Search

Your search keyword '"Rijmers, Jamie"' showing total 10 results
Start Over Author "Rijmers, Jamie"
10 results on '"Rijmers, Jamie"'

5. ABCB1 attenuates brain exposure to the KRASG12C inhibitor opnurasib whereas binding to mouse carboxylesterase 1c influences its plasma exposure

Author

Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Rijmers, Jamie, Retmana, Irene A, Bui, Viët, Arguedas, Davinia, Lebre, Maria C, Sparidans, Rolf W, Beijnen, Jos H, Schinkel, Alfred H, Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Rijmers, Jamie, Retmana, Irene A, Bui, Viët, Arguedas, Davinia, Lebre, Maria C, Sparidans, Rolf W, Beijnen, Jos H, and Schinkel, Alfred H

Published
2024

6. Development and validation of an LC-MS/MS method for the quantification of KRASG12C inhibitor opnurasib in several mouse matrices and its application in a pharmacokinetic mouse study

Author

Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Retmana, Irene A., Çelebi, Nefise, Rijmers, Jamie, Schinkel, Alfred H., Beijnen, Jos H., Sparidans, Rolf W., Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Retmana, Irene A., Çelebi, Nefise, Rijmers, Jamie, Schinkel, Alfred H., Beijnen, Jos H., and Sparidans, Rolf W.

Published
2024

9. Pharmacokinetics of the KRAS G12C inhibitor adagrasib is limited by CYP3A and ABCB1, and influenced by binding to mouse plasma carboxylesterase 1c.

Author

Loos, Nancy H C, Retmana, Irene A, Rijmers, Jamie, Wang, Yaogeng, Gan, Changpei, Lebre, Maria C, Sparidans, Rolf W, Beijnen, Jos H, Schinkel, Alfred H, Loos, Nancy H C, Retmana, Irene A, Rijmers, Jamie, Wang, Yaogeng, Gan, Changpei, Lebre, Maria C, Sparidans, Rolf W, Beijnen, Jos H, and Schinkel, Alfred H

Abstract

Adagrasib (Krazati™) is the second FDA-approved specific KRAS G12C 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 AUC 0-8 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.

Published
2023

10. Pharmacokinetics of the KRAS G12C inhibitor adagrasib is limited by CYP3A and ABCB1, and influenced by binding to mouse plasma carboxylesterase 1c.

Author

Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Loos, Nancy H C, Retmana, Irene A, Rijmers, Jamie, Wang, Yaogeng, Gan, Changpei, Lebre, Maria C, Sparidans, Rolf W, Beijnen, Jos H, Schinkel, Alfred H, Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Loos, Nancy H C, Retmana, Irene A, Rijmers, Jamie, Wang, Yaogeng, Gan, Changpei, Lebre, Maria C, Sparidans, Rolf W, Beijnen, Jos H, and Schinkel, Alfred H

Published
2023

Catalog

Books, media, physical & digital resources
See catalog results