Optimizing Brentuximab Vedotin Dosing in Pediatric Patients with Advanced Hodgkin Lymphoma: A Population Pharmacokinetic and Exposure-Response Analysis.

Pediatric patients with advanced-stage newly diagnosed Hodgkin lymphoma (HL) were treated with brentuximab vedotin (BV) combined with adriamycin, vinblastine, and dacarbazine (A + AVD). Weight-based BV dosing is employed in adult patients, while both body weight- and body surface area (BSA)-based dosing are used in pediatric patients. Data from two pediatric studies were used for a population pharmacokinetics (PK) analysis. Study 1 was a phase I/II dose-escalation study in which patients with relapsed or refractory systemic anaplastic large-cell lymphoma or HL received single-agent weight-based BV 1.4-1.8 mg/kg every 3 weeks. Study 2 tested BSA-based BV 48 mg/m every 2 weeks with AVD in patients with advanced-stage, newly diagnosed HL. Sources of PK variability were quantified using nonlinear mixed-effects modeling. The relationships between antibody-drug conjugate (ADC) or payload monomethyl auristatin E (MMAE) exposures and progression-free survival (PFS) or incidence of adverse events were analyzed by Cox proportional hazards and logistic regression, respectively. Population PK models of ADC and MMAE were developed using data from 95 patients. BSA was identified as a significant covariate for the clearance of ADC and MMAE. BSA-based BV dosing resulted in similar systemic exposures of ADC and MMAE in pediatric patients across age groups (< 12, 12-16, and > 16 years). A significant increase (P < 0.05) in the incidence of febrile neutropenia was related to increasing exposure of MMAE. No apparent relationship was identified between ADC or MMAE exposures and PFS. The analyses support BSA-based BV dosing in combination with AVD in pediatric patients.