Assessment of Transporter‐Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

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 in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation.An in vitro study showed that enasidenib at clinically relevant concentrations has effects on multiple drug metabolic enzymes and transporters, including inhibition of P-glycoprotein, breast cancer resistance protein, organic anion transporter (OAT) P1B1, and OATP1B3 transporters. Therefore, a drug-drug interaction study was conducted to assess the impact of enasidenib at steady state on the pharmacokinetics of several probe compounds in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome, including the probes herein described in this article, digoxin and rosuvastatin. Results from 8 patients (all Asian) with a mean age of 67.1 years showed that following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), digoxin's (0.25 mg) area under the plasma concentration-time curve from time 0 to 30 days was 1.2-fold (90% confidence interval, 0.9-1.6), compared with digoxin alone. Following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), rosuvastatin's (10 mg) area under the plasma concentration-time curve from time 0 to infinity was 3.4-fold (90% confidence interval, 2.6-4.5) compared with rosuvastatin alone. These results should serve as the basis for dose recommendations for drugs that are substrates of P-glycoprotein, breast cancer resistance protein, OATP1B1, and OATP1B3 transporters, when used concomitantly with enasidenib.

Model‐based analysis for the population pharmacokinetics of iberdomide and its major active metabolite in healthy subjects and patients with relapsed and refractory multiple myeloma

“…Of note, a similar observation was seen with lenalidomide, 15 in which higher exposure was observed in MM patients than healthy subjects. Other compounds, including pomalidomide, enasidenib and CC‐122 also exhibited disease specific PK 16–18 …”

“…Other compounds, including pomalidomide, enasidenib and CC-122 also exhibited disease specific PK. [16][17][18] Due to the lack of M12 data in healthy subjects in this analysis, the influence of subject type on metabolite PK (Kpm and CLm) was not assessed.…”

An open‐label, phase 1, randomized, three treatments, three‐period, crossover, relative bioavailability study of CC‐292, a potent and orally available inhibitor of bruton tyrosine kinase

“…Similar as previous study, 16 safety was evaluated throughout the study by the monitoring of adverse events (AEs), electrocardiograms (ECGs), physical examinations (PEs), clinical laboratory tests and pregnancy tests for female subjects, vital signs, and recording of concomitant medications and procedures. All concomitant medications and procedures were reviewed and recorded from the time the subject signs the ICF until study completion.…”

An Updated Overview of the Role of CYP450 during Xenobiotic Metabolization in Regulating the Acute Myeloid Leukemia Microenvironment

“…Enasidenib reduces the oncometabolite 2-hydroxyglutarate by 90.6% [ 250 , 251 , 252 , 253 ]. In vitro research shows that enasidenib inhibits several CYP enzymes and transporters and induces CYP3A4 [ 254 ]. Since enasidenib may induce or inhibit drug-metabolizing enzymes and transporters, the co-administration of enasidenib may increase or reduce the concentrations of combination drugs [ 254 ].…”

“…In vitro research shows that enasidenib inhibits several CYP enzymes and transporters and induces CYP3A4 [ 254 ]. Since enasidenib may induce or inhibit drug-metabolizing enzymes and transporters, the co-administration of enasidenib may increase or reduce the concentrations of combination drugs [ 254 ]. However, among patients with relapsed or refractory acute myeloid leukemia, the overall response rate is approximately 40.3% [ 17 ].…”