title: CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies.
abstract: 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.
authors.affiliation: Seattle Genetics, Inc., Bothell, WA 98021, USA. than@seagen.com
authors.forename: Tae H
authors.initials: TH
authors.lastname: Han
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Gopal
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Ramchandren
authors.forename: Andre
authors.initials: A
authors.lastname: Goy
authors.forename: Robert
authors.initials: R
authors.lastname: Chen
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Matous
authors.forename: Maureen
authors.initials: M
authors.lastname: Cooper
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Grove
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Alley
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Lynch
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000079963:Brentuximab Vedotin; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005243:Feces / Q000737:chemistry; D005260:Female; D019337:Hematologic Neoplasms / Q000378:metabolism*; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000008:administration & dosage / Q000009:adverse effects; D017730:Ki-1 Antigen / Q000276:immunology*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D009842:Oligopeptides / Q000378:metabolism*; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D018796:Immunoconjugates; D017730:Ki-1 Antigen; D009842:Oligopeptides; D000079963:Brentuximab Vedotin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D007654:Ketoconazole; C495575:monomethyl auristatin E; D012293:Rifampin
keywords: biotechnology; clinical pharmacology; clinical trials; drug metabolism; oncology; pharmacokinetics