The effect of fluconazole on the pharmacokinetics of rosuvastatin.
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 (AUC(0-t)) and peak plasma concentration (C(max)) 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 AUC(0-t) ranged from 0.59 to 2.23, and for C(max) ranged from 0.52 to 2.28. The limited data available for the N-desmethyl metabolite show that geometric mean C(max) 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 AUC(0-t) and C(max), 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.
Cooper
K J
KJ
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
Martin
P D
PD
Dane
A L
AL
Warwick
M J
MJ
Schneck
D W
DW
Cantarini
M V
MV
D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000097:blood*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides
D000935:Antifungal Agents; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D015725:Fluconazole