{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:58:39Z","timestamp":1790621919395,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100008728","name":"Japan Research Foundation for Clinical Pharmacology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008728","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Pulmonary arterial hypertension (PAH) is a syndrome characterized by elevated pulmonary artery pressure. We developed a population pharmacokinetic (PPK) model using combined plasma drug concentration data from Japanese paediatric (&lt;15\u2009years) and adult (\u226515\u2009years) patients with PAH to investigate the pharmacokinetic characteristics of PAH treatments (sildenafil, tadalafil, bosentan and ambrisentan).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      PPK analysis was conducted using a nonlinear mixed\u2010effects modelling approach. A one\u2010compartment model was selected as the structural model, and an exponential error model was used to describe interindividual variability. Individual patient clearance (CL), adjusted for bioavailability (F) using Bayesian estimation based on the PPK model, was used to estimate the steady\u2010state plasma concentrations (C\n                      <jats:sub>ss<\/jats:sub>\n                      ) of the drugs in paediatric and adult patients receiving clinical dosages.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PPK analysis was performed on data from 35 paediatric and 16 adult subjects to estimate pharmacokinetic parameters. The population mean CL\/F values for sildenafil, tadalafil, bosentan and ambrisentan were estimated at 60.6, 1.76, 8.85 and 0.594\u2009L\/h, respectively. Covariates that improved model performance and were incorporated into the final model included the effect of bodyweight on the CL\/F of each drug. The estimated C\n                      <jats:sub>ss<\/jats:sub>\n                      values for all drugs were 26.0%\u201372.2% lower in paediatric than in adult patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study clarified the pharmacokinetic parameters and their variability for sildenafil, tadalafil, bosentan and ambrisentan using combined data from Japanese paediatric and adult patients with PAH. The results of Bayesian estimation suggest that at current clinical dosages, plasma concentrations of these drugs may be lower in paediatric than adult patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70676","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T17:05:58Z","timestamp":1782925558000},"page":"3611-3621","source":"Crossref","is-referenced-by-count":1,"title":["Development of a population pharmacokinetic model using combined paediatric and adult data for four pulmonary arterial hypertension drugs"],"prefix":"10.1002","volume":"92","author":[{"given":"Motoyasu","family":"Miura","sequence":"first","affiliation":[{"name":"Departments of Pharmacy Practice &amp; Science, School of Pharmaceutical Sciences University of Shizuoka  Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimako","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Departments of Pharmacy Practice &amp; 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