title: Systematic Evaluation of Wajima Superposition (Steady-State Concentration to Mean Residence Time) in the Estimation of Human Intravenous Pharmacokinetic Profile.
abstract: We present a systematic evaluation of the Wajima superpositioning method to estimate the human intravenous (i.v.) pharmacokinetic (PK) profile based on a set of 54 marketed drugs with diverse structure and range of physicochemical properties. We illustrate the use of average of "best methods" for the prediction of clearance (CL) and volume of distribution at steady state (VDss) as described in our earlier work (Lombardo F, Waters NJ, Argikar UA, et al. J Clin Pharmacol. 2013;53(2):178-191; Lombardo F, Waters NJ, Argikar UA, et al. J Clin Pharmacol. 2013;53(2):167-177). These methods provided much more accurate prediction of human PK parameters, yielding 88% and 70% of the prediction within 2-fold error for VDss and CL, respectively. The prediction of human i.v. profile using Wajima superpositioning of rat, dog, and monkey time-concentration profiles was tested against the observed human i.v. PK using fold error statistics. The results showed that 63% of the compounds yielded a geometric mean of fold error below 2-fold, and an additional 19% yielded a geometric mean of fold error between 2- and 3-fold, leaving only 18% of the compounds with a relatively poor prediction. Our results showed that good superposition was observed in any case, demonstrating the predictive value of the Wajima approach, and that the cause of poor prediction of human i.v. profile was mainly due to the poorly predicted CL value, while VDss prediction had a minor impact on the accuracy of human i.v. profile prediction.
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139. Electronic address: franco.lombardo@biogen.com.
authors.forename: Franco
authors.initials: F
authors.lastname: Lombardo
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Berellini
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Labonte
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139.
authors.forename: Guiqing
authors.initials: G
authors.lastname: Liang
authors.affiliation: Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139.
authors.forename: Sean
authors.initials: S
authors.lastname: Kim
mesh_terms: D061605:Administration, Intravenous / Q000379:methods; D000818:Animals; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D004364:Pharmaceutical Preparations / Q000097:blood* / Q000378:metabolism*; D051381:Rats; D012044:Regression Analysis; D013045:Species Specificity
chemical_list: D004364:Pharmaceutical Preparations
keywords: Wajima superposition; human dose projection; mean-residence time; steady-state concentration