Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects.
OBJECTIVE
To examine in vivo the effect of ketoconazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.


METHODS
This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 14) received ketoconazole 200 mg or placebo twice daily for 7 days, and rosuvastatin 80 mg was coadministered on day 4 of dosing. Plasma concentrations of rosuvastatin, and active and total HMG-CoA reductase inhibitors were measured up to 96 h postdose.


RESULTS
Following coadministration with ketoconazole, rosuvastatin geometric least square mean AUC(0,t) and Cmax were unchanged compared with placebo (treatment ratios (90% confidence intervals): 1.016 (0.839, 1.230), 0.954 (0.722, 1.260), respectively). Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (> 85%) of the total inhibitors. Ketoconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin.


CONCLUSIONS
Ketoconazole did not produce any change in rosuvastatin pharmacokinetics in healthy subjects. The data suggest that neither cytochrome P450 3A4 nor P-gp-mediated transport contributes to the elimination of rosuvastatin.
Cooper
Kelvin J
KJ
AstraZeneca, Alderley Park, Macclesfield, UK.
Martin
Paul D
PD
Dane
Aaron L
AL
Warwick
Mike J
MJ
Raza
Ali
A
Schneck
Dennis W
DW
D000293:Adolescent; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides
D000935:Antifungal Agents; D005464:Fluorobenzenes; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D007654:Ketoconazole