Inter-ethnic comparisons of the pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin

Aims During the world-wide clinical development of the HMG-CoA reductase inhibitor cerivastatin, pharmacokinetic data have been collected from studies performed in Europe, North America and Japan, covering different ethnic groups, mainly Caucasians and Japanese subjects, but also Black and Hispanics. The aim of the present investigation was to search for any inter-ethnic differences in cerivastatin pharmacokinetics. Methods All concentration data were assessed by fully validated specific h.p.l.c. assays employing post-column photochemical derivatization with ultra-violet light and subsequent fluorescence detection. The comparability of analytical results was guaranteed by cross-validations between all analytical laboratories. The inter-ethnic comparison was based on retrospective analysis of the overall pharmacokinetic data pool (n=340 complete profiles) in the key parameters AUG, C(max) t(max) and t(1/2), assessed via non-compartmental methods. Results Based on the comparison of selected individual single- and multiple-dose escalation studies in healthy young males, performed when starting the clinical development, exposure and disposition of the parent compound and its cytochrome P450-mediated biotransformation products M-1 and M-23, and amounts of metabolites M-l, M-23 and M-24 excreted in urine were comparable for US Americans, mainly Caucasians, and Japanese. Retrospective analysis of the complete pharmacokinetic data pool revealed that there are no statistically significant differences in dose-normalized AUC- and C(max)-values. The respective ratios of weight-adjusted geometric least-squares (LS) means (95% confidence intervals) between Japanese and Caucasians were: for AUC(dose-norm) 0.96 (0.86-1.08) for single dose, and 1.04 (0.86-1.24) for multiple dose; for C(max,dose-norm) 0.93 (0.83-1.05) for single dose, and 1.01 (0.82-1.25) for multiple dose. Half-life was slightly, but statistically significantly shorter in Japanese than in Caucasian subjects following single dose: ratios (95% CI) were 0.68 (0.61-0.77) for single dose, and 1.00 (0.79-1.26) for multiple dose. Times to peak tended to be slightly greater in Japanese: differences of weight-adjusted LS means (95% CI) were 0.60 h (0.28 h-0.92 h) for single dose, and 1.15 h (0.48 h-1.81 h) for multiple dose. Black and Hispanics did not differ in their pharmacokinetic characteristics from Caucasians. Conclusions Based on inter-study comparisons and a retrospective analysis of the complete PK data pool there is no evidence for any clinically relevant inter-ethnic differences in cerivastatin pharmacokinetics in Caucasians, Black and Japanese subjects after oral therapeutic doses.