Assessment of Transporter-Mediated Drug Interactions for Enasidenib based on a Cocktail Study in Patients with Relapse or Refractory Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS).

Abstract

As a first-in-class, selective, potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation. An in vitro study showed that enasidenib at clinical relevant concentrations, has effects on multiple drug metabolic enzymes and transporters, including inhibition of P-gp, BCRP, OATP1B1 and OATP1B3 transporters. Therefore, a drug-drug interaction (DDI) study was conducted to assess the impact of enasidenib at steady state on the pharmacokinetics (PK) of several probe compounds in patients with relapsed or refractory AML or myelodysplastic syndrome (MDS), including the probes herein described in this article, digoxin and rosuvastatin. Results from eight patients (all Asian) with a mean age of 67.1 years showed that following co-administration of enasidenib (100 mg, 28-day QD schedule) for 28 days (at steady-state), digoxin (0.25 mg) AUC0-30 was 1.2-fold (90% CI:0.9, 1.6), compared with digoxin alone. Following co-administration of enasidenib (100 mg, 28-day QD schedule) for 28 days (at steady-state), rosuvastatin (10 mg) AUC0-inf was 3.4-fold (90% CI: 2.6, 4.5) compared with rosuvastatin alone. These results should serve as the basis for dose recommendations for drugs which are substrates of P-gp, BCRP, OATP1B1 and OATP1B3 transporters, when used concomitantly with enasidenib. This article is protected by copyright. All rights reserved.