Drug-drug interaction between trastuzumab emtansine (T-DM1) and orally administered tacrolimus in a patient and in rats

Abstract

We have experienced a 2.3-fold increase in the trough concentration of orally administered tacrolimus in a patient for 7 days after intravenous administration of trastuzumab emtansine (T-DM1), an antibody-drug conjugate. Retrospective clinical study revealed no change in factors known to alter the pharmacokinetics of tacrolimus, and the change in the trough concentration of tacrolimus was reversed after switching T-DM1 to trastuzumab (Tmab). Thus, interaction with T-DM1 was suspected as the cause of the increased trough concentration of tacrolimus. An animal study in rats showed that T-DM1 significantly increased the AUC_0-∞ of orally administered tacrolimus by more than 2-fold on day 0, day 3, and day 7, whereas no change was observed in the case of intravenous administration of tacrolimus. T-DM1 also significantly increased F_a・F_g of tacrolimus by more than 2-fold on day 7. In contrast, Tmab itself had no effect on the blood concentration of tacrolimus. These results suggest that T-DM1 increased the blood concentration of orally administered tacrolimus, and the effect persisted for 1 week after T-DM1 administration. Metabolites of T-DM1 excreted via the biliary route may contribute to the increase in the gastrointestinal absorption of tacrolimus.