Exploring the Impact of Pharmacological Target-Mediated Low Plasma Exposure in Lead Compound Selection in Drug Discovery – A Modeling Approach

Mullard A. 2023 FDA approvals. Nat Rev Drug Discov. 2024;23(2):88–95. https://doi.org/10.1038/d41573-024-00001-x.

Article  CAS  PubMed  Google Scholar 

Mullard A. 2022 FDA approvals. Nat Rev Drug Discov. 2023;22(2):83–8. https://doi.org/10.1038/d41573-023-00001-3.

Article  CAS  PubMed  Google Scholar 

Mullard A. 2021 FDA approvals. Nat Rev Drug Discov. 2022;21(2):83–8. https://doi.org/10.1038/d41573-022-00001-9.

Article  CAS  PubMed  Google Scholar 

Mullard A. 2020 FDA drug approvals. Nat Rev Drug Discov. 2021;20(2):85–90. https://doi.org/10.1038/d41573-021-00002-0.

Article  CAS  PubMed  Google Scholar 

Mullard A. 2019 FDA drug approvals. Nat Rev Drug Discov. 2020;19(2):79–84. https://doi.org/10.1038/d41573-020-00001-7.

Article  CAS  PubMed  Google Scholar 

Thomas D MA, LaFever S. Clinical development success rates and contributing factors 2011–2020. 2021. Available from: https://go.bio.org/rs/490-EHZ-999/images/ClinicalDevelopmentSuccessRates2011_2020.pdf.

Arrowsmith J. Trial watch: phase III and submission failures: 2007–2010. Nat Rev Drug Discov. 2011;10(2):87. https://doi.org/10.1038/nrd3375.

Article  CAS  PubMed  Google Scholar 

Arrowsmith J, Miller P. Trial watch: phase II and phase III attrition rates 2011–2012. Nat Rev Drug Discov. 2013;12(8):569. https://doi.org/10.1038/nrd4090.

Article  CAS  PubMed  Google Scholar 

Harrison RK. Phase II and phase III failures: 2013–2015. Nat Rev Drug Discov. 2016;15(12):817–8. https://doi.org/10.1038/nrd.2016.184.

Article  CAS  PubMed  Google Scholar 

Dowden H, Munro J. Trends in clinical success rates and therapeutic focus. Nat Rev Drug Discov. 2019;18(7):495–6. https://doi.org/10.1038/d41573-019-00074-z.

Article  CAS  PubMed  Google Scholar 

Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022;12(7):3049–62. https://doi.org/10.1016/j.apsb.2022.02.002.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Di EHKaL. Chapter 19 - Pharmacokinetics. In: Edward H. Kerns LD, editors. Drug-like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization. San Diego: Academic Press; 2016. pp. 228–41.

An G, Katz DA. Importance of Target-Mediated Drug Disposition (TMDD) of small-molecule compounds and its impact on drug development-example of the class effect of HSD-1 inhibitors. J Clin Pharmacol. 2023;63(5):526–38. https://doi.org/10.1002/jcph.2185.

Article  CAS  PubMed  Google Scholar 

An G, Liu W, Katz DA, Marek GJ, Awni W, Dutta S. Population pharmacokinetics of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor ABT-384 in healthy volunteers following single and multiple dose regimens. Biopharm Drug Dispos. 2014;35(7):417–29. https://doi.org/10.1002/bdd.1912.

Article  CAS  PubMed  Google Scholar 

Wu N, Katz DA, An G. A target-mediated drug disposition model to explain nonlinear pharmacokinetics of the 11beta-Hydroxysteroid dehydrogenase type 1 inhibitor SPI-62 in healthy adults. J Clin Pharmacol. 2021;61(11):1442–53. https://doi.org/10.1002/jcph.1925.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wright DH, Stone JA, Crumley TM, Wenning L, Zheng W, Yan K, et al. Pharmacokinetic-pharmacodynamic studies of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor MK-0916 in healthy subjects. Br J Clin Pharmacol. 2013;76(6):917–31. https://doi.org/10.1111/bcp.12131.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gong J, Hansen L, Iacono L. Clinical Pharmacokinetics and the Impact of Genetic Polymorphism on a CYP2C19 Substrate, BMS-823778, Healthy Subjects. Drug Metab Dispos. 2018;46(3):316–25. https://doi.org/10.1124/dmd.117.078824.

Article  PubMed  Google Scholar 

Yuan X, An G. Characterizing the nonlinear pharmacokinetics and pharmacodynamics of BI 187004, an 11beta-Hydroxysteroid dehydrogenase type 1 inhibitor, in humans by a target-mediated drug disposition model. J Clin Pharmacol. 2024. https://doi.org/10.1002/jcph.2438.

Article  PubMed  Google Scholar 

Bellaire S, Walzer M, Wang T, Krauwinkel W, Yuan N, Marek GJ. Safety, pharmacokinetics, and pharmacodynamics of ASP3662, a novel 11beta-hydroxysteroid dehydrogenase type 1 inhibitor, in healthy young and elderly subjects. Clin Transl Sci. 2019;12(3):291–301. https://doi.org/10.1111/cts.12618.

Article  CAS  PubMed  PubMed Central  Google Scholar 

An G, Liu W, Dutta S. Small-molecule compounds exhibiting target-mediated drug disposition - A case example of ABT-384. J Clin Pharmacol. 2015;55(10):1079–85. https://doi.org/10.1002/jcph.531.

Article  CAS  PubMed  Google Scholar 

An G, Katz DA. Importance of target-mediated drug disposition (TMDD) of small-molecule compounds and its impact on drug development - example of the class effect of HSD-1 inhibitors. J Clin Pharmacol. 2022. https://doi.org/10.1002/jcph.2185.

Article  PubMed  Google Scholar 

Rowland M, Peck C, Tucker G. Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol. 2011;51:45–73. https://doi.org/10.1146/annurev-pharmtox-010510-100540.

Article  CAS  Google Scholar 

Cao Y, Jusko WJ. Applications of minimal physiologically-based pharmacokinetic models. J Pharmacokinet Pharmacodyn. 2012;39(6):711–23. https://doi.org/10.1007/s10928-012-9280-2.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10(7):1093–5. https://doi.org/10.1023/a:1018943613122.

Article  CAS  PubMed  Google Scholar 

Hall C, Lueshen E, Mosat A, Linninger AA. Interspecies scaling in pharmacokinetics: a novel whole-body physiologically based modeling framework to discover drug biodistribution mechanisms in vivo. J Pharm Sci. 2012;101(3):1221–41. https://doi.org/10.1002/jps.22811.

Article  CAS  Google Scholar 

Murphrey MB, Quaim L, Rahimi N, Varacallo M. Biochemistry, Epidermal Growth Factor Receptor. StatPearls. Treasure Island (FL) ineligible companies. Disclosure: Lamisa Quaim declares no relevant financial relationships with ineligible companies. Disclosure: Nader Rahimi declares no relevant financial relationships with ineligible companies. Disclosure: Matthew Varacallo declares no relevant financial relationships with ineligible companies. 2024.

The Human Protein Atlas. [cited 2024 8/21]; Available from: https://www.proteinatlas.org/ENSG00000097007-ABL1/tissue.

The Human Protein Atlas. [cited 2024 8/21]; Available from: https://www.proteinatlas.org/ENSG00000132155-RAF1/tissue.

D’Cunha RR, Murry DJ, An G. Nilotinib alters the efflux transporter-mediated pharmacokinetics of afatinib in mice. J Pharm Sci. 2019;108(10):3434–42. https://doi.org/10.1016/j.xphs.2019.05.028.

Article  CAS  PubMed  Google Scholar 

Bi Y, Deng J, Murry DJ, An G. A whole-body physiologically based pharmacokinetic model of gefitinib in mice and scale-up to humans. AAPS J. 2016;18(1):228–38. https://doi.org/10.1208/s12248-015-9836-3.

Article  CAS  PubMed  Google Scholar 

Bae S, D’Cunha R, Shao J, An G. Effect of 5,7-dimethoxyflavone on Bcrp1-mediated transport of sorafenib in vitro and in vivo in mice. Eur J Pharm Sci. 2018;117:27–34. https://doi.org/10.1016/j.ejps.2018.02.004.

Article  CAS  PubMed  Google Scholar 

D’Cunha RR. Treatment strategies to reverse efflux transporter-mediated resistance to tyrosine kinase inhibitors [Thesis]: University of Iowa; 2018.

Zhang SR, Zhu LC, Jiang YP, Zhang J, Xu RJ, Xu YS, et al. Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice. Acta Pharmacol Sin. 2017;38(2):233–40. https://doi.org/10.1038/aps.2016.107.

Article  CAS  PubMed  Google Scholar 

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