Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses*

OBJECTIVES: To study pravastatin and lovastatin pharmacokinetic and pharmacodynamic effects and their interactions with cydosporine (INN, ciclosporin) in kidney transplant patients after single and multiple doses. SUBJECTS AND METHODS: The pharmacokinetic and pharmacodynamic effects of administration of 20 mg/day oral pravastatin and lovastatin for 28 days and their interactions with cyclosporine (2 to 6 mg/kg/day) were studied in a double-blind, double-dummy, randomized, parallel-group multicenter trial in 44 stable kidney graft recipients. RESULTS: The median area under the curve [AUC(0-24)] of pravastatin was 249 microg x hr/L (range, 104 to 1026 microg x hr/L) after a single dose (day 1) and 241 microg x hr/L (114 to 969 microg x hr/L) after multiple doses (day 28) and was fivefold higher than values reported in the absence of cyclosporine. The median AUC(0-24) of lovastatin was 243 microg x hr/L (105 to 858 microg x hr/L) on day 1 and 459 microg x hr/L (140 to 1508 microg x hr/L) on day 28. Besides a significant accumulation during the study period (p < 0.001), the lovastatin AUC(0-24) values were twentyfold higher than values reported without cyclosporine. Coadministration of pravastatin or lovastatin did not alter cyclosporine pharmacokinetics. In this study, 20 mg/day doses of both drugs resulted in a significant improvement of the lipid profile and were well tolerated. CONCLUSIONS: In contrast to lovastatin, pravastatin did not accumulate over the study period, which is probably one of the reasons rhabdomyolysis has been reported in lovastatin-treated but not pravastatin-treated transplant patients receiving cyclosporine immunosuppression.