Daraxonrasib (RMC-6236) is an innovative, first-in-class oral pan-RAS inhibitor leveraging a unique molecular glue mechanism to target all RAS protein isoforms. Ongoing phase III clinical trials aim to treat solid tumors harboring RAS mutations, including non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC). KRAS-mutant NSCLC develops brain metastases in 30% of patients. Effective therapies are urgently needed and the blood-brain barrier (BBB) may pose an additional therapeutic hurdle. We assessed how drug efflux transporters expressed at the BBB (ABCB1, ABCG2), drug-metabolizing enzymes (CYP3A, CES1, CES2), and drug uptake transporters (OATP1A/1B) affect the plasma exposure and organ disposition of oral daraxonrasib. In vitro, human ABCB1 transported daraxonrasib. Oral daraxonrasib pharmacokinetics were studied in transporter- and enzyme-deficient mice, and in CYP3A4-humanized mice. Compared to wild-type controls, Abcb1a/1b- and Oatp1a/1b-deficient mice had significantly increased plasma exposure of daraxonrasib (P < 0.01), suggesting that these proteins transport daraxonrasib in vivo. Abcb1a/1b-mediated transport of daraxonrasib across the BBB was validated by oral co-administration of the ABCB1/ABCG2 inhibitor elacridar, resulting in 20-fold increased brain penetration in wild-type mice (P < 0.01). In CYP3A4-humanized Cyp3a-/- 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.
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