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Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics Study

Zheng Yuan1, Xin Yu1, Siyang Wu1

  • 1Center for DMPK Research of Herbal Medicines, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.

Frontiers in Pharmacology
|August 8, 2022
PubMed

Insights

Osimertinib, a key drug for non-small-cell lung cancer, is unstable in plasma due to a Michael addition reaction. A new method significantly enhances its stability, aiding pharmacokinetic studies.

Area of Science:

  • Pharmacology and Drug Metabolism
  • Analytical Chemistry

Background:

  • Osimertinib is a crucial third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for non-small-cell lung cancer (NSCLC).
  • Concerns exist regarding the low stability of osimertinib and its metabolites (AZ-5104, AZ-7550) in plasma.

Purpose of the Study:

  • To investigate the reasons behind the instability of osimertinib and its metabolites in rat plasma.
  • To develop and validate a method for stabilizing osimertinib and its metabolites in plasma for accurate pharmacokinetic analysis.

Main Methods:

  • Investigated the degradation pathway of osimertinib and its metabolites in rat plasma.
  • Developed a stabilization assay to improve the stability of osimertinib and its metabolites.
  • Validated an ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) method for pharmacokinetic studies.

Main Results:

  • Identified a Michael addition reaction between osimertinib's Michael acceptor and plasma cysteine as the cause of instability.
  • The developed assay significantly enhanced the stability of osimertinib, AZ-5104, and AZ-7550 in plasma.
  • The UPLC-MS/MS method demonstrated accuracy, precision, and reliability for pharmacokinetic assessment.

Conclusions:

  • The Michael addition reaction is the primary cause of osimertinib and metabolite instability in plasma.
  • The developed stabilization assay and UPLC-MS/MS method provide a robust solution for analyzing osimertinib pharmacokinetics.
  • This research offers insights into the stability challenges of Michael acceptor-containing EGFR-TKIs.
Keywords:
UPLC-MS/MSacetonitrilecysteinenon-small-cell lung cancerosimertinibplasma stability

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