Assessment of a pharmacokinetic and pharmacodynamic interaction between simvastatin and anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects

摘要

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ? Inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for the treatment of dyslipidaemia, for which hydroxy-3-methylglutaryl coenzyme A reductase inhibitors remain a cornerstone of therapy. ? Clinical studies published to date with other investigational CETP inhibitors, torcetrapib (Pfizer) and dalcetrapib (Roche), have been evaluated in the presence of statins, but it remains unclear whether there is a clinically meaningful interaction between a CETP inhibitor and a statin, and whether the low-density lipoprotein-cholesterol (LDL-C)-lowering effects are additive with the combination. WHAT THIS STUDY ADDS ? This is the first study to show that there is no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin. ? When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C- and apolipoprotein (Apo) B-lowering efficacy, due to CETP inhibition, the magnitude of which appears greater than any combination of CETP inhibitor and statin evaluated to date. ? The study also provides useful insights into the LDL-C- and Apo B-lowering effects when a CETP inhibitor is given in combination with a statin. AIMS Anacetrapib is an orally active, potent inhibitor of cholesteryl ester transfer protein (CETP), which is in development for the treatment of dyslipidaemia. Because of the likely use of anacetrapib with hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, we aimed to evaluate the potential for a pharmacokinetic interaction with simvastatin. METHODS A randomized, two-period, two-treatment, balanced, open-label, crossover study in 12 healthy subjects was performed. Subjects received simvastatin 40 mg alone or anacetrapib 150 mg co-administered with simvastatin 40 mg, once daily. Both treatments were administered following a low-fat breakfast for 14 days, separated by a wash-out period of at least 14 days. Safety and tolerability, simvastatin and simvastatin acid concentrations, and lipoproteins, were assessed. RESULTS Both treatments were well tolerated. The pharmacokinetics of simvastatin and simvastatin acid were similar with and without anacetrapib administration {AUC _{0–24 h} geometric mean ratio [90% confidence interval (CI)] for simvastatin acid and simvastatin were 1.36 [1.17, 1.57] and 1.30 [1.14, 1.47], respectively} based on the prespecified comparability bounds of (0.50, 2.00). Treatment with simvastatin alone led to a mean (95% CI) % reduction from baseline in low-density lipoprotein-cholesterol (LDL-C) of ?36% (?27, ?46) compared with a reduction of ?54% (?44, ?63) for anacetrapib co-administered with simvastatin. CONCLUSIONS There appears to be no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin. When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C-lowering efficacy, due to CETP inhibition. Co-administration of anacetrapib and simvastatin was well tolerated.