PI-037 - AN OPEN-LABEL STUDY TO ASSESS THE EFFECT OF ITRACONAZOLE AND RIFAMPIN ON INCB000928 PHARMACOKINETICS WHEN ADMINISTERED ORALLY IN HEALTHY PARTICIPANTS.

Y. Yang¹, x. gong¹, p. wang², x. liu¹, J. Getsy¹, S. Yeleswaram¹, x. Chen¹, K. Rockich¹; ¹Incyte Corporation, Wilmington, DE, USA, ²Incyte Corporation, Wilmington. DE, USA.

Background: INCB000928 is an oral, potent, and highly selective ALK2 inhibitor being developed for the treatment of fibrodysplasia ossificans progressive patients and anemia in patients with myelofibrosis, myelodysplastic syndromes, and multiple myeloma. Itraconazole is a strong CYP3A inhibitor and rifampin is a strong CYP3A inducer. In vitro studies have indicated INCB000928 as a CYP3A4/5 substrate. This study assesses the effect of multiple doses of itraconazole or rifampin on the single-dose PK of INCB000928 in healthy volunteers.

Methods: This phase 1, open‐label, fixed‐sequence, drug-drug interaction study consists of 2 cohorts. Participants in cohort 1 (N=18) received 100 mg INCB000928 on days 1 and 10, and 200 mg itraconazole once daily on days 6-13. Blood samples were collected on days 1 and 10 up to 240 h post-INCB000928 dose. Participants in cohort 2 (N=18) received 100 mg INCB000928 on days 1 and 13, and 600 mg rifampin once daily on days 6-15. Blood samples were collected on days 1 and 13 up to 120 h post-INCB000928 dose. All PK parameters were estimated using a noncompartmental method.

Results: With the concomitant administration of itraconazole, the geometric mean Cmax and AUC0-inf of INCB000928 increased 1.28- and 2.13-fold, respectively. With the concomitant administration of rifampin, there was a 56% and 79% reduction of the geometric mean of Cmax and AUC0-inf of INCB000928, respectively. INCB000928 alone or in combination with rifampin or itraconazole was generally well tolerated.

Conclusion: Coadministration with itraconazole or rifampin significantly affected the exposure of INCB000928. The coadministration of INCB000928 with a strong or moderate CYP3A4/5 inducer should be avoided, and the dose of INCB000928 needs to be reduced when coadministrated with a strong CYP3A4/5 inhibitor.