PII-027 - FORMULATION IMPACT OF SSZ ON MTX EXPOSURE: A REPEAT DDI STUDY FOR A MK2 INHIBITOR BMS-986371

M. Chen¹, A. Paris¹, Y. Xu¹, T. Mitchell¹, D. Beyer¹, J. Chen¹, C. Tang², G. Tirucherai³, H. Wardell⁴, B. Murthy¹; ¹Bristol Myers Squibb, ²Takeda, ³Scholar Rock, ⁴Fortrea.

Background: BMS-986371 is a covalent inhibitor of mitogen-activated protein kinase-activated protein kinase 2, and an inhibitor of the breast cancer resistance protein, for which methotrexate (MTX) and sulfasalazine (SSZ) are reported as substrates. A repeat drug-drug interaction (DDI) study was designed to evaluate the impact of BMS-986371 on MTX exposure, with or without immediate release (IR) or enteric coated (EC) SSZ, due to unexpected low MTX exposure observed when co-administered with IR SSZ in the first DDI study.

Methods: In part 1 of this open-label study, 16 healthy subjects received single oral doses of 7.5 mg MTX on day 1, 10 and 17, and concurrent daily 150 mg BMS-987371 doses from day 7 to 21. On day 17, BMS-986371 was dosed 2 hours after MTX. In part 2, 14 subjects received same dose regimens of MTX and BMS-986371 (dosed concurrently on all days), with addition of 1000 mg EC SSZ dose on day 1 and 10, and 1000 mg IR SSZ dose on day 17. Serial blood samples were collected after MTX dosing for pharmacokinetic analysis.

Results: In part 1, concurrent BMS-986371 dosing resulted in geometric mean ratios (GMRs) with coefficient of variation (CV%) of MTX maximum concentration (Cmax) and area under the concentration–time curve (AUC) of 0.876 (19.8) and 0.915 (21.3) vs. MTX alone. Concurrent BMS-986371 dosing resulted in MTX Cmax and AUC GMRs (CV%) of 1.15 (23.9) and 1.12 (28.9) vs. 2 hr delayed dosing. In part 2, co-administration of BMS-986371 and EC SSZ resulted in MTX Cmax and AUC GMRs (CV%) of 0.795 (23.7) and 0.872 (21.9) vs. EC SSZ alone. Co-administration of BMS-986371 and IR SSZ resulted in MTX Cmax and AUC GMRs (CV%) of 0.313 (51.2) and 0.361 (41.2) vs. BMS-986371 and EC SSZ. No severe adverse events (AEs) and only mild AEs were observed and resolved during the study.

Conclusion: Co-administration of BMS-986371 had no meaningful effect on MTX exposure. Co-administration of IR SSZ with MTX and BMS-986371 resulted in significantly lower MTX exposure, which was consistent with the result of the first DDI study, confirming this decrease was indeed caused by IR SSZ co-administration. Combination therapy with IR SSZ should be used cautiously to avoid unwanted reduced exposure and loss of MTX efficacy.