Abstract 1268: The impact of P-glycoprotein, breast cancer resistance protein and CYP3A on pharmacokinetics and metabolism of galunisertib
Authors: Li Wenlong , Tibben Matthijs , Wang Yaogeng , Lebre Maria C. , Rosing Hilde , Beijnen Jos H. , Schinkel Alfred H. 
Published: August 2019

Transforming growth factor-beta (TGF-β) signaling plays a pivotal role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. Galunisertib (LY2157299 monohydrate) is an oral small-molecule inhibitor of the TGF-β receptor I kinase that specifically down-regulates the phosphorylation of SMAD2, abrogating activation of this canonical pathway. Galunisertib showed promising antitumor activity in tumor-bearing animal models for breast, colon, and lung cancers, and for hepatocellular carcinoma.

Potential drug transport mediated by ATP-binding cassette (ABC) transporters and metabolism by CYP3A are of clinical and regulatory concern, as these could modulate the systemic exposure and/or organ distribution of substrate drugs, and thus affect their therapeutic efficacy and toxicity. We here aimed to investigate the roles of two ABC transporters (P-glycoprotein/ABCB1 and Breast Cancer Resistance Protein/ABCG2) and CYP3A enzyme in the pharmacokinetics and tissue distribution of galunisertib.

Transepithelial drug transport was tested using polarized monolayers of Madin-Darby Canine Kidney (MDCK-II) parental cells and its subclones overexpressing human (h) ABCB1, hABCG2, or mouse (m) Abcg2 cDNA. The results suggest that galunisertib is an excellent transport substrate of hABCB1 and endogenous canine ABCB1. mAbcg2 could modestly transport galunisertib, but hABCG2 could not. Based on the in vitro transport experiments, we performed an in vivo pharmacokinetic study in wild-type, ABC transporter knockout (Abcb1a/1b;Abcg2-/-), and Cyp3a knockout (Cyp3a-/-) mice. Following oral administration (20 mg/kg galunisertib), plasma exposure (AUC) in mice was similar to that achieved in humans dosed at 300 mg once daily. Interestingly, the brain-to-plasma ratio was 26-fold higher in Abcb1a/1b;Abcg2-/- mice compared to wild-type mice. However, no significant differences were observed in other tested tissue distributions or in oral availability of galunisertib among these three mouse strains.

Our data suggest that ABC transporters play an important role in restricting the brain penetration of galunisertib, but have little impact on oral availability and other relative tissue distribution. Mouse Cyp3a appears to have little, if any, effect on the pharmacokinetics and metabolism of galunisertib. Our results suggest a potential way to boost brain penetration of galunisertib by pharmacological inhibition of transporters in the BBB with chemical inhibitors, especially for patients with brain metastases. These insights might be used to optimize the clinical application of galunisertib.

Citation Format: Wenlong Li, Matthijs Tibben, Yaogeng Wang, Maria C. Lebre, Hilde Rosing, Jos H. Beijnen, Alfred H. Schinkel. The impact of P-glycoprotein, breast cancer resistance protein and CYP3A on pharmacokinetics and metabolism of galunisertib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1268.