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.

Keywords: antibacterial; best practices/recommendations; clinical; dose selection; drug development; drug penetration; patient population; pharmacokinetics/pharmacodynamics; translation; workshop.

FIG 1

Area under the plasma concentration-time curve (AUC_0–inf) distributions for three different doses of a hypothetical antibacterial agent. (Reprinted from reference with permission from Elsevier.)

FIG 2

Approaches for assessing optimal dosing for the treatment of pneumonia.

FIG 3

Probability of target attainment for the FDA-approved moderate renal impairment ceftazidime-avibactam dose relative to the phase 3 clinical trial dose among patients whose renal function improved from moderate impairment to the mild impairment (CL_CR, 51 to 80 ml/min) and normal function (CL_CR, >80 ml/min) categories. (Reprinted from reference with permission from John Wiley & Sons, Inc.)