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.

Absorption, Distribution, Metabolism, and Excretion Considerations for the Development of Antibody-Drug Conjugates

“…In turn, those transporters may increase or reduce the intracellular concentration of a small-molecule drug in tumors and/or normal tissues (Chu et al, 2013). Strategies have been developed to reduce the liabilities associated with upregulation of P-glycoprotein and other potential transporters in tumor cells (Kovtun et al, 2010;Kung Sutherland et al, 2013) This may affect the small molecule PK (Han et al, 2013a) as well as the antitumor effect (Naito et al, 2000;Jager et al, 2011). Both MMAE and mertansine (DM1), two lead drugs used in ADCs, have been implicated as a substrate of P-glycoprotein (Seattle Genetics, 2011;CDER, 2013).…”

“…The metabolism of other maytanisinoid-containing catabolites released from ADCs with different drug-linkers were also studied and reviewed (Sun et al, 2011;Davis et al, 2012;Erickson and Lambert, 2012). After administration of brentuximab vedotin in patients, MMAE was the only released drug identified in plasma with peak concentrations in the low nanomolar range (CDER, 2011;Han et al, 2013a). In vitro data indicate that MMAE is both a substrate and inhibitor of CYP3A.…”

“…On the other hand, the DDI potential of the unconjugated small-molecule drugs as an inhibitor appear to be small as the inhibitory K i values estimated from the in vitro assays are typically in the micromolar range (Davis et al, 2012;Han et al, 2013a), several log orders greater than those observed circulating drug levels. However, due to the dmd.aspetjournals.org mechanism of ADC internalization and intracellular release of the drug, it is possible that the intracellular drug levels in the liver could be higher than those in plasma.…”

“…About 80% of radioactivity was recovered in the feces, and 50% was recovered in the bile (Shen et al, 2012a). A clinical excretion study of brentuximab vedotin showed that over a 1-week period the primary excretion route of MMAE was via feces, which accounted for approximately 72% of the recovered MMAE, with the remaining MMAE recovered in urine (Han et al, 2013a). These data suggest that for unconjugated DM1 and MMAE the liver is the major elimination organ and that ADCs conjugated to these drug species should be considered for the evaluation of the relationship of hepatic function and drug exposure during clinical development.…”

“…The unconjugated drugs are potent cytotoxins and are often the substrate or inhibitor of P450 enzymes. In the case of brentuximab vedotin, a dedicated clinical DDI study was conducted to evaluate the effect of a strong CYP3A inhibitor, ketoconazole, and an inducer, rifampin, on MMAE exposure and the effect of MMAE on the exposure of a CYP3A substrate, midazolam (Han et al, 2013a). Brentuximab vedotin did not affect midazolam exposures, and the ADC exposures were unaffected by concomitant rifampin or ketoconazole; however, the unconjugated MMAE exposures were 31-46% lower with rifampin and 34-73% higher with ketoconazole.…”