Abstract 6322: The role of multidrug efflux transporters and CYP3A in the pharmacokinetics and tissue distribution of abemaciclib and its active metabolites
Authors: Chavez Alejandra Martinez , Tibben Matthijs M. , Lebre Maria C. , Rosing Hilde , Beijnen Jos H. , Schinkel Alfred H. 
Published: September 2020

Abstract
Abemaciclib is the third CDK4/6 inhibitor approved by the U.S. Food and Drug Administration to treat some types of breast cancer in combination with an aromatase inhibitor. Currently it is also in clinical development to treat other types of cancer, including lung and brain cancers. Abemaciclib is mainly metabolized by CYP3A4, with the formation of three active metabolites with similar potency to abemaciclib, including N-desethylabemaciclib (M2), hydroxyabemaciclib (M20) and N-desethylhydroxyabemaciclib. The systemic exposure and/or tissue distribution of these active compounds could be affected by drug transporters and CYP3A enzymes, and hence the efficacy and safety of abemaciclib. In this study we aimed to determine the effect of P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and CYP3A on the pharmacokinetics and tissue distribution of abemaciclib and its active metabolites.
We performed pharmacokinetic experiments in several mouse models, including ABC transporter knockout (Abcb1a/1b-/-;Abcg2-/-), Cyp3a knockout (Cyp3a-/-), a humanized mouse model with the expression of human CYP3A4 in liver and small intestine in a Cyp3a-/- background (Cyp3aXAV), and wild-type mice. To support these studies, we set up a bioanalytical method using LC-MS/MS for the (semi-)quantification of abemaciclib and its metabolites.
After a single oral administration of abemaciclib at 10 mg/kg, the plasma exposure (AUC0-24h) of abemaciclib was not significantly different, but the AUC0-24h of N-desethylabemaciclib increased 5.3-fold in Abcb1a/1b-/-;Abcg2-/- compared to the wild-type mice. In Abcb1a/1b-/-;Abcg2-/- mice also the brain-to-plasma ratio of abemaciclib and N-desethylabemaciclib increased respectively 25- and 4-fold relative to wild-type mice. Regarding CYP3A, the abemaciclib plasma exposure increased 3.1-fold in Cyp3a-/- compared to the wild-type mice, and it decreased 7.6-fold in Cyp3aXAV compared to the Cyp3a-/- mice. However, the plasma exposure of N-desethylabemaciclib was not significantly different among these mouse strains. No other meaningful differences were observed including the distribution of abemaciclib and N-desethylabemaciclib in other tissues.
Based on our preliminary data, Abcb1a/1b and/or Abcg2 limit the penetration of abemaciclib and N-desethylabemaciclib into the brain, and they also decrease the oral exposure of the active metabolite N-desethylabemaciclib. CYP3A4 extensively metabolizes abemaciclib, restricting the plasma exposure of the parental drug, but without significantly altering the plasma exposure of N-desethylabemaciclib. It therefore might be important to consider the high risk of variation in oral exposure of abemaciclib due to variable CYP3A4 activity. The insights gained from this study may be useful to optimize the clinical use of abemaciclib, especially for the treatment of brain tumors.
Citation Format: Alejandra Martinez Chavez, Matthijs M. Tibben, Maria C. Lebre, Hilde Rosing, Jos H. Beijnen, Alfred H. Schinkel. The role of multidrug efflux transporters and CYP3A in the pharmacokinetics and tissue distribution of abemaciclib and its active metabolites [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6322.