monomethyl-auristatin-e and Hematologic-Neoplasms

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Brentuximab Vedotin; Child; Female; Hematologic Neoplasms; Humans; Immunoconjugates; Ki-1 Antigen; Male; Middle Aged; Models, Biological; Oligopeptides; Young Adult

Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E (MMAE) into CD30-expressing cells. This study evaluated the CYP3A-mediated drug-drug interaction potential of brentuximab vedotin and the excretion of MMAE. Two 21-day cycles of brentuximab vedotin (1.2 or 1.8 mg/kg intravenously) were administered to 56 patients with CD30-positive hematologic malignancies. Each patient also received either a sensitive CYP3A substrate (midazolam), an effective inducer (rifampin), or a strong inhibitor (ketoconazole). Brentuximab vedotin did not affect midazolam exposures. ADC exposures were unaffected by concomitant rifampin or ketoconazole; however, MMAE exposures were lower with rifampin and higher with ketoconazole. The short-term safety profile of brentuximab vedotin in this study was generally consistent with historic clinical observations. The most common adverse events were nausea, fatigue, diarrhea, headache, pyrexia, and neutropenia. Over a 1-week period, ∼23.5% of intact MMAE was recovered after administration of brentuximab vedotin; all other species were below the limit of quantitation. The primary excretion route is via feces (median 72% of the recovered MMAE). These results suggest that brentuximab vedotin (1.8 mg/kg) and MMAE are neither inhibitors nor inducers of CYP3A; however, MMAE is a substrate of CYP3A.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Brentuximab Vedotin; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Feces; Female; Hematologic Neoplasms; Humans; Immunoconjugates; Ketoconazole; Ki-1 Antigen; Male; Midazolam; Middle Aged; Oligopeptides; Rifampin; Young Adult