The use of ROC analysis for the qualitative prediction of human oral bioavailability from animal data.
OBJECTIVE
To develop and evaluate a tool for the qualitative prediction of human oral bioavailability (Fhuman) from animal oral bioavailability (Fanimal) data employing ROC analysis and to identify the optimal thresholds for such predictions.


METHODS
A dataset of 184 compounds with known Fhuman and Fanimal in at least one species (mouse, rat, dog and non-human primates (NHP)) was employed. A binary classification model for Fhuman was built by setting a threshold for high/low Fhuman at 50%. The thresholds for high/low Fanimal were varied from 0 to 100 to generate the ROC curves. Optimal thresholds were derived from 'cost analysis' and the outcomes with respect to false negative and false positive predictions were analyzed against the BDDCS class distributions.


RESULTS
We successfully built ROC curves for the combined dataset and per individual species. Optimal Fanimal thresholds were found to be 67% (mouse), 22% (rat), 58% (dog), 35% (NHP) and 47% (combined dataset). No significant trends were observed when sub-categorizing the outcomes by the BDDCS.


CONCLUSIONS
Fanimal can predict high/low Fhuman with adequate sensitivity and specificity. This methodology and associated thresholds can be employed as part of decisions related to planning necessary studies during development of new drug candidates and lead selection.
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
Andrés
A
Olivares-Morales
Oliver J D
OJ
Hatley
David
D
Turner
Aleksandra
A
Galetin
Leon
L
Aarons
Amin
A
Rostami-Hodjegan
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D006801:Humans; D051379:Mice; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D012372:ROC Curve; D051381:Rats
D004364:Pharmaceutical Preparations