Time‐varying brentuximab vedotin pharmacokinetics and weight‐based dosing in paediatric patients despite lower exposure in those aged 2 to <6 and 6–11 years

Abstract

AimsWe studied the pharmacokinetics and exposure–response relationships of the brentuximab vedotin (BV) antibody–drug conjugate (ADC) and unconjugated monomethyl auristatin E in haematologic malignancies.MethodsThis population pharmacokinetic analysis included data from five adult and three paediatric studies. Exposures in virtual adult and paediatric populations following BV 1.8 mg/kg (maximum 180 mg) intravenously every 3 weeks were simulated. Clinical endpoints included overall response rate, grade ≥2 peripheral neuropathy (PN) and grade ≥3 neutropenia.ResultsBV ADC exhibited linear pharmacokinetics, well‐described by a three‐compartment model, with body weight being the only significant covariate for exposure. Monomethyl auristatin E exhibited time‐varying formation rate. Simulated steady‐state BV ADC exposures in patients aged 12 to <18 years were similar to those of adult patients, but 23%–38% lower in patients aged 2 to <12 years. Despite lower exposure, clinical activity was observed with BV 1.8 mg/kg every 3 weeks in those aged 2 to <12 years (overall response rate: 2 to <12 years, 60%; 12 to <18 years, 43%). In adult, but not paediatric patients, increased BV ADC exposures were associated with grade ≥2 PN and grade ≥3 neutropenia occurrence.ConclusionsBV pharmacokinetics in adult and paediatric patients were consistent. BV ADC exposures were lower in patients aged 2 to <12 years vs. ≥12 years, but no apparent clinically relevant differences in efficacy, grade ≥2 PN or grade ≥3 neutropenia were observed. These data support body weight‐based dosing of BV in patients irrespective of age; thus, dose adjustment in those 2 to <12 years does not appear warranted.