Metabolic Stability Assessment of New PARP Inhibitor Talazoparib Using Validated LC-MS/MS Methodology: In silico Metabolic Vulnerability and Toxicity Studies

Drug Design, Development and Therapy
Mohamed W AttwaHassan A Alhazmi

Abstract

Talazoparib (BMN673) is a new poly(ADP-ribose) polymerase inhibitor that has been FDA approved for patients suffering from metastatic breast cancer with germline BRCA mutations. In the current study, an accurate and efficient liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical methodology was developed for TZB estimation in addition to its metabolic stability assessment. TZB and lapatinib (LAP) (which is chosen as an internal standard; IS) were separated using reversed phase elution system (Hypersil C18 column) with an isocratic mobile phase. The linearity range of the established method was 5-500 ng/mL (r2 ≥ 0.999) in the human liver microsomes (HLMs) matrix. Different parameters were calculated to confirm the method sensitivity (limit of quantification was 2.0 ng/mL), and reproducibility (intra- and inter-day precision and accuracy were below 3.1%) of our methodology. For evaluation of TZB metabolic stability in HLM matrix, intrinsic clearance (9.59 µL/min/mg) and in vitro half-life (72.7 mins) were calculated. TZB treatment discontinuations were reported due to adverse events and dose accumulation, so in silico metabolic vulnerability (experimental and in silico) and toxicity assessment (in silico) of TZB we...Continue Reading

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Citations

Oct 3, 2020·Journal of Separation Science·Szymon Ulenberg, Tomasz Bączek
Nov 1, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ali S AbdelhameedAdnan A Kadi
Jan 8, 2021·Analytical Methods : Advancing Methods and Applications·Nasser S Al-ShakliahAdnan A Kadi
Dec 17, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·A F M Motiur RahmanYurngdong Jahng
Jul 30, 2021·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Gamal A E MostafaHaitham AlRabiah
Jul 31, 2021·British Journal of Clinical Pharmacology·Daranjit SandhuAlan M Jones

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Software Mentioned

Agilent Mass Hunter
mathord
DEREK
StarDrop

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