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Selpercatinib is a targeted, FDA-approved, oral, small-molecule inhibitor for the treatment of rearranged during transfection (RET) proto-oncogene mutation-positive cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in selpercatinib pharmacokinetics. Selpercatinib was efficiently transported by hABCB1 and mAbcg2, but not hABCG2, and was not a substrate of human OATP1A2, -1B1 or -1B3 in vitro. In vivo, brain and testis penetration were increased by 3.0- and 2.7-fold in  Abcb1a/1b -/-   mice and by 6.2- and 6.4-fold in  Abcb1a/1b;Abcg2 -/-   mice, respectively. Oatp1a/1b deficiency did not alter selpercatinib pharmacokinetics. The ABCB1/ABCG2 inhibitor elacridar boosted selpercatinib brain penetration in wild-type mice to the levels seen in  Abcb1a/1b;Abcg2 -/-   mice.  Cyp3a -/-   mice showed a 1.4-fold higher plasma AUC 0–4h  than wild-type mice, which was then 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. In summary, ABCG2, and especially ABCB1, limit brain and testis penetration of selpercatinib. Elacridar coadministration could mostly reverse these effects, without causing acute toxicity. CYP3A-mediated metabolism can limit selpercatinib oral exposure and hence its tissue concentrations. These insights may be useful in the further clinical development of selpercatinib.

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P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)