokinetic modelling and to build up a clinical trial simulation approach for optimal bioequivalence (BE) design considering the genotype
Methods: The population pharmacokinetic analysis was performed using NONMEM7 based on plasma samples from a single dose PK with genotyping study in 28 healthy subjects. With the use of a two-compartment model with first order absorption, the influence of SLCO1B1 genotype on absorption rate constant and oral bioavailability was examined. The final pharmacokinetic model was used for clinical trial simulation of bioequivalence study. Simulation scenario consists of varying the sample size from 40 to 64 and variant genotype frequencies from 0 to 100%. Each study was simulated 300 times using TrialSimulator2.2.1 and the percent of successful BE results was calculated as a statistical power.
Results: The SLCO1B1 genotype showed a significant influence on atorvastatin pharmacokinetics. Oral clearance was 23 L/h, volume of distribution of steady-state was 180.5 L, inter-compartmental clearance was 43 L/h, the absorption rate constant was 1.51 h-1 for wild-type and 0.82 for variant-type, and bioavailability was 7.2% for wild-type and 10.9% for variant-type. A large intersubject variability was found to affect atorvastatin absorption (CV 54.7%), and the residual variability was large (CV 48%). An inverse correlation between the percentage of SLCO1B1 variant-type and the success rate (power) of average BE were detected by clinical trial simulation. For achieving 80% power, minimum 46 subjects would be necessary and cut off for variant-type frequency in study population was 10%. For the 90% power, minimum subjects and the cut off were 64 and 30%, respectively.
Conclusions: The SLCO1B1 genotype frequency in study population may influence the success rate of bioequivalence study. Applying genotyping to subject screening could be a valuable option for a more efficient and successful approach to the BE study design of atorvastatin.
References:
[1] Lee YJ, Lee MG, Lim LA, Jang SB, Chung JY. Effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in healthy Korean subjects. Int J Clin Pharmacol Ther. 2010 Jan; 48(1):36-45.
