Assessment of a pharmacokinetic and pharmacodynamic interaction between simvastatin and anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.
OBJECTIVE
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.
Krishna
Rajesh
R
Merck & Co., Inc., Whitehouse Station, NJ, USA. rajesh_krishna@merck.com
Garg
Amit
A
Jin
Bo
B
Keshavarz
Sara Sadeghi
SS
Bieberdorf
Frederick A
FA
Chodakewitz
Jeffrey
J
Wagner
John A
JA
D000293:Adolescent; D000328:Adult; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000493:pharmacokinetics*; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019821:Simvastatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult
D053480:Cholesterol Ester Transfer Proteins; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D023303:Oxazolidinones; D019821:Simvastatin; C530884:anacetrapib