Simultaneous Determination of Osimertinib and its Metabolites in Human Plasma for Clinical Applications Using
Jingjing Wu1, Liuxian Guo1,2, Guojin Zhou3
1Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Background:
Osimertinib, the first-line treatment for nonsmall cell lung cancer, has 2 main active metabolites, AZ5104 and AZ7550, which demonstrate potency against wild-type epidermal growth factor receptor mutations. In this study, a simple and sensitive analytical method using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/mass spectrometry) was developed and validated to simultaneously quantify osimertinib and its active metabolites in human plasma.
Methods:
Plasma samples were subjected to protein precipitation with zinc sulfate solution and acetonitrile using osimertinib- 13 C, d 3 as an internal standard. The separation was performed on a ThermoScientific Hypersil GOLD C18 column (4.6 × 50 mm, 5 μm) with a mobile phase composed of 0.1% formic acid water-acetonitrile through gradient elution. The compounds were monitored using electrospray ionization in the positive mode with multiple reaction monitoring.
Results:
Excellent linearity of calibration curves was observed over the ranges of 10-1000 ng·mL -1 for osimertinib, and 1.5-120 ng·mL -1 for AZ7550 and AZ5104 in human plasma. Both within-run and between-run accuracies were within ±15%, with the coefficient of variation <15%.
Conclusions:
The method met all the validation criteria and was successfully applied to clinical samples from patients with nonsmall cell lung cancer. Furthermore, the correlation between steady-state trough concentrations of osimertinib, AZ5104, and AZ7550 and patients' baseline characteristics were explored. Women exhibited a significantly higher C min, ss for AZ7550 ( P = 0.023). In addition, body mass index was associated with the C min, ss of both AZ5104 ( P = 0.047) and AZ7550 ( P = 0.001).
Insights
A new HPLC-MS/MS method accurately measures osimertinib and its active metabolites in lung cancer patients. Patient characteristics like sex and BMI correlate with metabolite levels, aiding personalized treatment.
Area of Science:
- Pharmacology and Toxicology
- Analytical Chemistry
- Oncology
Background:
- Osimertinib is a first-line treatment for nonsmall cell lung cancer (NSCLC).
- AZ5104 and AZ7550 are potent active metabolites of osimertinib.
- Understanding their pharmacokinetics is crucial for optimizing NSCLC treatment.
Purpose of the Study:
- To develop and validate a sensitive analytical method for simultaneous quantification of osimertinib and its active metabolites (AZ5104, AZ7550) in human plasma.
- To apply the validated method to clinical samples from NSCLC patients.
- To explore correlations between metabolite concentrations and patient baseline characteristics.
Main Methods:
- High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was employed.
- Plasma samples underwent protein precipitation.
- Quantification was performed using electrospray ionization in positive mode with multiple reaction monitoring.
Main Results:
- The method demonstrated excellent linearity over specified ranges for osimertinib, AZ7550, and AZ5104.
- Accuracy and precision were within acceptable validation criteria (within ±15% and <15% CV).
- The method was successfully applied to clinical NSCLC patient samples.
Conclusions:
- The validated HPLC-MS/MS method is suitable for analyzing osimertinib and its metabolites in NSCLC patient plasma.
- Steady-state trough concentrations of AZ7550 were significantly higher in women.
- Body mass index was associated with the steady-state trough concentrations of both AZ5104 and AZ7550.
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