Biodistribution and Pharmacokinetics of Antimicrobials

Abstract

Inadequate drug concentrations in target tissues can lead to treatment failure and/or selection of drug-resistant organisms. Additionally, altered pharmacokinetics in diseased patients may elevate tissue drug levels leading to organ toxicity or failure. A major advantage of PET-based bioimaging is its ability to measure in situ biodistribution of antimicrobials in real time and simultaneously in multiple organ system/compartments in live animals, with relatively unaltered physiology. This technology overcomes some fundamental limitations of current methodologies and could provide detailed preclinical data for appropriate dosing of new and existing antimicrobials. Such tracers could also enable the first-in-human clinical (phase 0) studies that are recognized by the US Food and Drug Administration to support Investigational New Drug Applications (FDA, Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078933.pdf, 2012). Human subject safety may be improved by using a PET tracer microdosing approach in early drug development which could eliminate the development of drugs with an unfavorable pharmacokinetic profiles and potential toxicities at higher doses. The approach can be extended to drug-drug interaction studies and to vulnerable populations, such as hepatically or renally impaired patients. Finally, PET tracers could also be adapted to study pharmacogenetics or personalized medicine approaches in the practice of medicine.