Due to the high frequency of oncogenic KRAS driver mutations in human tumors and the relevance of KRAS aberrant signaling pathways, intensive therapeutic development efforts have been directed towards KRAS inhibitors. To date, there are no FDA-approved KRAS inhibitors other than Sotorasib and Adagrasib, which target uniquely the KRASG12C mutation. Targeting KRASG12D is of great importance, as it is the dominant KRAS driver mutation in pancreatic cancer (37%), colorectal cancer (12.5%), bile duct carcinoma (10.9%) and the second most common KRAS alteration in NSCLC (16.4%). The first KRASG12D inhibitor to enter clinical trials was MRTX113, currently in phase 1/2, directed towards solid tumors harboring the KRASG12D mutation (NCT05737706). Pharmacokinetic (PK) studies of newly developed drugs are essential to determine their ADME properties, effective dosing regimens, toxicity and clinical drug–drug interactions. The aim of this PK study is to define which drug transporters play a role in the modulation of plasma pharmacokinetics and tissue disposition of MRTX1133.

We tested the transport of MRTX1133 across a monolayer of MDCK-II cells overexpressing the ABC transporters human P-gp(ABCB1), human BCRP(ABCG2) and mouse Bcrp(Abcg2) in an in vitro transwell assay. In vivo, we used different knockout mouse strains lacking the drug transporters P-gp, Bcrp, and Oatp1.

The transwell assay suggested that MRTX1133 is actively transported by P-gp and Bcrp. The plasma pharmacokinetics of intraperitoneally administered MRTX1133 were not substantially affected by the absence of Abcb1 and Abcg2. The brain, liver and kidney concentrations and organ-to-plasma ratios of MRTX1133 in Abcb1a/b;Abcg2−/− mice were significantly increased compared to those in wild-type mice. The mouse Oatp1a/b transporters did not appear to affect the pharmacokinetics of MRTX1133. Unexpectedly, we observed significant toxicity of MRTX1133 in some of our mice. We are currently looking further into the background and causes of this toxicity.

This study highlights the relevance of ABCB1/ABCG2 in the transporter-mediated restriction of brain penetration and reduction of kidney and liver accumulation of MRTX1133. We hypothesize that co-administration of the dual ABCB1/ABCG2 inhibitor elacridar could promote brain penetration and increase kidney and liver exposure for MRTX1133. The insights gained may contribute to enhancing the safety and efficacy of MRTX1133 in the clinic.