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.