Rationale for Fixed Dosing of Pertuzumab in Cancer Patients Based on Population Pharmacokinetic Analysis

Objective. Our objectives were to develop the population pharmacokinetic (PK) for pertuzumab and examine the variability of steady-state trough serum concentrations (CSS,trough) and exposure after fixed, body-weight-based, or body-surface area (BSA)-based dosing methods in cancer patients. Methods. Pertuzumab was administered by IV infusion (every 3 weeks) either as a weight-based dose (0.5Y15 mg/kg) or a fixed dose (420 or 1050 mg). Data from three clinical studies, comprising 153 patients and 1458 concentration-time points, were pooled for this analysis using NONMEM. Results. A linear two-compartment model best described the data. Body weight and BSA were significant covariates affecting clearance (CL) and distribution volume (Vc), respectively. However, weight and BSA only explained small percentage of interpatient variability for CL and Vc, respectively. Simulation results indicated that PK profiles were very similar after the three dosing methods. Compared to fixed dosing, weight- and BSA-based dosing only reduced the population variability of