Evaluation of innovative Tools in development of Antibiotics

Due to economic reasons the development of novel antibiotics was neglected by the pharmaceutical industry in the last decade. However, bacteria that are resistant to all available antibiotics have recently been recognized as emerging treat globally. Novel and faster ways of clinical development of new antibiotics are urgently needed. Supported by recent guidelines from regulatory bodies pharmacokinetic (PK) studies, i.e. studies describing how a drug is distributed in the human body, have gained a key role in the development of antibiotics. PK in plasma and at the infection site, e.g. the lung, thereby can build the base for estimation of efficacy of antibiotics without the need of large pivotal studies involving several hundred patients. The current project aims at the development and validation of sampling techniques in order to allow for accelerating and optimizing the development of new antibiotics. Hypothesis: Currently PK properties of a new antibiotic are mainly studied in blood and organs or healthy subjects. These data build the base for important decisions during clinical development. We hypothesize that relevant differences between infected patients and healthy volunteers exist and it is necessary and feasible to determine plasma and tissue PK in patients much earlier during antimicrobial drug development. Methods: Usual PK studies in patients might not be initiated before a wide range of preclinical and clinical studies have been performed. Microdosing is a method which allows determining PK of a drug by using extremely low doses of a drug in combination with highly sensitive quantification methods early during development while minimizing the risk for the study participants. However, it is unknown, whether microdosing can be performed in combination with techniques for determination of the tissue penetration of antibiotics. The present study will set out to explore potential differences in PK of ciprofloxacin and imipenem, two antibiotics used in the treatment of bacterial pneumonia, in plasma and in the lung between healthy subjects and patients. Antibiotic concentrations will be determined in blood and the fluid obtained from the lung lavage. Healthy volunteers will additionally receive a microdose of ciprofloxacin and undergo microdialysate sampling, which is a technique for determination concentrations in the skin, another potential site of infection. What is new: This study will provide information if PK data obtained from healthy volunteers can be used as surrogate for patients with pneumonia, potentially leading to a paradigm change in modern development of antibiotics. Furthermore this study will show whether microdosing might be extended to assessment of tissue PK of antibiotics. For the first time the combination of microdialysis, lung lavage and microdosing will support the societys demand for faster and cost effective antimicrobial development.

An innovative tool for accelerating and optimizing the development of new antibiotics Due to economic reasons the development of novel antibiotics was neglected by the pharmaceutical industry in the last decade. However, bacteria that are resistant to all available antibiotics have recently been recognized as emerging treat globally. Novel and faster ways of clinical development of new antibiotics are urgently needed. Supported by recent guidelines from regulatory bodies pharmacokinetic (PK) studies, i.e. studies describing how a drug is distributed in the human body, have gained a key role in the development of antibiotics. PK in plasma and at the infection site, e.g. the skin or the lung, thereby can build the base for estimation of efficacy of antibiotics without the need of large pivotal studies involving several hundred patients. The current project aimed at the development and validation of sampling techniques in order to allow for accelerating and optimizing the Microdosing is a nuclear-medicine method which allows determining the PK of a drug by using extremely low doses of a drug in combination with highly sensitive quantification methods early during development while minimizing the risk for the study participants. However, it is unknown, whether microdosing can be performed in combination with techniques for determination of the tissue penetration of antibiotics. By investigating 18 healthy volunteers we were for the first time able to demonstrate that microdosing indeed can be used to determine tissue concentrations of antibiotics. Microdosing predicted the clinical pharmacokinetics with high accuracy but without exposing volunteers to the potential harm of clinically active doses. Thereby we generated a novel tool that may support the society's demand for faster and cost effective antimicrobial development and at the same time reduces the need for preclinical experiments in animals.