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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. Whereas several studies have described the effects of the CETP inhibitors, torcetrapib (Pfizer) and dalcetrapib (Roche), on lipids and lipoproteins, few studies have characterized the effect of rising single doses on the pharmacokinetics and pharmacodynamics (CETP activity) of an individual CETP inhibitor or have described the effects of intrinsic and extrinsic factors on the pharmacokinetics and pharmacodynamics of these agents. WHAT THIS STUDY ADDS • We have characterized the exposure/response relationship for the inhibition of CETP activity over a wide exposure range. We have shown that single doses of anacetrapib produced marked and dose-dependent inhibition of serum CETP activity with peak effects of ∼90% inhibition at tmax and persistent inhibition at 24 h post-dose. We have also shown that whereas food increased exposures to anacetrapib significantly and variably, age, gender and obese status did not meaningfully influence the pharmacokinetics and pharmacodynamics of anacetrapib. AIMS Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. METHODS Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. RESULTS Anacetrapib was rapidly absorbed, with peak concentrations occurring at ∼4 h post-dose and an apparent terminal half-life ranging from ∼9 to 62 h in the fasted state and from ∼42 to ∼83 h in the fed state. Plasma AUC and Cmax appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of ∼90% inhibition at tmax and ∼58% inhibition at 24 h post-dose. An Emax model best described the plasma anacetrapib concentration vs CETP activity relationship with an E C50 of ∼22 nm. Food increased exposure to anacetrapib; up to ∼two–three-fold with a low-fat meal and by up to ∼six–eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. CONCLUSIONS Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics. [ABSTRACT FROM AUTHOR]

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 {AUC0–24 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. [ABSTRACT FROM AUTHOR]

In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probeinhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC[sub0-∞] and C[submax] were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole - specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/ anacetrapib alone for AUC[sub0-∞] and C[submax] were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A. [ABSTRACT FROM AUTHOR]