INTERETHNIC COMPARISONS OF THE PHARMACOKINETICS OF THE HMG-COA REDUCTASE INHIBITOR CERIVASTATIN

Aims During the world-wide clinical development of the HMG-CoA reducta se inhibitor cerivastatin, pharmacokinetic data have been collected fr om studies performed in Europe, North America and Japan, covering diff erent ethnic groups, mainly Caucasians and Japanese subjects, but also Black and Hispanics. The aim of the present investigation was to sear ch for any inter-ethnic differences in cerivastatin pharmacokinetics. Methods All concentration data were assessed by fully validated specif ic h.p.l.c. assays employing post-column photochemical derivatization with ultra-violet light and subsequent fluorescence detection. The com parability of analytical results was guaranteed by cross-validations b etween all analytical laboratories. The inter-ethnic comparison was ba sed 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 c ytochrome P450-mediated biotransformation products M-1 and M-23, and a mounts of metabolites M-l, M-23 and M-24 excreted in urine were compar able 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 l east-squares (LS) means (95% confidence intervals) between Japanese an d 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,C-dose-norm 0.93 ( 0.83-1.05) for single dose, and 1.01 (0.82-1.25) for multiple dose. Ha lf-life was slightly, but statistically significantly shorter in Japan ese 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 multip le dose. Times to peak tended to be slightly greater in Japanese: diff erences 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. Blac k and Hispanics did not differ in their pharmacokinetic characteristic s from Caucasians. Conclusions Based on inter-study comparisons and a retrospective analysis of the complete PK data pool there is no eviden ce for any clinically relevant inter-ethnic differences in cerivastati n pharmacokinetics in Caucasians, Black and Japanese subjects after or al therapeutic doses.