Landscape of regulatory quantitative systems pharmacology submissions to the U.S. Food and Drug Administration: An update report.

Publisher: Wiley Country of Publication: United States NLM ID: 101580011 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2163-8306 (Electronic) Linking ISSN: 21638306 NLM ISO Abbreviation: CPT Pharmacometrics Syst Pharmacol Subsets: MEDLINE

Publication: 2015- : Hoboken, NJ : Wiley
Original Publication: New York, NY : Nature Pub. Group

United States Food and Drug Administration* ; Drug Development*/methods ; Network Pharmacology*; United States ; Humans ; Drug Approval

The number of quantitative systems pharmacology (QSP) submissions to the U.S. Food and Drug Administration has continued to increase over the past decade. This report summarizes the landscape of QSP submissions as of December 2023. QSP was used to inform drug development across various therapeutic areas and throughout the drug development process of small molecular drugs and biologics and has facilitated dose finding, dose ranging, and dose optimization studies. Though the majority of QSP submissions (>66%) focused on drug effectiveness, QSP was also utilized to simulate drug safety including liver toxicity, risk of cytokine release syndrome (CRS), bone density, and others. This report also includes individual contexts of use from a handful of new drug applications (NDAs) and biologics license applications where QSP modeling was used to demonstrate the utility of QSP modeling in regulatory drug development. According to the models submitted in QSP submissions, an anonymous case was utilized to illustrate how QSP informed development of a bispecific monoclonal antibody with respect to CRS risk. QSP submissions for informing pediatric drug development were summarized along with highlights of a case in inborn errors of metabolism. Furthermore, simulations of response variability with QSP were described. In summary, QSP continues to play a role in informing drug development.
(Published 2024. This article is a U.S. Government work and is in the public domain in the USA. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Hosseini I, Gadkar K, Stefanich E, et al. Mitigating the risk of cytokine release syndrome in a phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling. NPJ Syst Biol Appl. 2020;6:28.
Bai JPF, Earp JC, Florian J, et al. Quantitative systems pharmacology: landscape analysis of regulatory submissions to the US Food and Drug Administration. CPT Pharmacometrics Syst Pharmacol. 2021;10:1479‐1484.
Bai JP, Wang J, Zhang Y, Wang L, Jiang X. Quantitative systems pharmacology for rare disease drug development. J Pharm Sci. 2023;112:2313‐2320.
US Food and Drug Administration. Drug Approval Package: XENPOZYME: Integrated Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761261Orig1s000IntegratedR.pdf. Accessed January 2024.
US Food and Drug Administration. PAXLOVID: Integrated Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217188Orig1s000IntegratedR.pdf. Accessed October 2023.
US Food and Drug Administration. Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans Guidance for Industry. https://www.fda.gov/media/86340/download#:~:text=A%20sponsor%20must%20submit%20an,between%20FDA%20and%20the%20sponsor. Accessed January 2024.
Li RJ, Ma L, Drozda K, et al. Model‐informed approach supporting approval of Nexviazyme (Avalglucosidase Alfa‐ngpt) in pediatric patients with late‐onset Pompe disease. AAPS J. 2023;25:16.
Abrams R, Kaddi CD, Tao M, et al. A quantitative systems pharmacology model of Gaucher disease type 1 provides mechanistic insight into the response to substrate reduction therapy with eliglustat. CPT Pharmacometrics Syst Pharmacol. 2020;9:374‐383.
Kaddi CD, Niesner B, Baek R, et al. Quantitative systems pharmacology modeling of acid sphingomyelinase deficiency and the enzyme replacement therapy olipudase alfa is an innovative tool for linking pathophysiology and pharmacology. CPT Pharmacometrics Syst Pharmacol. 2018;7:442‐452.
US Food and Drug Administraion. XENPOZYME Label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761261s002lbl.pdf. Accessed January 2024.
Bai JPF, Yu LR. Modeling clinical phenotype variability: consideration of genomic variations, computational methods, and quantitative proteomics. J Pharm Sci. 2022;112(4):904‐908.

Date Created: 20241018 Date Completed: 20241216 Latest Revision: 20241216

20241216

10.1002/psp4.13208

39423143