PI-042

Y. Xin,1 S. Jun,1 L. Moorehead,2 A. Zari,1 M. Hepner,1 S. Ramanathan1; 1Gilead Sciences, Inc, Foster City, CA, 2Gilead Sciences, Inc, Seattle, WA

BACKGROUND: Momelotinib (MMB) is a selective, small molecule inhibitor of JAK1 and 2, currently being evaluated to treat myelofibrosis. This study evaluated drug-drug interactions (DDI) of MMB.
METHODS: Healthy adults (n=48) were enrolled in four cohorts (12/cohort). As victim, MMB DDI was studied with ritonavir (RTV; strong CYP3A inhibitor) and rifampin single dose (RIF SD; OATP inhibitor) or multiple doses (RIF MD; inducer). As perpetrator, MMB effect on rosuvastatin (ROS; BCRP substrate) and midazolam (MDZ; CYP3A substrate) was evaluated. Safety was monitored throughout the study. Log-transformed AUC and Cmax were developed with parametric analysis of variance using mixed-effects model; geometric mean ratio (90% confidence intervals; GMR [90%CI]) for MMB, MDZ, or ROS were determined for combination vs. alone dosing.
RESULTS: MMB was a BCRP-inhibitor (2.7-fold increase in ROS AUC) and victim of induction (46% decrease in MMB AUC with RIF MD). Effects of RTV on MMB and MMB on MDZ were minor, indicating minimal CYP3A-mediated DDI potential. MMB AUC, as OATP substrate, was 57% higher with RIF SD. Adverse events and laboratory abnormalities were generally Grade 1 in severity.
PerpetratorRTVRIF SDRIF MDMMBMMB
VictimMMBMMBMMBMDZROS
Cmax, ng/mL123 (96.4, 157)140 (97.2, 203)70.6 (52.1, 95.7)91.8 (78.6, 107)323 (264, 394)
AUC, h·ng/mL114 (96.1, 134)157 (122, 202)53.9 (44.4, 65.5)83.8 (73.3, 95.9)273 (222, 334)

CONCLUSION: MMB does not undergo CYP3A-mediated interactions, is a victim of potent induction, and is a BCRP-inhibitor.