A comprehensive analysis of the role of correction factors in the allometric predictivity of clearance from rat, dog, and monkey to humans.
This study was conducted to comprehensively evaluate the performance of various allometric scaling methods for the prediction of human clearance. Allometric scaling was used to predict clearance for 103 compounds, for which clearance data in the rat, dog, monkey, and humans were available. Allometry was performed using all three preclinical species and with combinations of any two species. The methods employed included standard allometry and various correction factors, including brain weight, maximum lifespan potential, and glomerular filtration. Scaling was performed on all compounds universally and on segregated subsets based on allometric exponent, clearance, physicochemical property, or route of elimination. 776 allometric combinations with 27,313 individual outcomes were performed. A predicted-to-observed clearance ratio of 0.5 to twofold was preselected as the criterion for predictive success. The success rate of allometric scaling ranged from 18 to 53%; none of the correction factors resulted in substantially improved predictivity. Furthermore, none of the methods attempted in this study achieved a success rate greater than that observed by simply estimating human clearance based on monkey hepatic extraction. Prospective allometric scaling, with or without correction factors, represents a suboptimal technique for estimating human clearance based on in vivo preclinical data.
Nagilla
Rakesh
R
Preclinical Drug Discovery, Cardiovascular & Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406, USA. Rakesh2.Nagilla@gsk.com
Ward
Keith W
KW
D000818:Animals; D001699:Biometry; D001921:Brain / Q000033:anatomy & histology; D004285:Dogs; D005919:Glomerular Filtration Rate; D000882:Haplorhini; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000098:blood supply; D008954:Models, Biological; D009929:Organ Size; D010599:Pharmacokinetics; D051381:Rats; D012039:Regional Blood Flow; D013045:Species Specificity