Development and application of a mechanistic population modeling approach to describe abemaciclib pharmacokinetics.

Abemaciclib is an oral anticancer drug that inhibits cyclin dependent kinases (CDKs) 4 and 6, and is metabolized by cytochrome P450 3A in the intestines and liver to active metabolites. The objectives were (1) to develop a mechanistic model to characterize the pharmacokinetics (PK) of the active moieties and investigate the effect of patient factors, and (2) apply the model to data from two Phase 3 breast cancer trials of abemaciclib in combination with endocrine therapy. To develop the model, data from seven Phase 1 studies and two Phase 2 studies including 421 patients with cancer and 65 healthy individuals were pooled for nonlinear mixed-effects modeling. The PK was similar between patients and healthy subjects, and the effects of diarrhea, formulation, race and patient covariates on exposure was negligible. Application of the model confirmed its predictive performance and that abemaciclib PK did not change when co-administered with endocrine therapy.