Model-Based Development of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor

Abstract

Abstract. A model-based strategy was used to inform the early clinical development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor under development for the treatment of hyperlipidemia. The objectives of this model-based approach were to enable bridging variable pharmacokinetic effects, differences among formulations used in development, and to identify an appropriate dose for the phase III confirmatory program. Nonlinear mixed effects PK/PD models were initially developed based on data obtained from multiple phase I studies and later were updated with data from a phase IIb study. The population pharmacokinetic model described differences between the liquid-filled capsule used in phase I and phase IIb and the hot-melt extruded (HME) tablet formulation introduced in phase III, allowing for bridging of the two formulations, and quantified the complex relationship of apparent anacetrapib bioavailability with subject meal intake. Proportional E max models quantified the relationships between anacetrapib trough concentration and lipoprotein effects (LDL-C and HDL-C), with covariate effects of study population (normal volunteers vs. patients), and co-administration with HMG-CoA reductase inhibitor ("statin"). The interaction between anacetrapib and atorvastatin suggested pharmacological independence, i.e., that when given together, each agent exerts the same proportional lipid effect observed from monotherapy. Clinical trial simulation was used to examine the robustness of the effects to random dietary indiscretion, and found that the results were robust as long as patients generally adhered to a low-fat diet. These results allowed the selection of the 100 mg dose with the HME formulation for phase III development even though this dose and formulation were not specifically studied in a phase IIb trial.

Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects

“…The maximum mean percent inhibition of CETP activity was increased with food compared with in the fasted state. These results are consistent with modeling based on the data obtained in Western populations …”

Assessment of the persistence of anacetrapib and evacetrapib concentrations using two pharmacokinetic modeling approaches

“…Models that attempted to estimate all parameters for the 3‐compartment model failed to provide physiologically plausible estimates and did not converge completely, likely due to the limited data available. For this reason, inter‐compartmental clearance for peripheral compartment 1 (Q2/F), CL/F, K a , V/F, and V2/F were fixed to the values published for the 2‐compartment anacetrapib model . Only 3 parameters were estimated: relative bioavailability (F), apparent volume of peripheral compartment 2 (V3/F), and inter‐compartmental clearance for peripheral compartment 2 (Q3/F).…”

“…eBased on estimated parameters using PopPK modeling, where formulation and food were identified as covariates affecting the bioavailability of anacetrapib . The estimated bioavailability of 0.85 in subjects on a low‐fat diet was used in the final model.…”

Current Status of CETP Inhibitors in the Treatment of Hyperlipidemia: An Update

“…Compounds originally described as CETP inhibitors can be differentiated into two subclasses; CETP modulators such as dalcetrapib, and CETP inhibitors exemplified by anacetrapib [41]. The adverse effects observed with torcetrapib have been found to be outside the sphere of lipoprotein metabolism and independent of the CETP lowering effect.…”