This analysis described the population pharmacokinetics (popPK) of TALA in cancer patients to identify significant covariates, evaluate the PK comparability of 4 x 0.25 mg capsules and 1 x 1 mg capsule as a 1 mg dose, and provide individual PK predictions for PK/pharmacodynamic analysis.
The data used for the analysis included 6207 PK observations from 490 patients treated with TALA in 4 studies (PRP-001, PRP-002, ABRAZO, and EMBRACA); the detailed PK data will be disclosed in the poster. TALA concentration-time data were analyzed by using a nonlinear mixed-effects modeling approach with NONMEM. Inclusion of covariates was conducted by visual inspection of ETAs vs covariates of interest followed by statistical test (stepwise covariate modeling).
A 2-compartment model with 1st-order absorption best described the PK of TALA. The estimated population-typical value for apparent oral clearance (CL/F) was 6.37 L/h, apparent volume of central compartment (V2/F) 162 L, and absorption rate constant (ka) 1.22 1/hour. While food and formulation were significant covariates on ka, they had no impact on bioavailability (F). Coadministration with strong P-gp inhibitors increased the relative bioavailability by 44.7%. Baseline creatinine clearance was significant for CL/F with a 14.4% and 37.1% decrease in CL/F for patients with mild and moderate renal impairment, respectively. Asian (23.7% higher CL/F), age (on CL/F), and baseline body weight (BWT) (on V2/F) are significant covariates but not considered clinically relevant. Other covariates tested (sex, liver enzymes, acid-reducing agents) were not significant on relevant PK parameters.
The population PK model adequately described the observed PK data of TALA. Results suggest that no dose adjustment is necessary based on a patient’s age, BWT, race, or sex or for patients with mild renal or hepatic impairment or for patients taking acid-reducing agents. TALA can be taken without regard of food. The PK of 1 x 1 mg capsule and 4 x 0.25 mg capsules as 1 mg dose was comparable. The dose of TALA should be reduced to 0.75 mg for patients taking strong P-gp inhibitors or for patients with moderate renal impairment.
Clinical trial identification
NCT01945775, NCT02034916, NCT01286987, NCT01399840.
Legal entity responsible for the study
Editorial and medical writing support funded by Pfizer Inc. were provided by Edwin Thrower, PhD, Mary Kacillas and Paula Stuckart of Ashfield Healthcare Communications, Middletown, Connecticut.
Y. Yu, C. Durairaj, H. Shi, D.D. Wang: Employee: Pfizer, Inc.