The emergence of antimicrobial resistance is a major threat to both the public and medical progress and is forcing the scientific and regulatory communities to revise the requirements of clinical data to support new agents aimed at treating serious and life-threatening infections caused by highly resistant pathogens. As a result of a lack of patients infected with target bacterial species, conducting clinical trials to demonstrate efficacy against drug-resistant bacterial species is challenging. Pharmacokinetic/pharmacodynamics (PK/PD) data have become central to antibacterial drug development programs, and it is therefore necessary to consider how PK/PD information can support the clinical effectiveness of new antibacterial drugs.
Pharmacometrics represents a set of tools that help streamline the development of antibacterial agents. As development paths for indications involving multiple- or extensively drug-resistant pathogens evolve, it will be even more important to ensure that both preclinical and clinical PK/PD packages are strategically designed to account for the limited clinical data collected and that robust clinical PK and PK/PD data packages are assembled during early and late state development.
The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop in June 2017 titled “Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens” to discuss details and critical parameters of various PK/PD methods and to identify approaches for linking human PK data and drug efficacy analyses. Individuals from academia, industry, and government were included in this workshop.
For antibacterial dose selection and clinical PK/PD characterization, key clinical considerations discussed included a robust assessment of PK in patient populations of interest, critical considerations for assessing drug penetration in the lungs in the treatment of pneumonia, and an emphasis on special populations such as patients with renal impairment, are obese, and pediatric patients.
Ensuring optimal drug exposure at the infection site is highly important, especially in patients with pneumonia, in whom drug concentrations in the lungs can be assessed both in preclinical and clinical studies. At both extremes of renal function, it is critical for optimal dose selection, study drug clearance, and exposure profiles to be determined prior to phase 3 initiation. When selecting an antibiotic dosing regimen, consideration should be given to whether dosing should be fixed or weight-based. When efficacy can be extrapolated from adult studies, only pediatric PK and safety studies are required to establish the right dose. However, care should be taken to characterize and understand when differences in PK may manifest with antibacterial agents, especially in very young patients.
For this to be accomplished, it will be important to ensure that robust clinical PK and PK/PD data packages are assembled during early and late state development. Overall, the study authors concluded that, “consideration of studies and analyses described herein to support dose selection decisions for antibacterial agents will reduce the likelihood of drug development failures and more importantly, result in approved dosing regimens associated with optimized patient outcomes.”
Rizk ML, Bhavnani SM, Drusano G. Considerations for dose selection and clinical pharmacokinetics/pharmacodynamics for the development of antibacterial agents [published online March 4, 2019]. Antimicrob Agents Chemother. doi:10.1128/AAC.02309-18