The effect of fluconazole on the pharmacokinetics of rosuvastatin

Abstract Objective. To examine the effect of fluconazole, a potent inhibitor of CYP2C9 and CYP2C19, on the pharmacokinetics of rosuvastatin in healthy volunteers. Significantly increased plasma concentrations of fluvastatin have been observed following co-administration with fluconazole. Methods. This was a randomised, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n=14) were given fluconazole 200 mg or matching placebo once daily for 11 days; rosuvastatin 80 mg was co-administered on day 8 of dosing. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and active and total 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were measured up to 96 h post-dose. Results. Following co-administration with fluconazole, rosuvastatin geometric least-square mean area under the plasma concentration–time curve (AUC0–t) and peak plasma concentration (Cmax) were increased by 14% and 9%, respectively, compared with placebo (90% confidence intervals for the treatment ratios: 0.967 to 1.341 and 0.874 to 1.355, respectively). Individual treatment ratios for AUC0–t ranged from 0.59 to 2.23, and for Cmax ranged from 0.52 to 2.28. The limited data available for the N-desmethyl metabolite show that geometric mean Cmax was decreased by approximately 25% compared with placebo. Rosuvastatin accounted for essentially all of the circulating active HMG–CoA reductase inhibitors and most (>90%) of the total inhibitors. Fluconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. Conclusions. Fluconazole produced only small increases in rosuvastatin AUC0–t and Cmax, which were not considered to be of clinical relevance. The results support previous in-vitro findings that CYP2C9 and CYP2C19 metabolism is not an important clearance mechanism for rosuvastatin.