Effect of multiple cilostazol doses on single dose lovastatin pharmacokinetics in healthy volunteers

Objective: To assess the effects of cilostazol on lovastatin pharmacokinetics. Design: This was a single-centre, open-label, multiple dose, sequential treatment study. Participants received single oral doses of lovastatin 80mg on days 1, 7 and 9, as well as oral cilostazol 100mg twice daily on days 2 to 8, followed by a single oral 150mg cilostazol dose on day 9. Study Participants: 15 healthy, nonsmoking male or female volunteers (aged 18 to 60 years) were enrolled, and 12 completed the study. Main Outcome Measures: Pharmacokinetic parameters were calculated using plasma concentrations of lovastatin and its beta-hydroxy metabolite and of cilostazol and its metabolites. Differences in the pharmacokinetics of each drug when given alone or in combination were assessed by analysis of variance. Results: The maximum observed plasma concentration (C-max) of lovastatin or its metabolite did not differ significantly when lovastatin was given alone and when it was given with 100mg of cilostazol. The mean ratios of the area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUC(t)) for lovastatin coadministered with 100mg of cilostazol to that with lovastatin given alone were 1.6 for lovastatin and 1.7 for its metabolite. With 150mg of cilostazol, lovastatin Cmax did not change, whereas Cmax of the metabolite increased 2.2-fold. The mean AUC(t) ratios for lovastatin given with 150mg cilostazol/lovastatin given alone were 1.6 and 2.0 for lovastatin and its metabolite, respectively. All increases in lovastatin and metabolite AUC were statistically significant, except for the 1.6-fold increase in lovastatin AUC with 150mg of cilostazol. Maximum steady-state plasma drug concentration (C(ss)max) and AUC during a dosage interval (AUC(tau)) for cilostazol 100mg twice daily decreased 14 and 15%, respectively, upon lovastatin coadministration. Conclusions: Lovastatin and metabolite exposure is increased only by up to 2-fold when cilostazol is coadministered, which is considerably less than that observed for potent CYP3A inhibitors such as itraconazole and grapefruit juice. Absorption of cilostazol decreased approximately 15% when it was given with lovastatin. No dosage adjustments are necessary for cilostazol when coadministered with lovastatin, whereas lovastatin dose reductions may be needed when the 2 drugs are given together.