PI-072 - LIKELY INHIBITION OF NON-CYP450 PATHWAYS BY BMS-986196 LEADS TO DOUBLING OF EE EXPOSURE.

V. Goti¹, W. Li¹, H. Ho¹, M. Gleichmann², D. Tatosian³; ¹Bristol Myers Squibb, Princeton, New Jersey, USA, ²Bristol Myers Squibb, San Diego, California, USA, ³Bristol Myers Squibb, Summit, New Jersey, USA.

Background: A cocktail drug-drug interaction (DDI) study (IM038-022) and a combination oral contraceptive (COC) DDI study (IM038-023) were undertaken to evaluate the precipitant effect of BMS-986196 (a Bruton’s tyrosine kinase inhibitor). In the IM038-022 study, a validated cocktail of probe substrates was used to evaluate the DDI with CYP1A2 (caffeine), CYP2C8 (montelukast), CYP2C9 (flurbiprofen), CYP2C19 (omeprazole), CYP3A4 (midazolam), P-gp (digoxin) and OATP1B1 (pravastatin). Ethinyl estradiol (EE) [an estrogen metabolized by CYP3A4, CYP2C9, UGT1A1 and SULT1E1] with norethindrone (NET) [a progression] was the COC used in study IM038-023. In-vitro, BMS-986196 was not an inhibitor of UGT1A1 at 60 QD mg steady-state Cmax.

Methods: Single doses of the cocktail probe substrates and the COC were administered alone and co-administered with 60 mg oral solution of BMS-986196, which was administered QD for 13 days prior to co-administration. Both studies were open-label and conducted in healthy volunteers. Geometric mean ratios (GMRs) [i.e. with/without BMS-986196] of AUCs and Cmax of the cocktail probe substrates and COCs were assessed. The IM038-022 and IM038-023 studies included 18 and 15 subjects for 80% and 96% power, respectively, to demonstrate a no-effect outcome.

Results: In IM038-022, except flurbiprofen, the 90% CIs of GMRs for all other probe substrates were not entirely contained within 0.8-1.25 no-effect limits. The GMRs for AUC(INF) were 1.22 (caffeine), 1.31 (montelukast), 1.2 (flurbiprofen), 1.12 (omeprazole), 1.14 (midazolam), 1.1 (digoxin) and 0.784 (pravastatin) and not considered clinically meaningful. Similar results were obtained for Cmax GMRs, with digoxin Cmax GMR of 1.38 notable due to its narrow therapeutic index. In IM038-023, for NET Cmax only, the 90% CI was slightly outside the 0.8-1.25 limits, and deemed not clinically significant. For EE however, the GMRs for Cmax and AUC(INF) were 2.02 and 2.16 respectively.

Conclusion: Except in terms of P-gp (digoxin Cmax GMR of 1.38), a clinically significant DDI with CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and OATP1B1 is unlikely. The interaction with EE does not appear to be via CYP3A4 or UGT1A1, instead by another pathway potentially including SULT1E1.