Drug Design, Development and Therapy (Feb 2020)
Metabolic Stability Assessment of New PARP Inhibitor Talazoparib Using Validated LC–MS/MS Methodology: In silico Metabolic Vulnerability and Toxicity Studies
Abstract
Mohamed W Attwa, 1, 2 Adnan A Kadi, 1 Ali S Abdelhameed, 1 Hassan A Alhazmi 3, 4 1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 2Students’ University Hospital, Mansoura University, Mansoura 35516, Egypt; 3Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, Saudi Arabia; 4Substance Abuse and Toxicology Research Centre, Jazan University, Jazan, Saudi ArabiaCorrespondence: Ali S Abdelhameed Tel +966 1146 98314Fax +966 1146 76220Email [email protected]: 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.Method and Results: 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 C 18 column) with an isocratic mobile phase. The linearity range of the established method was 5– 500 ng/mL (r 2 ≥ 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 were performed utilizing P450 Metabolism and DEREK modules of StarDrop software.Conclusion: TZB is slowly metabolized by the liver. TZB was reported to be minimally metabolized by the liver that approved our outcomes. We do recommend that plasma levels be monitored in cases when talazoparib is used for a long period of time, since it is possible for TZB to bioaccumulate after multiple doses to toxic levels. According to our knowledge, the current method is considered the first LC-MS/MS methodology for evaluating TZB metabolic stability. Further drug discovery studies can be done depending on this concept allowing the designing of new series of compounds with more safety profile through reducing side effects and improving metabolic behavior.Keywords: talazoparib, metabolic stability evaluation, human liver microsomes, tandem mass spectrometry, DEREK, StarDrop software
