Daraxonrasib (RMC-6236) pharmacokinetics: impact of transporters and drug-metabolizing enzymes on a first-in-class pan-RAS molecular glue.

mice, the plasma exposure of daraxonrasib was significantly reduced (>3-fold, P < 0.05). Ces1 and Ces2 deficiency left daraxonrasib pharmacokinetics mostly unchanged. Thus, ABCB1 efflux and OATP1A/1B uptake transporters and human CYP3A4 are important determinants of daraxonrasib pharmacokinetics. ABCB1 function could limit brain penetration and possibly efficacy of daraxonrasib against brain metastases. Collectively, these preclinical findings may help in optimizing the application of daraxonrasib in clinical settings.