{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:44:38Z","timestamp":1790750678036,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,12,15]],"date-time":"2019-12-15T00:00:00Z","timestamp":1576368000000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HHSN275201000003I"],"award-info":[{"award-number":["HHSN275201000003I"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N\u2010desmethyl sildenafil (DMS), in premature infants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed a multicentre, open\u2010label trial to characterize the PK of sildenafil in infants \u226428\u00a0weeks gestation and\u00a0&lt;\u00a0365 postnatal days (cohort 1) or\u00a0&lt;\u00a032\u00a0weeks gestation and 3\u201342 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose\u2010exposure simulations using the software NONMEM\u00ae.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We enrolled 34 infants (cohort 1 <jats:italic>n<\/jats:italic>\u00a0=\u00a025; cohort 2 <jats:italic>n<\/jats:italic>\u00a0=\u00a09) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42\u20132.09\u00a0mg\/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25\u00a0mg\/kg) in all infants in cohort 2. A 2\u2010compartment PK model for sildenafil and 1\u2010compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (<jats:italic>n<\/jats:italic>\u00a0=\u00a04), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1\u00a0mg\/kg every 8\u00a0hours (in the absence of fluconazole) resulted in steady\u2010state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow\u2010up, phase II study.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.14111","type":"journal-article","created":{"date-parts":[[2019,9,2]],"date-time":"2019-09-02T07:44:19Z","timestamp":1567410259000},"page":"2824-2837","source":"Crossref","is-referenced-by-count":18,"title":["Population pharmacokinetics of sildenafil in extremely premature infants"],"prefix":"10.1111","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5522-5686","authenticated-orcid":false,"given":"Daniel","family":"Gonzalez","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy The University of North Carolina at Chapel Hill  Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew M.","family":"Laughon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine The University of North Carolina at Chapel Hill  Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. 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