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Pivotal Role of Translation in Anti-Infective Development.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2021 Apr; Vol. 109 (4), pp. 856-866. Date of Electronic Publication: 2021 Mar 08. - Publication Year :
- 2021
-
Abstract
- The value of model-based translation in drug discovery and development is now effectively being recognized in many disease areas and among various stakeholders. Such quantitative approaches are expected to facilitate the selection on which compound to prioritize for successful development, predict the human efficacious dose based on preclinical data with adequate precision, guide design, and de-risk later development stages. The importance of time-dependencies, which are typically species-dependent due to different turnover rates of biological processes, is, however, often neglected. For bacterial infections, the choice of dosing regimen is typically relying on preclinical pharmacokinetic (PK) and pharmacodynamic (PD) data, because the bacterial load and disease severity, and consequently the PK/PD relationship, cannot be quantified well on clinical data, given the low-information end points used. It is time to recognize the limitations of using time-collapsed approaches for translation (i.e., methods where targets are based on summary measures of exposure and response). Models describing the full time-course captures important quantitative information of drug distribution, bacterial growth, antibiotic killing, and resistance development, and can account for species-differences in the PK profiles driving the killing. Furthermore, with a model-based approach for translation, we can take a holistic approach in development of a joint model for in vitro, in vivo, and clinical data, as well as incorporating information on the contribution of the immune system. Such advancements are anticipated to facilitate rational decision making during various stages of drug development and in the optimization of treatment regimens for different groups of patients.<br /> (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Aminoglycosides pharmacology
Anti-Infective Agents pharmacokinetics
Antiviral Agents pharmacology
Carbapenems pharmacology
Dose-Response Relationship, Drug
Drug Approval organization & administration
Drug Discovery organization & administration
Drug Evaluation, Preclinical methods
Drug Resistance, Microbial drug effects
Drug Resistance, Microbial physiology
Drug Therapy, Combination
Humans
Nebramycin analogs & derivatives
Nebramycin pharmacology
Research Design
United States
United States Food and Drug Administration standards
Anti-Infective Agents pharmacology
Drug Development organization & administration
Models, Biological
United States Food and Drug Administration organization & administration
Subjects
Details
- Language :
- English
- ISSN :
- 1532-6535
- Volume :
- 109
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 33523464
- Full Text :
- https://doi.org/10.1002/cpt.2182