2. Academic Validation
  3. Quantitation of navtemadlin in human plasma and brain tissue by liquid chromatography-tandem mass spectrometry

Quantitation of navtemadlin in human plasma and brain tissue by liquid chromatography-tandem mass spectrometry

  • Biomed Chromatogr. 2022 Nov;36(11):e5467. doi: 10.1002/bmc.5467.
Amanda B Kagan 1,  Nicole M Anders 2 3,  Avelina Hemingway 2 3,  Eudocia Q Lee 4,  Kevin R Kelly 5,  Hans C Lee 6,  Meng Xu-Welliver 7,  Richard Piekarz 8,  Michelle A Rudek 1 2 3
Affiliations

Affiliations

  • 1 Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • 2 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
  • 3 Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • 4 Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Division of Hematology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
  • 6 Department of Lymphoma/Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7 Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA.
  • 8 Investigational Drug Branch, Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, Bethesda, MD, USA.
PMID: 35895384 DOI: 10.1002/bmc.5467
Abstract

Navtemadlin is an orally bioavailable small molecule that blocks the protein-protein interaction between murine double minute 2 protein (MDM2) and the tumor suppressor protein p53, leading to p53-mediated cell cycle arrest and Apoptosis. It is being evaluated in clinical trials for a variety of malignancies, both as a single agent and in combination regimens. A sensitive, robust LC-tandem mass spectrometry (LC-MS/MS) method was developed to quantitate navtemadlin in plasma, and this method was also validated using brain tissue homogenate. Sample preparation involved protein precipitation of plasma or brain tissue homogenate using acetonitrile. Navtemadlin, navtemadlin glucuronide, and the internal standard, D6 -navtemadlin, were separated from microsomal incubation extracts using gradient elution and a ZORBAX XDB C18 column. Analytes were detected using a SCIEX 5500 triple quadrupole mass spectrometer in positive electrospray ionization mode. The assay range of 1-1000 ng/mL was shown to be accurate (96.1-102.0% and 95.7-104%) and precise (coefficient of variation ≤ 10.6% and ≤ 6.6%) in plasma and brain tissue homogenate, respectively. An 8000 ng/mL navtemadlin sample diluted 1:10 (v/v) with plasma was also accurately quantitated. Navtemadlin has been stable in frozen plasma at -70°C for at least 20 months. This validated LC-MS/MS method was applied to determine navtemadlin concentrations in plasma and brain tissue samples from two separate patients receiving 120 mg/day navtemadlin on protocol ABTC1604.

Keywords

assay; navtemadlin; tandem mass spectrometry; validation.

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