Does In Vitro Potency Predict Clinically Efficacious Concentrations?
Open Access
- 10 April 2020
- journal article
- research article
- Published by Wiley in Cancer Cell
- Vol. 108 (2), 298-305
- https://doi.org/10.1002/cpt.1846
Abstract
The in vitro affinity of a compound for its target is an important feature in drug discovery, but what remains is how predictive in vitro properties are of in vivo therapeutic drug exposure. We assessed the relationship between in vitro potency and clinically efficacious concentrations for marketed small molecule drugs (n = 164) and how they may differ depending on therapeutic indication, mode of action, receptor type, target localization, and function. Approximately 70% of compounds had a therapeutic unbound plasma exposure lower than in vitro potency; the median ratio of exposure in relation to in vitro potency was 0.32, and 80% had ratios within the range of 0.007 to 8.7. We identified differences in the in vivo–to–in vitro potency ratio between indications, mode of action, target type, and matrix localization, and whether or not the drugs had active metabolites. The in vitro–assay variability contributions appeared to be the smallest; within the same drug target and mode of action the within‐variability was slightly broader; but both were substantially less compared with the overall distribution of ratios. These data suggest that in vitro potency conditions, estimated in vivo potency, required level of receptor occupancy, and target turnover are key components for further understanding the link between clinical drug exposure and in vitro potency.Keywords
This publication has 40 references indexed in Scilit:
- In Vitro–In Vivo Correlation of the Inhibition Potency of Sodium-Glucose Cotransporter Inhibitors in Rat: A Pharmacokinetic and Pharmacodynamic Modeling ApproachJournal of Pharmacology and Experimental Therapeutics, 2013
- The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discoveryNature Reviews Drug Discovery, 2010
- Drug profiling: knowing where it hitsDrug Discovery Today, 2010
- Early integration of pharmacokinetic and dynamic reasoning is essential for optimal development of lead compounds: strategic considerationsDrug Discovery Today, 2009
- Target site occupancy: Emerging generalizations from clinical and preclinical studiesPharmacology & Therapeutics, 2009
- Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 670 Drug CompoundsDrug Metabolism and Disposition, 2008
- On The Rate and Extent of Drug Delivery to the BrainPharmaceutical Research, 2007
- Establishment of Correlation between in Vitro Enzyme Binding Potency and in Vivo Pharmacological Activity: Application to Liver Glycogen Phosphorylase a InhibitorsJournal of Pharmacology and Experimental Therapeutics, 2006
- International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative PharmacologyPharmacological Reviews, 2003
- Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reactionBiochemical Pharmacology, 1973