Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites

Abstract

Background: The pharmacokinetic interactions of the widely used statin atorvastatin with fibrates and enzyme inducers are not known. Therefore we studied the effects of rifampin (INN, rifampicin) and gemfibrozil on the pharmacokinetics of atorvastatin.

Methods: Two randomized crossover studies were conducted. In study 1, 10 healthy volunteers took 600 mg rifampin or placebo once daily for 5 days. On day 6, they ingested a single 40-mg dose of atorvastatin. In study 2, 10 healthy volunteers took 600 mg gemfibrozil or placebo twice daily for 5 days. On day 3, they ingested a single 20-mg dose of atorvastatin. Plasma concentrations of atorvastatin (in nanograms per milliliter) and its metabolites (in arbitrary units) were measured by liquid chromatography-tandem mass spectrometry up to 48 to 72 hours after dosing.

Results: Rifampin reduced the total area under the plasma concentration-time curve (AUC) of unchanged atorvastatin (acid) by 80% (95% confidence interval [CI], 73% to 84%; P < .001), that of the active metabolites 2-hydroxyatorvastatin acid by 43% (95% CI, 29% to 51%; P < .001) and 4-hydroxyatorvastatin acid by 81% (95% CI, 74% to 84%; P < .001), and that of their lactones by 93% (95% CI, 90% to 95%), by 61% (95% CI, 50% to 69%), and by 76% (95% CI, 70% to 81%), respectively (P < .001). The peak plasma concentration of 2-hydroxyatorvastatin acid was increased by 68% (95% CI, 21% to 127%; P = .005) by rifampin. Rifampin shortened (P < .001) the half-lives of atorvastatin (by 74%; 95% CI, 67% to 81%) and its metabolites, for example, atorvastatin lactone (by 82%; 95% CI, 80% to 85%) and 2-hydroxyatorvastatin acid (by 70%; 95% CI, 64% to 78%). Gemfibrozil increased the AUC of atorvastatin (by 24%; 95% CI, -1% to 50%; P =.059), 2-hydroxyatorvastatin acid (by 51%; 95% CI, 28% to 70%; P < .001) and its lactone (by 29%; 95% CI, 13% to 53%; P =.003), and 4-hydroxyatorvastatin acid (by 82%; 95% CI, 60% to 126%; P < .001) and its lactone (by 28%; 95% CI, 15% to 51%; P =.001). The half-lives of atorvastatin and its lactone metabolites were slightly shortened by gemfibrozil (P < .05).

Conclusions: Rifampin markedly decreases and gemfibrozil moderately increases the plasma concentrations of atorvastatin and its metabolites. It is advisable to increase the dosage of atorvastatin and preferable to administer it in the evening to guarantee adequate concentrations during the nighttime rapid cholesterol synthesis when rifampin or other potent inducers of cytochrome P450 3A4 are coadministered. Care is warranted, and only low doses of atorvastatin should be used if coadministration with gemfibrozil is needed.