Anna-Karin Sohlenius-Sternbeck, Juliette Janson, Johan Bylund, Pawel Baranczewski, Anna Breitholtz-Emanuelsson, Yin Hu, Carrie Tsoi, Anders Lindgren, Olle Gissberg, Tjerk Bueters, Sveinn Briem, Sanja Juric, Jenny Johansson, Margareta Bergh and Janet Hoogstraate Pages 253 - 270 ( 18 )
Background: The disposition of a drug is dependent on interactions between the body and the drug, its molecular properties and the physical and biological barriers presented in the body. In order for a drug to have a desired pharmacological effect it has to have the right properties to be able to reach the target site in sufficient concentration. This review details how drug metabolism and pharmacokinetics (DMPK) and physicochemical deliveries played an important role in data interpretation and compound optimization at AstraZeneca R&D in Södertälje, Sweden.
Methods: A selection of assays central in the evaluation of the DMPK properties of new chemical entities is presented, with guidance and consideration on assay outcome interpretation. Early in projects, solubility, LogD, permeability and metabolic stability were measured to support effective optimization of DMPK properties. Changes made to facilitate high throughput, efficient bioanalysis and the handling of large amounts of samples are described. Already early in drug discovery, we used an integrated approach for the prediction of the fate of drugs in human (early dose to man) based on data obtained from in vitro experiments. The early dose to man was refined with project progression, which triggered more intricate assays and experiments. At later stages, preclinical in vivo pharmacokinetic (PK) data was integrated with pharmacodynamics (PD) to allow predictions of required dose, dose intervals and exposure profile to achieve the desired effect in man.
Results and Conclusions: A well-defined work flow of DMPK activities from early lead identification up to the selection of a candidate drug was developed. This resulted in a cost effective and efficient optimization of chemical series, and facilitated informed decision making throughout project progress.
Clearance, DMPK, dose to man prediction, drug metabolism, optimization, permeability, pharmacokinetics, physicochemical properties.
DMPK, CNSP iMed, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden