ABCB1 restricts brain accumulation of the novel RORγ agonist cintirorgon, while OATP1A/1B and CYP3A limit its oral availability

Cintirorgon (LYC-55716), a first-in-class, small-molecule, oral selective ROR gamma agonist, has been developed as a new immuno-oncology drug for solid tumors. We here studied the functions of the ABCB1 and ABCG2 multidrug efflux transporters, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A enzyme complex in cintirorgon pharmacokinetics using genetically modified mouse models. Cintirorgon was modestly transported by human ABCB1 and mouse Abcg2 in vitro. Upon oral administration at 40 mg/kg, net cintirorgon brain penetration was enhanced in Abcb1a/1b(-/-)(2.1-fold) and Abcb1a/1b;Abcg2(-/-)(2.7-fold) relative to wild-type mice. Deficiency of Oatp1a/1b led to a substantial (2.4-fold) increase in cintirorgon systemic exposure, with a corresponding (2.3-fold) decrease in hepatic distribution. However, these changes were not rescued in mice overexpressing human OATP1B1 or human OATP1B3 in liver, although this did partially reverse the altered cintirorgon glucuronide pharmacokinetics in Oatp1a/1b(- /-)mice. In Cyp3a(- /-) mice,the cintirorgon plasma AUC0-8h was 1.4-fold increased, and then decreased by 1.5-fold upon overexpression of transgenic human CYP3A4 in intestine and liver. Cintirorgon brain accumulation was thus markedly restricted by ABCB1. Mouse Oatp1a/1b mediated cintirorgon uptake into the liver, thus limiting its plasma exposure. Moreover, oral avail-ability of cintirorgon was limited by CYP3A. These insights could help optimizing cintirorgon's clinical application.

Automated summary

In this study, the functions of ABC transporters (ABCB1 and ABCG2), uptake transporters (OATP1A/1B), and drug-metabolizing enzyme complex (CYP3A) in the pharmacokinetics of Cintirorgon were investigated. The results showed that ABCB1 and Oatp1a/1b played important roles in the brain penetration and systemic exposure of Cintirorgon, while CYP3A affected its oral availability.