2. Academic Validation
  3. Metabolism and pharmacokinetic study of deuterated osimertinib

Metabolism and pharmacokinetic study of deuterated osimertinib

  • Biopharm Drug Dispos. 2023 Jan 17. doi: 10.1002/bdd.2347.
Xuyi Zhan 1 2 3,  Shaoyin Bao 1 4,  Xumei Li 5,  Shaojun Zhou 1,  Maha Raja Dahar 1,  Nengming Lin 2 6,  Xiugui Chen 7,  Chengshan Niu 7,  Kaige Ji 7,  Yusheng Wu 7,  Kui Zeng 1,  Zhihua Tang 8,  Lushan Yu 1 2
Affiliations

Affiliations

  • 1 Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 2 Cancer Center, Zhejiang University, Hangzhou, China.
  • 3 Quzhou Hospital of Traditional Chinese Medicine (Four Provincial Marginal Hospitals of Traditional Chinese Medicine Affiliated to Zhejiang University of Traditional Chinese Medicine), Quzhou, China.
  • 4 School of Engineering, Zhejiang University, Hangzhou, China.
  • 5 Department of Pharmacy, The Second Hospital of Jiaxing, Jiaxing, China.
  • 6 Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacy, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 TYK Medicines, Inc, Hangzhou, China.
  • 8 Department of Pharmacy, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China.
PMID: 36649539 DOI: 10.1002/bdd.2347
Abstract

Osimertinib is a highly selective third-generation irreversible inhibitor of epidermal growth factor receptor mutant, which can be utilized to treat non-small cell lung Cancer. As the substrate of Cytochrome P450 enzyme, it is mainly metabolized by the CYP3A Enzyme in humans. Among the metabolites produced by osimertinib, AZ5104, and AZ7550, which are demethylated that is most vital. Nowadays, deuteration is a new design approach for several drugs. This popular strategy is deemed to improve the pharmacokinetic characteristics of the original drugs. Therefore, in this study the metabolism profiles of osimertinib and its deuterated compound (osimertinib-d3) in liver microsomes and human recombinant Cytochrome P450 isoenzymes and the pharmacokinetics in rats and humans were compared. After deuteration, its kinetic isotope effect greatly inhibited the metabolic pathway that produces AZ5104. The plasma concentration of the key metabolite AZ5104 of osimertinib-d3 in rats and humans decreased significantly compared with that of the osimertinib. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib-d3 had higher systemic exposure (AUC) and peak concentration (Cmax ) compared with the osimertinib in rats and human body.

Keywords

deuteration; metabolism; osimertinib; pharmacokinetics.

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