Abstract
Patritumab deruxtecan is an antibody-drug conjugate consisting of a fully human monoclonal antibody against human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. As part of the pharmacometric analysis informing dose selection for later-stage development, population pharmacokinetics (PK) analysis of patritumab deruxtecan was conducted with pooled serum PK data from patients with HER3-expressing solid tumors (from 3 phase 1/2 studies in breast, lung, and colorectal cancer; N = 425) treated over the dose range of 1.6 to 8.0 mg/kg intravenously every 3 weeks. Population PK modeling for deruxtecan (DXd)-conjugated antibody (representing patritumab deruxtecan) and unconjugated MAAA-1181a (DXd, payload) was carried out sequentially. DXd-conjugated antibody PK was described using a 2-compartment model with parallel linear and nonlinear clearance. Unconjugated DXd PK was described using a 1-compartment model with linear clearance and release of DXd as a first-order, time-dependent function of the level of DXd-conjugated antibody in the central compartment. Preliminary covariate evaluation was conducted for prespecified covariates of pharmacological plausibility and clinical interest. The final model retained weight (on linear clearance and central volume) and albumin level, sex, and tumor type (on linear clearance) for DXd-conjugated antibody, and weight (on release rate constant) and hepatic function (on clearance) for unconjugated DXd. Effects of these covariates on the exposure metrics were generally mild and did not require dose adjustment for subpopulations in subsequent development. Further PK characterization for patritumab deruxtecan will evolve with emerging data.