Gilead Sciences, Inc, Foster City, CA, 2
Gilead Sciences, Inc, Seattle, WABACKGROUND:
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.
|Perpetrator||RTV||RIF SD||RIF MD||MMB||MMB|
|Cmax, ng/mL||123 (96.4, 157)||140 (97.2, 203)||70.6 (52.1, 95.7)||91.8 (78.6, 107)||323 (264, 394)|
|AUC, h·ng/mL||114 (96.1, 134)||157 (122, 202)||53.9 (44.4, 65.5)||83.8 (73.3, 95.9)||273 (222, 334)|
MMB does not undergo CYP3A-mediated interactions, is a victim of potent induction, and is a BCRP-inhibitor.