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The objective is to develop (1091 subjects, 7335 observations) and validate (678 subjects, 3012 observations) a population pharmacokinetic model to describe tolvaptan pharmacokinetics in ADPKD subjects. The final model was evaluated with a bootstrapping method. The final model was internally and externally evaluated using visual predictive checks (VPC). Pharmacokinetics was best described by a 1\u2010compartmental model with 0\u2010order absorption, nonlinear relative bioavailability (F1), and first\u2010order elimination. Accounting for changes in F1 significantly improved the model: as the dose increased from 15\u00a0mg to 120\u00a0mg, F1 decreased by 36%. Population estimates for clearance\/F (CL\/F), volume of distribution\/F (Vd\/F), duration of absorption (D1), the highest dose at which F1 is lowest, and the amount of dose at which F1 is 50% were 12.6 L\u00b7h<jats:sup>\u20101<\/jats:sup>, 110 L, 0.58\u00a0hour, 182\u00a0mg, and 166\u00a0mg, respectively. The interindividual variability was 64% in CL\/F, 70% in Vd\/F, and 238% in D1. Residual variability was described by a combined\u2010error model. The VPC (500 data sets simulated) showed that 76% to 92% of the observed data fell within the 90% prediction intervals. The model stability assessed by a 1000\u2010run bootstrap analysis showed that the mean parameter estimates of data were within 10% of those obtained with the final model. The developed model is robust and stable. Internal and external validation confirmed the model ability to describe the data optimally.<\/jats:p>","DOI":"10.1002\/jcph.1370","type":"journal-article","created":{"date-parts":[[2019,1,9]],"date-time":"2019-01-09T02:52:16Z","timestamp":1547002336000},"page":"763-770","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Population Pharmacokinetic Analyses and Model Validation of Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease"],"prefix":"10.1002","volume":"59","author":[{"given":"Shankar","family":"Lanke","sequence":"first","affiliation":[{"name":"Otsuka Pharmaceutical Development &amp; Commercialization, Inc  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan E.","family":"Shoaf","sequence":"additional","affiliation":[{"name":"Otsuka Pharmaceutical Development &amp; Commercialization, Inc  Princeton NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,1,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-011-6303-y"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-011-6348-y"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1586\/17474124.2014.903797"},{"key":"e_1_2_10_5_1","unstructured":"European Medical Agency.Samsca: summary of product characteristics.http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Product_Information\/human\/000980\/WC500048716.pdfAccessed May 15 2018."},{"key":"e_1_2_10_6_1","unstructured":"US Food and Drug Administration.Samsca prescribing information.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2013\/022275s009lbl.pdfAccessed June 12 2018."},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.2217\/fca.13.3"},{"key":"e_1_2_10_8_1","unstructured":"European Medicines Agency.Jinarc: summary of product characteristics.http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Product_Information\/human\/002788\/WC500187921.pdfAccessed June 12 2018."},{"key":"e_1_2_10_9_1","unstructured":"US Food andDrug Administration.Jynarque: NDA approval letter.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/appletter\/2018\/204441Orig1s000ltr.pdfAccessed June 12 2018."},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013040398"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.880"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1159\/000456087"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1205511"},{"key":"e_1_2_10_14_1","unstructured":"US Food and Drug Administration.Drug interactions & labeling.https:\/\/www.fda.gov\/drugs\/developmentapprovalprocess\/developmentresources\/druginteractionslabeling\/ucm093664.htm. 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