ABCB1 and ABCG2 limit brain penetration and, together with CYP3A4, total plasma exposure of abemaciclib and its active metabolites

Abemaciclib is the third cyclin-dependent kinase (CDK) 4/6 inhibitor approved for the treatment of breast Cancer and currently under investigation for other malignancies, including brain Cancer. Primarily CYP3A4 metabolizes abemaciclib, forming three active metabolites (M2, M20 and M18) that are likely relevant for abemaciclib efficacy and toxicity. We investigated the impact of ABCB1 (P-gp), ABCG2 (BCRP) and CYP3A on the pharmacokinetics and tissue distribution of abemaciclib and its metabolites using genetically modified mice. In vitro, abemaciclib was efficiently transported by hABCB1 and mAbcg2, and slightly by hABCG2, but the active metabolites were transported even better. Upon oral administration of 10 mg/kg abemaciclib, absence of Abcg2 and especially Abcb1a/1b significantly increased the plasma AUC_{0-24 h} and C_max of M2 and M18. Furthermore, the relative brain penetration of abemaciclib, M2 and M20 was dramatically increased by 25-, 4- and 60-fold, respectively, in Abcb1a/1b;Abcg2^-/- mice, and to a lesser extent in single Abcb1a/1b- or Abcg2-deficient mice. The recovery of all active compounds in the small intestine content was profoundly reduced in Abcb1a/1b;Abcg2^-/- mice, with smaller effects in single Abcb1a/1b^-/- and Abcg2^-/- mice. Our results indicate that Abcb1a/1b and Abcg2 cooperatively and profoundly limit the brain penetration of abemaciclib and its active metabolites, and likely also participate in their hepatobiliary or direct intestinal elimination. Moreover, transgenic human CYP3A4 drastically reduced the abemaciclib plasma AUC_{0-24 h} and C_max by 7.5- and 5.6-fold, respectively, relative to Cyp3a^-/- mice. These insights may help to optimize the clinical development of abemaciclib, especially for the treatment of brain malignancies.