Background: To improve the success of treatment for Hodgkin Lymphoma (HL) the novel agent brentuximab vedotin (anti-CD30 agent) was developed as CD30 is highly expressed in both HL and anaplastic large cell lymphoma. Based off the success of phase 1 and II trials it is now used as a frontline agent in a high-risk pediatric HL trial HLHR13.
Purpose: The primary goal of this study was to evaluate the variability of pharmacokinetics for weekly dosing of 1.2 mg/kg of brentuximab vedotin, determine factors that may explain this variability, compare our drug exposure with published data for the recommended 1.8 mg/kg every 3 week dosing and evaluate toxicity with this novel agent in the pediatric population.
Methods: Serum samples for brentuximab vedotin levels were collected at day 1 pre and post infusion, 48 hours and day 8 pre-infusion for 16 patients. A compartmental pharmacokinetic model was fit to the data using non-linear mixed effects modeling methods. Serum concentration of anti-therapeutic antibody was measured prior to the first 3 courses and at the end of therapy.
Results: Brentuximab vedotin and MMAE clearance and volume were significantly correlated with weight (p<1e-10) and accounting for weight explained 75%, 84%, 61%, and 94% of the inter-individual variability in the ADC clearance, ADC volume, MMAE apparent clearance, and MMAE apparent volume respectively. The ADC clearance and volume differed by gender; clearance and volume were higher in male vs female patients (17%; p=0.08, and 17%; p=0.03, respectively) and explained an additional 11% and 36% of the inter-individual variability in the ADC clearance and volume respectively compared to the weight-normalized model. The ADC AUC and Cmax in our pediatric study were lower compared to those reported in adult studies (25% and 11%, respectively at 1.2 mg/kg and 35% and 16%, respectively at 1.8 mg/kg). Toxicity was comparable to that published for the standard of care backbone. All 16 patients remained negative for anti-therapeutic antibodies during and at the end of therapy.
Conclusion: As in previous studies, weight continues to be the most significant factor explaining brentuximab vedotin pharmacokinetic variability in pediatric patients. Exposure with weekly dosing appeared safe and tolerable in pediatric patients. Given the promising clinical results of brentuximab vedotin, more studies are warranted to demonstrate safety and allow for increased use in the pediatric population.