In vitro characterization of the drug-drug interaction potential of catabolites of antibody-maytansinoid conjugates.

ABSTRACT

The in vitro characterization of the inhibition potential of four representative maytansinoid species observed upon hepatic and/or tumor in vivo processing of antibody-maytansine conjugates (AMCs) with cleavable and noncleavable linkers is reported. We investigated the free maytansinoid species N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), (S)-methyl-DM1, and N(2')-deacetyl-N(2')-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) as representative cleavable linker catabolites and Lysine-N(ε)-N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate-DM1 (Lys-MCC-DM1) as the representative noncleavable linker catabolite. Studies with recombinant human cytochromes P450 (P450s) indicate CYP2D6, CYP3A4, and CYP3A5 are the primary isoforms responsible for the oxidative metabolism of DM1, (S)-methyl-DM1, and DM4. Lys-MCC-DM1 was not metabolized by any of the P450 isoforms studied. DM1 was shown to be a reversible inhibitor of CYP2C8 (K(i) = 11 ± 3 µM) and CYP2D6 (K(i) = 14 ± 2 µM). Lys-MCC-DM1 and (S)-methyl-DM1 showed no reversible or time-dependent inactivation of any of the P450s studied. DM1 and DM4 inactivated CYP3A from human liver microsomes with K(i)/k(inact) values of 4.8 ± 0.9 µM/0.035 ± 0.002 min(-1) and 3.3 ± 0.2 µM/0.114 ± 0.002 min(-1), respectively. DM1 and DM4 inactivated recombinant CYP3A4 with K(i)/k(inact) values of 3.4 ± 1.0 µM/0.058 ± 0.005 min(-1) and 1.4 ± 0.3 µM/0.117 ± 0.006 min(-1), respectively. Because of instability in plasma, further characterization of the DM1 and DM4 intramolecular and intermolecular disulfide conjugates observed in vivo is required before an accurate drug-drug interaction (DDI) prediction can be made. AMCs with noncleavable thioether-linked DM1 as the cytotoxic agent are predicted to have no potential for a DDI with any of the major human P450s studied.