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These models were evaluated for their ability to estimate realistic values for unbound tissue to plasma partition coefficients (Kpu) and simulate observed pharmacokinetic (PK) data. Two approaches are presented: using either established kinetic lumping methods based on tissue time constants (drug\u2010dependent) or a novel clustering analysis to identify tissues sharing common Kpu values or Kpu scalars based on similarities of tissue composition (drug\u2010independent). PBPK models derived from these approaches were assessed using PK data of diazepam in rats and humans. Although the clustering analysis produced minor differences in tissue grouping depending on the method used, two larger groups of tissues emerged. One including the kidneys, liver, spleen, gut, heart, and lungs, and another including bone, brain, muscle, and pancreas whereas adipose and skin were generally considered distinct. Overall, a subdivision into four tissue groups appeared most physiologically relevant in terms of tissue composition. Several models were found to have similar abilities to describe diazepam i.v. data as empirical models. Comparability of estimated Kpus to experimental Kpu values for diazepam was one criterion for selecting the appropriate PK model structure.<\/jats:p>","DOI":"10.1002\/psp4.12911","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T04:21:13Z","timestamp":1675916473000},"page":"333-345","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Investigation of simplified physiologically\u2010based pharmacokinetic models in rat and human"],"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 (CAPKR) The University of Manchester  Manchester UK"},{"name":"Roche Pharma Research and Early Development (pRED) Roche Innovation Center Basel  Basel Switzerland"},{"name":"Sanofi R&amp;D, DMPK France  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9959-0810","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Olivares\u2010Morales","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development (pRED) Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayode","family":"Ogungbenro","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research (CAPKR) The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Aarons","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research (CAPKR) The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gertz","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development (pRED) Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2005.02560.x"},{"key":"e_1_2_10_3_1","first-page":"197","volume-title":"New Insights into Toxicity and Drug Testing","author":"Reddy MB","year":"2013"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.22550"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12234"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2016.10.036"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1023272707390"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1049\/iet-syb:20070055"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-009-9141-9"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-010-9165-1"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-005-0054-y"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026194618660"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-014-9349-1"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-005-0004-8"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-018-9584-y"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","unstructured":"DokoumetzidisA.Lumping of compartments. 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