title: Application of hybrid approach based on empirical and physiological concept for predicting pharmacokinetics in humans--usefulness of exponent on prospective evaluation of predictability.
abstract: We developed a hybrid method for predicting plasma concentration-time curves in humans by integrating species differences in in vitro intrinsic clearance (CL(int)) into the Dedrick approach based on the allometry concept. With prediction of clearance (CL) by allometric scaling, taking in vitro CL(int) into consideration improved the accuracy and reduced the average fold error from 2.72 to 1.99. With the hybrid approach of applying the same concept to the Dedrick approach, the predictability of plasma concentration profiles was compared with the results of the conventional Dedrick approach and the physiologically based pharmacokinetic model using 15 compounds with widely ranging physicochemical and pharmacokinetic profiles. The hybrid approach showed the highest predictability among the examined methods. For CL and the apparent volume of distribution at the steady state (V(ss)), the relationship between the exponent of allometric equation and fold error was also evaluated with the hybrid approach. The relationship appeared to be a horseshoe curve. Six compounds with exponents ranging from 0.7 to 1.1 for both CL and V(ss) [antipyrine, caffeine, epiroprim, propafenone, theophylline, and verapamil] displayed higher predictability. Three compounds with an exponent ranging from 0.7 to 1.1 for CL showed better predictability for CL, and the other four compounds appeared to display similar relationship between the exponent and predictability for V(ss). These findings indicated that the exponent becomes a preliminary index to speculate on predictability. Combination of the hybrid approach and exponent allows us to prospectively draw human plasma concentration-time curves, with the implication of possible prediction accuracy prior to clinical studies.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan TobaccoInc., Osaka, Japan. hiroshi.komura@jt.com
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sayama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Komura
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kogayu
mesh_terms: D000818:Animals; D001835:Body Weight; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D008099:Liver / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D009929:Organ Size; D004364:Pharmaceutical Preparations / Q000097:blood / Q000378:metabolism*; D010599:Pharmacokinetics; D011446:Prospective Studies; D011817:Rabbits; D051381:Rats; D015203:Reproducibility of Results; D013045:Species Specificity
chemical_list: D004364:Pharmaceutical Preparations