Affiliation:
1. Walter Reed Army Institute of Research, Experimental Therapeutics, Silver Spring, MD 20910, USA
Abstract
We sought to better understand the utility and role of animal models of infection for Food and Drug Administration (FDA)-approved antibiotics for the indications of community-, hospital-acquired-, and ventilator-associated bacterial pneumonia (CABP, HABP, VABP), complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), and acute bacterial skin and structural infections (ABSSSIs). We reviewed relevant documents from new drug applications (NDA) of FDA-approved antibiotics from 2014–2019 for the above indications. Murine neutropenic thigh infection models supported the choice of a pharmacokinetic-pharmacodynamic (PKPD) target in 11/12 NDAs reviewed. PKPD targets associated with at least a 1-log bacterial decrease were commonly considered ideal (10/12 NDAs) to support breakpoints. Plasma PK, as opposed to organ specific PK, was generally considered most reliable for PKPD correlation. Breakpoint determination was multi-disciplinary, accounting at minimum for epidemiologic cutoffs, non-clinical PKPD, clinical exposure-response and clinical efficacy. Non-clinical PKPD targets in combination with probability of target attainment (PTA) analyses generated breakpoints that were consistent with epidemiologic cutoffs and clinically derived breakpoints. In 6/12 NDAs, there was limited data to support clinically derived breakpoints, and hence the non-clinical PKPD targets in combination with PTA analyses played a heightened role in the final breakpoint determination. Sponsor and FDA breakpoint decisions were in general agreement. Disagreement may have arisen from differences in the definition of the optimal PKPD index or the ability to extrapolate protein binding from animals to humans. Overall, murine neutropenic thigh infection models supported the reviewed NDAs by providing evidence of pre-clinical efficacy and PKPD target determination, and played, in combination with PTA analysis, a significant role in breakpoint determination for labeling purposes.
Reference35 articles.
1. Role of animal models in biomedical research: A review;Mukherjee;Lab. Anim. Res.,2022
2. How necessary are animal models for modern drug discovery?;Singh;Expert Opin. Drug Discov.,2021
3. FDA Public Workshop Summary: Advancing Animal Models for Antibacterial Drug Development;Byrne;Antimicrob. Agents Chemother.,2020
4. Food and Drug Administration (2023, September 27). Microbiology Data for Systemic Antibacterial Drugs—Development, Analysis, and Presentation Guidance for Industry, Available online: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/microbiological-data-systemic-antibacterial-drug-products-development-analysis-and-presentation.
5. Food and Drug Administration (2023, September 27). Antibacterial Therapies for Patients with an Unmet Medical Need for the Treatment of Serious Bacterial Diseases Questions and Answers (Revision 1) Guidance for Industry, Available online: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/antibacterial-therapies-patients-unmet-medical-need-treatment-serious-bacterial-diseases-questions.