CYP3A‐Mediated Drug–Drug Interaction Potential and Excretion of Brentuximab Vedotin, an Antibody−Drug Conjugate, in Patients With CD30‐Positive Hematologic Malignancies. (10th June 2013)

• Record Type: Journal Article
• Authors: Han, Tae H.; Gopal, Ajay K.; Ramchandren, Radhakrishnan; Goy, Andre; Chen, Robert; Matous, Jeffrey V.; Cooper, Maureen; Grove, Laurie E.; Alley, Stephen C.; Lynch, Carmel M.; O'Connor, Owen A.
• Is Part Of: Journal of clinical pharmacology. Volume 53:Number 8(2013:Aug.)
• Page Start: 866
• Page End: 877
• Publication Date: 2013-06-10
• Subjects: Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.116
• Languages: English
• ISSNs: 0091-2700

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="jcph116-sec-0001" sec-type="section"> <p>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.</p> </sec> </abstract>