Simvastatin Does Not Have a Clinically Significant Pharmacokinetic Interaction With Fenofibrate in Humans

Abstract

Simvastatin and fenofibrate are both commonly used lipid-regulating agents with distinct mechanisms of action, and their coadministration may be an attractive treatment for some patients with dyslipidemia. A 2-period, randomized, open-label, crossover study was conducted in 12 subjects to determine if fenofibrate and simvastatin are subject to a clinically relevant pharmacokinetic interaction at steady state. In treatment A, subjects received an 80-mg simvastatin tablet in the morning for 7 days. In treatment B, subjects received a 160-mg micronized fenofibrate capsule in the morning for 7 days, followed by a 160-mg micronized fenofibrate capsule dosed together with an 80-mg simvastatin tablet on days 8 to 14. Because food increases the bioavailability of fenofibrate, each dose was administered with food to maximize the exposure of fenofibric acid. The steady-state pharmacokinetics (AUC(0-24h), C(max), and t(max)) of active and total HMG-CoA reductase inhibitors, simvastatin acid, and simvastatin were determined following simvastatin administration with and without fenofibrate. Also, fenofibric acid steady-state pharmacokinetics were evaluated with and without simvastatin. The geometric mean ratios (GMRs) for AUC(0-24h) (80 mg simvastatin [SV] + 160 mg fenofibrate)/(80 mg simvastatin alone) and 90% confidence intervals (CIs) were 0.88 (0.80, 0.95) and 0.92 (0.82, 1.03) for active and total HMG-CoA reductase inhibitors. The GMRs and 90% CIs for fenofibric acid (80 mg SV + 160 mg fenofibrate/160 mg fenofibrate alone) AUC(0-24h) and C(max) were 0.95 (0.88, 1.04) and 0.89 (0.77, 1.02), respectively. Because both the active inhibitor and fenofibric acid AUC GMR 90% confidence intervals fell within the prespecified bounds of (0.70, 1.43), no clinically significant pharmacokinetic drug interaction between fenofibrate and simvastatin was concluded in humans. The coadministration of simvastatin and fenofibrate in this study was well tolerated.

The role of fenofibrate in clinical practice

“…[43][44][45] By contrast, co-administration of fenofibrate and a range of commonly prescribed statins does not appear to influence the pharmacokinetics of the statin significantly ( figure 4). [46][47][48][49] These data indicate that fenofibrate would be the preferred fibrate for combination with a statin, a view confirmed by a recent consensus review of fibrate safety. 50 …”

Rac1 Regulation of Surface Expression of Protease-Activated Receptor-1 and Responsiveness to Thrombin in Vascular Smooth Muscle Cells

“…Such effective concentrations are similar to the plasma concentrations of simvastatin after the oral administration. 32 However, application of 1 mol/L simvastatin 10 minutes before and during stimulation with 1 U/mL thrombin had no effect on the thrombin-induced [Ca 2ϩ ] i elevation (data not shown). The similar attenuation of the thrombin-induced [Ca 2ϩ ] i elevation was observed with fluvastatin at a similar concentration range (data not shown).…”

Atorvastatin Glucuronidation Is Minimally and Nonselectively Inhibited by the Fibrates Gemfibrozil, Fenofibrate, and Fenofibric Acid

“…Smaller changes in statin AUC (1.25-to 2-fold) were observed for rosuvastatin (Schneck et al, 2004) and pitavastatin (Mathew et al, 2004). A similar pharmacokinetic interaction has not been observed with fluvastatin (Spence et al, 1995) and, except for a metabolite of pravastatin (Pan et al, 2000), is generally not observed during coadministration of statins with other fibrates (fenofibrate or bezafibrate) (Kyrklund et al, 2001;Martin et al, 2003;Bergman et al, 2004). The relative potential for gemfibrozil to have a pharmacokinetic drug-drug interaction with atorvastatin was, however, until recently, not known (Backman et al, 2005;Whitfield et al, 2005).…”