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Metabolism and pharmacokinetic study of deuterated osimertinib

Xuyi Zhan1,2,3, Shaoyin Bao1,4, Xumei Li5

  • 1Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Biopharmaceutics & Drug Disposition
|January 17, 2023
PubMed

Insights

Deuteration of osimertinib (osimertinib-d3) significantly reduces the formation of its key metabolite, AZ5104. This deuterated compound shows improved pharmacokinetic properties, including higher systemic exposure and peak concentration in rats and humans.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Medicinal Chemistry

Background:

  • Osimertinib is a third-generation EGFR inhibitor for non-small cell lung cancer.
  • CYP3A enzymes are primary metabolizers of osimertinib, producing key metabolites like AZ5104.
  • Deuteration is a strategy to enhance drug pharmacokinetic properties.

Purpose of the Study:

  • To compare the metabolism and pharmacokinetics of osimertinib and its deuterated analog, osimertinib-d3.
  • To investigate the impact of deuteration on the metabolic pathway producing AZ5104.
  • To evaluate the in vivo performance of osimertinib-d3.

Main Methods:

  • In vitro studies using liver microsomes and human recombinant cytochrome P450 isoenzymes.
  • In vivo pharmacokinetic studies in rats and humans.
  • Comparison of plasma concentrations, area under the curve (AUC), and maximum concentration (Cmax).

Main Results:

  • Deuteration of osimertinib (osimertinib-d3) significantly inhibited the metabolic pathway forming AZ5104 due to the kinetic isotope effect.
  • Plasma concentrations of AZ5104 were significantly lower for osimertinib-d3 compared to osimertinib in both rats and humans.
  • Osimertinib-d3 demonstrated higher systemic exposure (AUC) and peak concentration (Cmax) than osimertinib in vivo.

Conclusions:

  • Deuteration effectively modulates osimertinib metabolism by reducing AZ5104 formation.
  • Osimertinib-d3 exhibits enhanced pharmacokinetic characteristics compared to the parent drug.
  • This deuteration strategy holds promise for improving the therapeutic profile of osimertinib.
Keywords:
deuterationmetabolismosimertinibpharmacokinetics

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