Effect of itraconazole on the pharmacokinetics of rosuvastatin

• Published in: Clinical pharmacology and therapeutics 2003-04, Vol.73 (4), p.322-329
• Main Authors: Cooper, Kelvin J., Martin, Paul D., Dane, Aaron L., Warwick, Mike J., Schneck, Dennis W., Cantarini, Mireille V.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Area Under Curve; Biological and medical sciences; Cross-Over Studies; Double-Blind Method; Drug Interactions; Fluorobenzenes - blood; Fluorobenzenes - pharmacokinetics; General and cellular metabolism. Vitamins; Half-Life; Humans; Itraconazole - pharmacology; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Pyrimidines; Rosuvastatin Calcium; Sulfonamides
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/S0009-9236(02)17633-8

Background Rosuvastatin is a new 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor. Itraconazole, an inhibitor of cytochrome P450 (CYP) 3A4 and the transport protein P‐glycoprotein, is known to interact with other HMG‐CoA reductase inhibitors. The current trials aimed to examine in vivo the effect of itraconazole on the pharmacokinetics of rosuvastatin. Methods Two randomized, double‐blind, placebo‐controlled, 2‐way crossover trials were performed. Healthy male volunteers (trial A, n = 12; trial B, n = 14) received itraconazole, 200 mg, or placebo once daily for 5 days; on day 4, 10 mg (trial A) or 80 mg (trial B) of rosuvastatin was coadministered. Plasma concentrations of rosuvastatin, rosuvastatin‐lactone (trial A only), and active and total HMG‐CoA reductase inhibitors were measured up to 96 hours after dosing. Results After coadministration with itraconazole, the rosuvastatin geometric least‐square mean for the treatment ratio was increased by 39% for AUC(0‐ct) (area under the rosuvastatin plasma concentration–time curve from time 0 to the last common time at which quantifiable concentrations were obtained for both treatments within a volunteer in trial A) and by 28% for AUC(0‐t) (area under the rosuvastatin plasma concentration–time curve from time 0 to the time of the last quantifiable concentration in trial B), with the treatment ratio for maximum observed plasma drug concentration increased by 36% in trial A and 15% in trial B compared with placebo. For trial A (but not for trial B), the upper boundary of the 90% confidence interval for the treatment ratios fell outside the preset limits (0.7‐1.43). The 95% confidence intervals for all treatment ratios (except maximum observed plasma drug concentration in trial B) did not include 1. These results indicate that itraconazole produces a modest increase in plasma concentrations of rosuvastatin. Rosuvastatin accounted for the majority of the circulating active HMG‐CoA reductase inhibitors (≥87%) and most of the total inhibitors (≥75%). Conclusions Itraconazole produced modest increases in rosuvastatin plasma concentrations, which are unlikely to be of clinical relevance. The results support previous in vitro metabolism findings that CYP3A4 plays a minor role in the limited metabolism of rosuvastatin. Clinical Pharmacology & Therapeutics (2003) 73, 322–329; doi: 10.1016/S0009‐9236(02)17633‐8