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In infants for whom treatment of pulmonary hypertension and prevention or treatment of invasive candidiasis are indicated, sildenafil with fluconazole may be given concurrently. To account for developmental changes in cytochrome P450 (CYP) 3A, we determined and incorporated fluconazole inhibition constants (<jats:italic>K<\/jats:italic><jats:sub>I<\/jats:sub>) for CYP3A4, CYP3A5, and CYP3A7 into a PBPK model developed for sildenafil and its active metabolite, N\u2010desmethylsildenafil. Pharmacokinetic (PK) data in preterm infants receiving sildenafil with and without fluconazole were used for model development and evaluation. The simulated PK parameters were comparable to observed values. Following fluconazole co\u2010administration, differences in the fold change for simulated steady\u2010state area under the plasma concentration vs. time curve from 0 to 24\u00a0hours (AUC<jats:sub>ss,0\u201324<\/jats:sub>) were observed between virtual adults and infants (2.11\u2010fold vs. 2.82\u2010fold change). When given in combination with treatment doses of fluconazole (12\u00a0mg\/kg i.v. daily), reducing the sildenafil dose by ~\u00a060% resulted in a geometric mean ratio of 1.01 for simulated AUC<jats:sub>ss,0\u201324<\/jats:sub>relative to virtual infants receiving sildenafil alone. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.<\/jats:p>","DOI":"10.1002\/cpt.1990","type":"journal-article","created":{"date-parts":[[2020,7,21]],"date-time":"2020-07-21T11:34:05Z","timestamp":1595331245000},"page":"253-262","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Physiologically\u2010Based Pharmacokinetic Modeling Characterizes the CYP3A\u2010Mediated Drug\u2010Drug Interaction Between Fluconazole and Sildenafil in Infants"],"prefix":"10.1111","volume":"109","author":[{"given":"Sara N.","family":"Salerno","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 North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Edginton","sequence":"additional","affiliation":[{"name":"School of Pharmacy University of Waterloo Kitchener Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline G.","family":"Gerhart","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew M.","family":"Laughon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics UNC School of Medicine The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namasivayam","family":"Ambalavanan","sequence":"additional","affiliation":[{"name":"Division of Neonatology School of Medicine University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M.","family":"Sokol","sequence":"additional","affiliation":[{"name":"Division of Neonatal\u2010Perinatal Medicine Indiana University School of Medicine Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi D.","family":"Hornik","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Duke University School of Medicine Durham North Carolina USA"},{"name":"Duke Clinical Research Institute Durham North Carolina USA"},{"name":"Department of Pharmacy Duke University Medical Center Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Stewart","sequence":"additional","affiliation":[{"name":"University of Louisville Norton Children\u2019s Hospital Louisville Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Mills","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Martz","sequence":"additional","affiliation":[{"name":"The Emmes Company, LLC Rockville Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Best Pharmaceuticals for Children Act \u2013 Pediatric Trials Network Steering Committee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,22]]},"reference":[{"key":"e_1_2_9_1_1","unstructured":"US Food and Drug Administration Center for Drug Evaluation and Research.Clinical drug interaction studies\u2010cytochrome P450 enzyme\u2010 and transporter\u2010mediated drug interactions. 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