Considerations for Dose Selection and Clinical Pharmacokinetics/Pharmacodynamics for the Development of Antibacterial Agents

Abstract

In June 2017, The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled “Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens” to discuss details and critical parameters of various PK/PD methods and identify approaches for linking human pharmacokinetic (PK) data and drug efficacy analyses. The workshop participants included individuals from academia, industry, and government. This and the accompanying minireview on nonclinical PK/PD summarize the workshop discussions and recommendations. It is important to consider how information like PK/PD can support the clinical effectiveness of new antibacterial drugs, as PK/PD data have become central to antibacterial drug development programs. Key clinical considerations for antibacterial dose selection and clinical PK/PD characterization discussed in this minireview include a robust assessment of PK in the patient population of interest, critical considerations for assessing drug penetration in the lung for the treatment of pneumonia, and an emphasis on special populations, including patients with renal impairment and augmented renal function, as well as on dosing in obese and pediatric patients. Successful application of such approaches is now used to provide a more informative drug development package to support the approval of new antibiotics.

Generating Robust and Informative Nonclinical In Vitro and In Vivo Bacterial Infection Model Efficacy Data To Support Translation to Humans

“…This may have implications for translation to broad coverage and clinical utility of antibiotics (53, 92–94). Moreover, this reinforces the need to include a sufficiently diverse spectrum of bacterial strains in nonclinical PK/PD models and to consider the potentially substantial between-patient variability in PK, especially in unstable patients with sepsis or septic shock (see companion review [95]).…”

Sex Steroids Induce Membrane Stress Responses and Virulence Properties in Pseudomonas aeruginosa

“…Despite emerging evidence of potential sex bias in infection, therapeutic strategies and antimicrobial treatments remain unchanged and do not currently account for gender ( 1 , 4 , 5 ). Antimicrobial dosing is currently largely determined using in vitro and in vivo pharmacotherapeutic studies with environmental conditions focused on host immunity, the pathogen’s antimicrobial susceptibility, and the antimicrobial agents’ pharmacokinetic properties ( 62 ). However, patients who are treated with concomitant and sometimes combination therapies are at the same time exposed to their natural circulating hormones that, based on the data presented, confer an additional and largely unrecognized effect on pathogen virulence and evolution and antimicrobial susceptibility.…”

The pharmacokinetic/pharmacodynamic paradigm for antimicrobial drugs in veterinary medicine: Recent advances and critical appraisal

“…2—a more advanced approach replaces the dose (external exposure) by a measured index of the internal exposure [Area Under the Plasma Concentration‐time Curve (AUC), Maximum plasma concentration (Cmax), Time above the MIC (T > MIC)] as independent variable. This approach provides more information than the external dose, because it encompasses inter‐animal variability of the explicative variable captured by PK variables (clearance and bioavailability) (Rizk et al., 2019). 3—The PK/PD approach scales the index of internal exposure by MIC, which is a measured PD variable, to predict both microbiological cure and clinical cure.…”

“…” The workshop aims were to discuss various PK/PD models and to promote the use of PK/PD relationships in designing optimal dosage regimens for patients. Two major reviews have summarized the discussions and recommendations on generating “ Nonclinical In Vitro and In Vivo Bacterial Infection Model Efficacy Data To Support Translation to Humans ” (Bulitta et al., 2019) and defined the key clinical considerations for antibacterial dose selection and clinical PK/PD characterization (Rizk et al., 2019).…”