Pharmacokinetics of Asciminib 200 mg in the Presence of a Strong CYP3A4 Inducer, Phenytoin, in Healthy Participants.

Abstract

Background and objectives: Asciminib is indicated for the treatment of adult patients with newly diagnosed or previously treated Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) at a total daily dose of 80 mg, as well as adult patients with Ph+ CML with the T315I mutation at 200 mg twice daily. In patients with the T315I mutation, responses have been observed at doses of ≥150 mg twice daily and dose reduction to 160 mg twice daily is permitted for management of adverse reactions. The objective of this study was to assess the effect of strong CYP3A4 induction, through phenytoin, on the pharmacokinetics (PK) of single dose asciminib 200 mg. Coproporphyrin-1 (CP-1) was also measured to evaluate the effect of asciminib 200 mg on organic anion transporting polypeptide 1B (OATP1B).

Methods: This Phase 1 open-label fixed-sequence study evaluated the PK of a single oral dose of asciminib in healthy participants when administered alone and in combination with phenytoin. A single dose of 200 mg asciminib was administered on Day 1, followed by the administration of phenytoin 100 mg three times daily from Day 6 to Day 23, taken 8 h apart to ensure full induction. On Day 20, the morning doses of phenytoin and asciminib were co-administered. Serial blood samples were collected for the assessment of asciminib PK and CP-1 plasma concentrations.

Results: All 15 participants who enrolled were male and 14 received study treatment per protocol. Following co-administration with phenytoin, asciminib-adjusted geometric mean maximum plasma concentration (C_max), area under the curve to the last plasma concentration (AUC_last) and AUC to infinity (AUC_0-inf) were reduced by 22%, 34%, and 34%, with test/reference ratios of 0.780 (90% CI: 0.718-0.847), 0.662 (90% CI: 0.624-0.703), and 0.664 (90% CI: 0.626-0.705), respectively. A single oral dose of asciminib 200 mg did not have a relevant effect on CP-1 plasma exposure.

Conclusions: These data support that, considering its large therapeutic window, asciminib 200 mg twice daily can be used without any dose adjustment when co-administered with a strong CYP3A4 inducer drug. Furthermore, asciminib is not an OATP1B inhibitor up to this dose.