Population PK/PD modeling picks the 100 mg tablet dose for anacetrapib phase III without a dedicated phase IIb trial to test it (AAPS J 2011)

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.