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After optimization with preclinical data, the performance of these models for extrapolation of distribution kinetics to human were evaluated to determine the best approach for the prediction of human drug disposition and volume of distribution (Vss) using PBPK modeling. Three lipophilic bases were tested (diazepam, midazolam, and basmisanil) for which intravenous PK data were available in rat, monkey, and human. The models with Kpu scalars using k\u2010means clustering were generally the best for fitting data in the preclinical species and gave plausible Kpu values. Extrapolations of plasma concentrations for diazepam and midazolam using these models and parameters obtained were consistent with the observed clinical data. For diazepam and midazolam, the human predictions of Vss after optimization in rats and monkeys were better compared with the Vss estimated from the traditional PBPK modeling approach (varying from 1.1 to 3.1 vs. 3.7\u2010fold error). For basmisanil, the sparse preclinical data available could have affected the model performance for fitting and the subsequent extrapolation to human. Overall, this work provides a rational strategy to predict human drug distribution using preclinical PK data within the PBPK modeling strategy.<\/jats:p>","DOI":"10.1002\/psp4.12915","type":"journal-article","created":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T09:50:47Z","timestamp":1673949047000},"page":"346-359","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A \u201cmiddle\u2010out approach\u201d for the prediction of human drug disposition from preclinical data using simplified physiologically based pharmacokinetic (PBPK) models"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8323-5080","authenticated-orcid":false,"given":"Estelle","family":"Yau","sequence":"first","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research The University of Manchester  Manchester UK"},{"name":"Roche Pharma Research and Early Development Roche Innovation Center Basel  Basel 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