For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
24
views
19
references
 Top references
cited by
17
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
1 collections
    0
    shares
      231
      similar
       All similar

      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

      88,007 Monthly downloads/views I 4.319 Impact Factor I 6.6 CiteScore I 1.12 Source Normalized Impact per Paper (SNIP) I 0.784 Scimago Journal & Country Rank (SJR)

       

      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          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.

          Most cited references19

          • Record: found
          • Abstract: found
          • Article: not found

          Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis.

          Mohammad Forouzanfar, Kyle J Foreman, Allyne M Delossantos … (2011)
          Breast and cervical cancer are important causes of mortality in women aged ≥15 years. We undertook annual age-specific assessments of breast and cervical cancer in 187 countries. We systematically collected cancer registry data on mortality and incidence, vital registration, and verbal autopsy data for the period 1980-2010. We modelled the mortality-to-incidence (MI) ratio using a hierarchical model. Vital registration and verbal autopsy were supplemented with incidence multiplied by the MI ratio to yield a comprehensive database of mortality rates. We used Gaussian process regression to develop estimates of mortality with uncertainty by age, sex, country, and year. We used out-of-sample predictive validity to select the final model. Estimates of incidence with uncertainty were also generated with mortality and MI ratios. Global breast cancer incidence increased from 641,000 (95% uncertainty intervals 610,000-750,000) cases in 1980 to 1,643,000 (1,421,000-1,782,000) cases in 2010, an annual rate of increase of 3·1%. Global cervical cancer incidence increased from 378,000 (256,000-489,000) cases per year in 1980 to 454,000 (318,000-620,000) cases per year in 2010-a 0·6% annual rate of increase. Breast cancer killed 425,000 (359,000-453,000) women in 2010, of whom 68,000 (62,000-74,000) were aged 15-49 years in developing countries. Cervical cancer death rates have been decreasing but the disease still killed 200,000 (139,000-276,000) women in 2010, of whom 46,000 (33,000-64,000) were aged 15-49 years in developing countries. We recorded pronounced variation in the trend in breast cancer mortality across regions and countries. More policy attention is needed to strengthen established health-system responses to reduce breast and cervical cancer, especially in developing countries. Susan G Komen for the Cure and the Bill & Melinda Gates Foundation. Copyright © 2011 Elsevier Ltd. All rights reserved.
          Article 0 comments Cited 310 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency.

            Yuqiao Shen, Farah L. Rehman, Ying Feng … (2013)
            PARP1/2 inhibitors are a class of anticancer agents that target tumor-specific defects in DNA repair. Here, we describe BMN 673, a novel, highly potent PARP1/2 inhibitor with favorable metabolic stability, oral bioavailability, and pharmacokinetic properties. Potency and selectivity of BMN 673 was determined by biochemical assays. Anticancer activity either as a single-agent or in combination with other antitumor agents was evaluated both in vitro and in xenograft cancer models. BMN 673 is a potent PARP1/2 inhibitor (PARP1 IC50 = 0.57 nmol/L), but it does not inhibit other enzymes that we have tested. BMN 673 exhibits selective antitumor cytotoxicity and elicits DNA repair biomarkers at much lower concentrations than earlier generation PARP1/2 inhibitors (such as olaparib, rucaparib, and veliparib). In vitro, BMN 673 selectively targeted tumor cells with BRCA1, BRCA2, or PTEN gene defects with 20- to more than 200-fold greater potency than existing PARP1/2 inhibitors. BMN 673 is readily orally bioavailable, with more than 40% absolute oral bioavailability in rats when dosed in carboxylmethyl cellulose. Oral administration of BMN 673 elicited remarkable antitumor activity in vivo; xenografted tumors that carry defects in DNA repair due to BRCA mutations or PTEN deficiency were profoundly sensitive to oral BMN 673 treatment at well-tolerated doses in mice. Synergistic or additive antitumor effects were also found when BMN 673 was combined with temozolomide, SN38, or platinum drugs. BMN 673 is currently in early-phase clinical development and represents a promising PARP1/2 inhibitor with potentially advantageous features in its drug class. ©2013 AACR.
            Article 0 comments Cited 180 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data.

              B Michael Silber, P Wastall, Sarah Liston … (1997)
              We describe a comprehensive retrospective analysis in which the abilities of several methods by which human pharmacokinetic parameters are predicted from preclinical pharmacokinetic data and/or in vitro metabolism data were assessed. The prediction methods examined included both methods from the scientific literature as well as some described in this report for the first time. Four methods were examined for their ability to predict human volume of distribution. Three were highly predictive, yielding, on average, predictions that were within 60% to 90% of actual values. Twelve methods were assessed for their utility in predicting clearance. The most successful allometric scaling method yielded clearance predictions that were, on average, within 80% of actual values. The best methods in which in vitro metabolism data from human liver microsomes were scaled to in vivo clearance values yielded predicted clearance values that were, on average, within 70% to 80% of actual values. Human t1/2 was predicted by combining predictions of human volume of distribution and clearance. The best t1/2 prediction methods successfully assigned compounds to appropriate dosing regimen categories (e.g., once daily, twice daily and so forth) 70% to 80% of the time. In addition, correlations between human t1/2 and t1/2 values from preclinical species were also generally successful (72-87%) when used to predict human dosing regimens. In summary, this retrospective analysis has identified several approaches by which human pharmacokinetic data can be predicted from preclinical data. Such approaches should find utility in the drug discovery and development processes in the identification and selection of compounds that will possess appropriate pharmacokinetic characteristics in humans for progression to clinical trials.
              Article 0 comments Cited 83 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): DDDT
                Journal ID (pmc): dddt
                Title: Drug Design, Development and Therapy
                Publisher: Dove
                ISSN (Electronic): 1177-8881
                Publication date (Electronic): 25 February 2020
                Publication date Collection: 2020
                Volume: 14
                Pages: 783-793
                Affiliations
                [1 ]Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University , Riyadh 11451, Saudi Arabia
                [2 ]Students’ University Hospital, Mansoura University , Mansoura 35516, Egypt
                [3 ]Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University , Jazan, Saudi Arabia
                [4 ]Substance Abuse and Toxicology Research Centre, Jazan University , Jazan, Saudi Arabia
                Author notes
                Correspondence: Ali S Abdelhameed Tel +966 1146 98314Fax +966 1146 76220 Email asaber@ksu.edu.sa
                Author information
                http://orcid.org/0000-0002-1147-4960
                http://orcid.org/0000-0002-5910-2832
                Article
                Publisher ID: 239458
                DOI: 10.2147/DDDT.S239458
                PMC ID: 7049284
                PubMed ID: 32158196
                SO-VID: bdecf322-90a0-4f3c-a12b-a1eba3250ac9
                Copyright © © 2020 Attwa et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 21 November 2019
                Date accepted : 08 February 2020
                Page count
                Figures: 8, Tables: 5, References: 26, Pages: 11
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: talazoparib,metabolic stability evaluation,human liver microsomes,tandem mass spectrometry,derek,stardrop software
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: talazoparib, metabolic stability evaluation, human liver microsomes, tandem mass spectrometry, derek, stardrop software

                Comments

                Comment on this article

                scite_

                Similar content231

                See all similar

                Cited by16

                See all cited by

                Most referenced authors477

                See all reference authors