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Clinical Trial
. 2013 Aug;53(8):866-77.
doi: 10.1002/jcph.116. Epub 2013 Jun 10.

CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies

Tae H Han  1 , Ajay K Gopal, Radhakrishnan Ramchandren, Andre Goy, Robert Chen, Jeffrey V Matous, Maureen Cooper, Laurie E Grove, Stephen C Alley, Carmel M Lynch, Owen A O'Connor
Affiliations
Clinical Trial

CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies

Tae H Han et al. J Clin Pharmacol. 2013 Aug.

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.

Trial registration: ClinicalTrials.gov NCT01026415.

Keywords: biotechnology; clinical pharmacology; clinical trials; drug metabolism; oncology; pharmacokinetics.

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Figures

Figure 1
Figure 1
Study design and patient evaluability.
Figure 2
Figure 2
Effects of brentuximab vedotin on midazolam (A), rifampin on ADC (B), ketoconazole on ADC (C), rifampin on MMAE (D), and ketoconazole on MMAE (E) concentration-time profiles. Data are presented as mean (SD).
Figure 3
Figure 3
Mean (A) and cumulative (B) excretion of MMAE over time.
See this image and copyright information in PMC

References

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