Pharmacokinetics, immunogenicity, and safety of weekly dosing of brentuximab vedotin in pediatric patients with Hodgkin lymphoma

Purpose: Because of the observed success of phase I/II trials, the novel anti-CD30 agent brentuximab vedotin is now being evaluated as a frontline agent in the high-risk pediatric Hodgkin lymphoma trial HLHR13. The objectives of this study were to evaluate the pharmacokinetic variability during weekly dosing of 1.2 mg/kg of brentuximab vedotin, determine factors that may explain this variability, compare our drug exposure with published data, and evaluate toxicity of brentuximab vedotin in the pediatric population. Methods: Brentuximab vedotin, MMAE and anti-therapeutic antibody levels were measured in the serum samples of 16 pediatric patients with Hodgkin lymphoma. A compartmental pharmacokinetic model was fit to the data by using nonlinear mixed-effects modeling. Results: Clearance and volume of brentuximab vedotin were significantly correlated with weight (p < .001), which was responsible for over 60% of the parameters inter-individual variability. Clearance and volume were higher in boys compared to girls (p = 0.08 and p = 0.03, respectively). Brentuximab vedotin’s AUC and C_max were lower in our pediatric study than those reported in adult studies (25 and 11%, respectively). Toxicity was comparable to that of the standard-of-care backbone using vincristine instead of brentuximab vedotin. The sera of all 16 patients remained negative for anti-therapeutic antibodies during and at the end of therapy. Conclusions: As in previous studies, weight continues to be the most significant factor explaining brentuximab vedotin’s pharmacokinetic variability in pediatric patients. Exposure to weekly dosing appears to be safe and tolerable in pediatric patients.