Translational PK/PD for the Development of Novel Antibiotics—A Drug Developer’s Perspective

Abstract

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.

Revisiting the Checkerboard to Inform Development of β-Lactam/β-Lactamase Inhibitor Combinations

“…The categorization of strains/isolates based on the predominant mechanism of action is particularly important when attempting to establish PK/PD indices for β-lactamase inhibitors with direct antibacterial effects, as well as inhibiting β-lactamase activity. While they have limitations (e.g., [28]), PK/PD indices are extensively used to extrapolate results from nonclinical models to a clinical setting and support clinical dose selection [9][10][11][12][13][29][30][31]. Standard PK/PD indices are believed to reflect the underlying mechanism of antibacterial activity, e.g., C max /MIC is associated with concentration-dependent bactericidal activity, while %T > MIC is associated with time-dependent effects.…”

“…For example, it has been reported that even high doses of nacubactam monotherapy are not effective in in vivo models against some carbapenem-resistant Enterobacterales isolates despite low in vitro nacubactam MICs [45]. In such circumstances, mechanistic or semi-mechanistic PK/PD modeling (e.g., [13,31,[46][47][48]) offers potential advantages over traditional PK/PD indices.…”

“…A number of β-lactam plus β-lactamase inhibitor combinations have received regulatory approval for clinical use, and more are currently in development [8]. All programs rely extensively on established pharmacokinetic/pharmacodynamic (PK/PD) principles to extrapolate nonclinical information and guide clinical development decisions [9][10][11][12][13], but there remains a lack of consensus about the best way to optimize dosing of the β-lactamase inhibitor (e.g., [14]), particularly if the β-lactamase inhibitor also has direct antibacterial activity.…”