1. Academic Validation
  2. ABCB1 limits brain exposure of the KRASG12C inhibitor sotorasib, whereas ABCB1, CYP3A, and possibly OATP1a/1b restrict its oral availability

ABCB1 limits brain exposure of the KRASG12C inhibitor sotorasib, whereas ABCB1, CYP3A, and possibly OATP1a/1b restrict its oral availability

  • Pharmacol Res. 2022 Apr;178:106137. doi: 10.1016/j.phrs.2022.106137.
Nancy H C Loos 1 Irene A Retmana 2 Wenlong Li 1 Margarida L F Martins 1 Maria C Lebre 1 Rolf W Sparidans 3 Jos H Beijnen 4 Alfred H Schinkel 5
Affiliations

Affiliations

  • 1 The Netherlands Cancer Institute, Division of Pharmacology, Amsterdam, The Netherlands.
  • 2 The Netherlands Cancer Institute, Division of Pharmacology, Amsterdam, The Netherlands; Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Utrecht, The Netherlands.
  • 3 Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Utrecht, The Netherlands.
  • 4 The Netherlands Cancer Institute, Division of Pharmacology, Amsterdam, The Netherlands; Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht, The Netherlands; The Netherlands Cancer Institute, Division of Pharmacy and Pharmacology, Amsterdam, The Netherlands.
  • 5 The Netherlands Cancer Institute, Division of Pharmacology, Amsterdam, The Netherlands. Electronic address: a.schinkel@nki.nl.
Abstract

Sotorasib (Lumakras™) is the first FDA-approved KRASG12C inhibitor for treatment of patients with non-small cell lung Cancer (NSCLC) carrying this mutation. Using genetically modified mouse models, we studied the influence of the efflux transporters ABCB1 and ABCG2, the OATP1a/1b uptake transporters, and the CYP3A drug-metabolizing Enzyme complex on the plasma pharmacokinetics and tissue distribution of oral sotorasib. In vitro, sotorasib was a potent substrate for human ABCB1 and a modest substrate for mouse Abcg2, but not for human ABCG2. In vivo, the brain-to-plasma ratio of sotorasib (40 mg/kg) was highly increased in Abcb1a/1b-/- (5.9-fold) and Abcb1a/1b;Abcg2-/- (7.6-fold) compared to wild-type mice, but not in single Abcg2-/- mice. Upon coadministering elacridar, an ABCB1/ABCG2 inhibitor, sotorasib brain accumulation increased 7.5-fold, approaching the levels observed in Abcb1a/1b-deficient mice. No acute CNS toxicity emerged upon boosting of the sotorasib exposure. In Oatp1a/1b-deficient mice, we observed a 2-fold reduction in liver disposition compared to wild-type mice, although these uptake transporters had no noticeable impact on sotorasib plasma exposure. However, plasma exposure was limited by mouse Cyp3a and human CYP3A4, as the AUC0-4 h in Cyp3a-/- mice was increased by 2.5-fold compared to wild-type mice, and subsequently strongly decreased (by 3.9-fold) in Cyp3aXAV mice transgenically overexpressing human CYP3A4 in liver and intestine. Collectively, the oral availability of sotorasib was markedly limited by CYP3A and possibly also by ABCB1 and OATP1a/b, whereas its brain accumulation was strongly restricted by ABCB1. The obtained results may help to further optimize the safety and efficacy of sotorasib in clinical use.

Keywords

10322450); 137278711); ABCB1/P-glycoprotein; ABCG2/Breast cancer resistance protein; Cytochrome P450 3A; Elacridar HCl (PubChem CID: 170320); KRAS(G12C) inhibitor; Ko143 (PubChem CID; Pharmacokinetics; Sotorasib; Sotorasib (PubChem CID; Zosuquidar (PubChem CID: 153997).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114277
    99.94%, KRAS G12C Inhibitor
    Ras