Pharmacokinetics of the KRASG12C inhibitor adagrasib is limited by CYP3A and ABCB1, and influenced by binding to mouse plasma carboxylesterase 1c

Biomed Pharmacother. 2023 Oct:166:115304. doi: 10.1016/j.biopha.2023.115304. Epub 2023 Aug 14.

Abstract

Adagrasib (Krazati™) is the second FDA-approved specific KRASG12C inhibitor for non-small cell lung cancer (NSCLC) patients harboring this mutation. The impact of the drug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing enzymes CYP3A and carboxylesterase 1 (CES1) on the pharmacokinetics of oral adagrasib were studied using genetically modified mouse models. Adagrasib was potently transported by human ABCB1 and modestly by mouse Abcg2 in vitro. In Abcb1a/b-/- and Abcb1a/b;Abcg2-/- mice, the brain-to-plasma ratios were enhanced by 33- and 55-fold, respectively, compared to wild-type mice, whereas ratios in Abcg2-/- mice remained unchanged. The influence of ABC transporters was completely reversed by coadministration of the dual ABCB1/ABCG2 inhibitor elacridar, increasing the brain penetration in wild-type mice by 41-fold while no signs of acute CNS toxicity were observed. Tumor ABCB1 overexpression may thus confer adagrasib resistance. Whereas the ABC transporters did not affect adagrasib plasma exposure, CYP3A and Ces1 strongly impacted its apparent oral availability. The plasma AUC0-8 h was significantly enhanced by 2.3-fold in Cyp3a-/- compared to wild-type mice, and subsequently 4.3-fold reduced in transgenic CYP3A4 mice, indicating substantial CYP3A-mediated metabolism. Adagrasib plasma exposure was strongly reduced in Ces1-/- compared to wild-type mice, but tissue exposure was slightly increased, suggesting that adagrasib binds to plasma Ces1c in mice and is perhaps metabolized by Ces1. This binding could complicate interpretation of mouse studies, especially since humans lack circulating CES1 enzyme(s). Our results may be useful to further optimize the clinical safety and efficacy of adagrasib, and give more insight into potential drug-drug interactions risks.

Keywords: ABCB1/P-glycoprotein; ABCG2/Breast cancer resistance protein; Adagrasib; Adagrasib (PubChem CID: 138611145); Carboxylesterase 1; Cytochrome P450 3A; Elacridar HCl (PubChem CID: 170320); KRAS(G12C) inhibitor; Ko143 (PubChem CID: 10322450); Zosuquidar (PubChem CID: 153997).

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Brain / metabolism
  • Carboxylesterase / genetics
  • Carboxylesterase / metabolism
  • Carboxylic Ester Hydrolases / genetics
  • Carboxylic Ester Hydrolases / metabolism
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism
  • Dogs
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Proto-Oncogene Proteins p21(ras) / metabolism

Substances

  • Cytochrome P-450 CYP3A
  • Carboxylesterase
  • adagrasib
  • Proto-Oncogene Proteins p21(ras)
  • ATP-Binding Cassette Transporters
  • Carboxylic Ester Hydrolases
  • KRAS protein, human
  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B