Translational PK/PD for the Development of Novel Antibiotics-A Drug Developer's Perspective

Antibiotic development traditionally involved large Phase 3 programs, preceded by Phase 2 studies. Recognizing the high unmet medical need for new antibiotics and, in some cases, challenges to conducting large clinical trials, regulators created a streamlined clinical development pathway in which a...

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Bibliographic Details
Published in:Antibiotics (Basel) 2024-01, Vol.13 (1), p.72
Main Authors: Bissantz, Caterina, Zampaloni, Claudia, David-Pierson, Pascale, Dieppois, Guennaelle, Guenther, Andreas, Trauner, Andrej, Winther, Lotte, Stubbings, William
Format: Article
Language:English
Subjects:
Antibiotics
Antimicrobial agents
Bacteria
Bacterial infections
Clinical trials
drug development
Drug dosages
Drug resistance
Effectiveness
FDA approval
Gram-negative bacteria
Infections
Infectious diseases
Pathogens
Patients
Pharmacodynamics
Pharmacokinetics
PK/PD index
Pneumonia
PTA
R&D
regulatory
Regulatory approval
Research & development
Risk reduction
Robustness
Sulbactam
Tazobactam
Tetracycline
Tetracyclines
Translation
translational PK/PD
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Summary:Antibiotic development traditionally involved large Phase 3 programs, preceded by Phase 2 studies. Recognizing the high unmet medical need for new antibiotics and, in some cases, challenges to conducting large clinical trials, regulators created a streamlined clinical development pathway in which a lean clinical efficacy dataset is complemented by nonclinical data as supportive evidence of efficacy. In this context, translational Pharmacokinetic/Pharmacodynamic (PK/PD) plays a key role and is a major contributor to a "robust" nonclinical package. The classical PK/PD index approach, proven successful for established classes of antibiotics, is at the core of recent antibiotic approvals and the current antibacterial PK/PD guidelines by regulators. Nevertheless, in the case of novel antibiotics with a novel Mechanism of Action (MoA), there is no prior experience with the PK/PD index approach as the basis for translating nonclinical efficacy to clinical outcome, and additional nonclinical studies and PK/PD analyses might be considered to increase confidence. In this review, we discuss the value and limitations of the classical PK/PD approach and present potential risk mitigation activities, including the introduction of a semi-mechanism-based PK/PD modeling approach. We propose a general nonclinical PK/PD package from which drug developers might choose the studies most relevant for each individual candidate in order to build up a "robust" nonclinical PK/PD understanding.
ISSN:2079-6382
2079-6382
DOI:10.3390/antibiotics13010072