462P - A Population Pharmacokinetic (Pk) Analysis of Palbociclib (Pd-0332991) in Patients (Pts) with Advanced Solid Tumors

Abstract

ABSTRACT Aim: Palbociclib, a selective oral inhibitor of cyclin-dependent kinases 4 and 6, is in phase 2 and 3 clinical trials across multiple oncology indications. Objectives of this analysis were to describe the population PK of palbociclib in cancer pts, identify significant covariates, and provide individual PK predictions. Methods: This analysis was based on pooled data from 183 pts treated with palbociclib isethionate salt capsules in 3 studies. Compartmental PK models were tested with food effect in the base model. Graphic inspection and stepwise covariate modeling were used to assess covariates of interest based on the metabolic mechanism, including demographic factors, laboratory test variables, and concomitant medications. The significant covariates included in the final model were evaluated for clinical importance by calculating the magnitude of effects on PK parameters. Diagnostic plots, visual predictive check (VPC), and standardized VPC were used for model evaluation. Results: Palbociclib PK was best described by a 2-compartment model with 1st order absorption. Population typical values were estimated to be 60.2 L/h for apparent oral clearance (CL/F) and 2710 L for volume of central compartment (V2/F) (inter-patient variability: CL/F, 36.2%; V2/F, 30.2%); the absorption rate constant and absorption lag time were estimated to be 0.367 1/h and 0.658 h, respectively. The relative bioavailability and absorption lag time of palbociclib were increased by 16.0% and 28.8%, respectively, when taken with a high-fat meal versus fasted conditions. Baseline body weight (BWT) and age were significant covariates on CL/F; BWT was a significant covariate on V2/F. However, they were not considered clinically important. Other tested covariates (liver enzymes, creatinine clearance, co-administration of acid-reducing agents) were not significant covariates on relevant PK parameters of palbociclib. Model evaluation showed no bias in model predictions. Conclusions: The population PK model of palbociclib was well defined. Results support the recommendation that no dose adjustment is necessary for age, BWT, sex, pts with mild or moderate renal impairment, or pts with mild hepatic impairment. Disclosure: W. Sun: Employment: Pfizer; D.D. Wang: Employment: Pfizer Stock ownership: Pfizer.