Abstract
AIM: Develop a population pharmacokinetic (PopPK) model to characterise the pharmacokinetics (PK) of anti-programmed cell death protein-1 (PD-1) antibody dostarlimab, identify covariates of clinical relevance, and investigate efficacy/safety exposure-response (ER) relationships. METHODS: A PopPK model was developed using Phase 1 GARNET (NCT02715284) trial data for dostarlimab (1, 3 or 10 mg kg(-1) every 2 wk; 500 mg every 3 wk or 1000 mg every 6 wk; 500 mg every 3 wk × 4 then 1000 mg every 6 wk [recommended regimen]) serum concentrations over time. Concentration-time data were analysed using nonlinear mixed effects modelling with standard stepwise covariate modelling. ER was explored for treatment-related adverse events and overall response rate (ORR) using logistic regression. RESULTS: PopPK model/adverse event ER analyses included 546 patients (ORR ER analysis n = 362). Dostarlimab PK was well described by a 2-compartment model with time-dependent linear elimination. Time-dependent clearance decreased over time to a maximum of 14.9%. At steady state, estimated dostarlimab geometric mean coefficient of variation % clearance was 0.179 (30.2%) L d(-1) ; volume of distribution was 5.3 (14.2%) L; terminal elimination half-life was 23.5 (22.4%) days. Statistically significant covariates were age, body weight, sex, time-varying albumin and alanine aminotransferase for clearance; body weight, albumin and sex for volume of distribution of the central compartment. Hepatic or renal impairment did not affect PK. There were no clinically significant ER relationships. CONCLUSION: Dostarlimab PK parameters are similar to other anti-programmed cell death protein-1 antibodies. The clinical impact of covariates on exposure was limited-to-moderate, supporting recommended dostarlimab monotherapy therapeutic dosing.