PT  - JOURNAL ARTICLE
AU  - Urban Fagerholm
TI  - Evaluation of the reliability and applicability of human unbound brain-to-plasma concentration ratios
AID  - 10.1101/2022.11.14.516429
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.11.14.516429
4099  - http://biorxiv.org/content/early/2022/11/20/2022.11.14.516429.short
4100  - http://biorxiv.org/content/early/2022/11/20/2022.11.14.516429.full
AB  - Background Blood-brain barrier permeability (BBB Pe) and unbound brain-to-plasma concentration ratio (Kp,uu,brain) are relevant parameters describing the brain uptake potential of compounds. BBB efflux by transporter proteins, mainly MDR-1 and BCRP, is an essential factor determining Kp,uu,brain. Kp,uu,brain-values are commonly estimated in vivo in rats and monkeys and predicted using in silico methodology. Such estimates can be used to predict corresponding human clinical values.Objective The objective of the study was to evaluate the reliability and applicability of human clinical Kp,uu,brain-data for understanding and predictions of brain uptake in man.Methodology Kp,uu,brain in rats, monkeys and humans, measured and in silico predicted MDR-1 and BCRP substrate specificities and in silico predicted passive Pe were used for the analysis. In silico predictions were done using the ANDROMEDA by Prosilico ADME/PK-prediction software.Results and Discussion Rat and monkey Kp,uu,brain-values were highly correlated (R^2=0.74; n=17). Based on this finding a correlation between rat and human Kp,uu,brain was expected. However, no correlation between rat and human Kp,uu,brain was found (R^2=0.01; n=13). There was no (as also anticipated) correlation between passive Pe and human Kp,uu,brain (R^2=0.04; n=16) and compounds with measured or predicted efflux did not have lower Kp,uu,brain than compounds without efflux. The compound with highest Kp,uu,brain in man (2.8) is effluxed and predicted to have high passive Pe and has no apparent efflux at the rat BBB. The MDR-1 substrate with highest Kp,uu,brain in rat (2.4) has very low Kp,uu,brain in man (0.15) is predicted to have high passive Pe.Conclusion Results indicate that available human Kp,uu,brain-data are too uncertain to be applicable for validation of predictions and understanding of clinical brain uptake of drugs and drug candidates.Competing Interest StatementUrban Fagerholm declares shares in Prosilico AB, a Swedish company that develops solutions for human clinical ADME/PK predictions.