monomethyl-auristatin-e and Chemotherapy-Induced-Febrile-Neutropenia

The efficacy of the CD30-directed antibody-drug conjugate (ADC) brentuximab vedotin was established in combination with chemotherapy as frontline treatment for advanced classical Hodgkin's lymphoma in the randomized phase III ECHELON-1 study. Population pharmacokinetic (PK) and exposure-response models were developed to quantify sources of PK variability and relationships between exposure and safety/efficacy end points in ECHELON-1. The influence of patient-specific factors on the PK of the ADC and the microtubule-disrupting payload monomethyl auristatin E (MMAE) was investigated; none of the significant covariates had a clinically relevant impact. Exposure-response analyses evaluated relationships between time-averaged area under the curve (AUC; ADC, MMAE) and efficacy end points (ADC) or safety parameters (ADC, MMAE). Exposure-efficacy analyses supported consistent treatment benefit with brentuximab vedotin across observed exposure ranges. Exposure-safety analyses supported the recommended brentuximab vedotin starting dose (1.2 mg/kg every 2 weeks), and effective management of peripheral neuropathy and neutropenia with dose modification/reduction and febrile neutropenia with granulocyte colony-stimulating factor primary prophylaxis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Area Under Curve; Brentuximab Vedotin; Chemotherapy-Induced Febrile Neutropenia; Dose-Response Relationship, Drug; Female; Granulocyte Colony-Stimulating Factor; Hodgkin Disease; Humans; Male; Middle Aged; Neutropenia; Oligopeptides; Peripheral Nervous System Diseases; Progression-Free Survival; Young Adult