Quantitative pharmacology or pharmacokinetic pharmacodynamic integration should be a vital component in integrative pharmacology.
Pharmacodynamics (PD) examines the relationship between drug concentration and onset, intensity, and duration of the pharmacological effect. Pharmacokinetics (PK) is the science of the time course of drugs in the organism. The quantitative pharmacological approach focuses on concentration-response and response-time relationships, with special emphasis on the proposed impact of the drug on the disease. The review aims to raise awareness among pharmacologists with regard to why pharmacokinetic-pharmacodynamic (PKPD) integration is essential in basic pharmacology research to improve interpretation of data. Quantitative pharmacology is vital in drug discovery for target validation, optimizing the development of lead compounds, and scaling compounds to humans and has become mandatory for regulatory bodies. However, its use is still comparatively rare in experimental pharmacology, and its absence diminishes the interpretative value of published experimental data and can allow the presentation of misleading information. A primary requirement for PKPD integration is establishing the inter-relationships between in vitro and in vivo PK and PD properties and extrapolation to the known or possible future clinical use of a compound. This review examines the use of PKPD in experimental pharmacology by reviewing drug exposure measurements, plasma protein binding, exposure-effect relationships, and the measurement of active metabolites. It examines the significance of dosing schedules, the importance of target engagement, and problems in examining time-response relationships. It shows how quantitative pharmacology adds significant value to study design and examines why ignoring pharmacokinetics can lead to misleading results and conclusions. Finally, a guide list of points to be considered when performing studies is provided.
Discovery DMPK and BAC, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. johan.gabrielsson@astrazeneca.com
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Gabrielsson
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Green
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D010599:Pharmacokinetics; D010600:Pharmacology / Q000379:methods*; D011485:Protein Binding; D013045:Species Specificity
D001798:Blood Proteins; D004364:Pharmaceutical Preparations