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) receiveditraconazole, 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 (> or =87%) and most of the total inhibitors (> or =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.
RCT Entities:
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 (> or =87%) and most of the total inhibitors (> or =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.
Authors: Jenni E Keskitalo; Kaisa J Kurkinen; Mikko Neuvonen; Janne T Backman; Pertti J Neuvonen; Mikko Niemi Journal: Br J Clin Pharmacol Date: 2009-08 Impact factor: 4.335
Authors: Helen C Swaisland; Malcolm Ranson; Robert P Smith; Joanna Leadbetter; Alison Laight; David McKillop; Martin J Wild Journal: Clin Pharmacokinet Date: 2005 Impact factor: 6.447
Authors: Steven G Simonson; Paul D Martin; Mike J Warwick; Patrick D Mitchell; Dennis W Schneck Journal: Br J Clin Pharmacol Date: 2004-03 Impact factor: 4.335
Authors: Vincent J C Lempers; Jeroen J M W van den Heuvel; Frans G M Russel; Rob E Aarnoutse; David M Burger; Roger J Brüggemann; Jan B Koenderink Journal: Antimicrob Agents Chemother Date: 2016-05-23 Impact factor: 5.191