{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T03:42:28Z","timestamp":1778038948300,"version":"3.51.4"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T00:00:00Z","timestamp":1628640000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"},{"start":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T00:00:00Z","timestamp":1628640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Pharmacokinet"],"published-print":{"date-parts":[[2022,2]]},"DOI":"10.1007\/s40262-021-01052-8","type":"journal-article","created":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T05:04:27Z","timestamp":1628658267000},"page":"249-262","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Population Pharmacokinetics of Tadalafil in Pediatric Patients with Pulmonary Arterial Hypertension: A Combined Adult\/Pediatric Model"],"prefix":"10.1007","volume":"61","clinical-trial-number":[{"clinical-trial-number":"nct01484431","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct00125918","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6507-7672","authenticated-orcid":false,"given":"Lisa","family":"Ferguson-Sells","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nieves","family":"Velez de Mendizabal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baohui","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Small","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,8,11]]},"reference":[{"key":"1052_CR1","first-page":"1","volume-title":"Executive summary from the world symposium on primary pulmonary hypertension (Evian, France; September 6\u201310, 1998)","author":"S Rich","year":"1998","unstructured":"Rich S, Rubin LJ, Abenhail L, et al. Executive summary from the world symposium on primary pulmonary hypertension (Evian, France; September 6\u201310, 1998). Geneva: World Health Organization; 1998. p. 1\u201327."},{"issue":"12 Suppl S","key":"1052_CR2","doi-asserted-by":"publisher","first-page":"40S","DOI":"10.1016\/j.jacc.2004.02.032","volume":"43","author":"RJ Barst","year":"2004","unstructured":"Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):40S-47S.","journal-title":"J Am Coll Cardiol"},{"issue":"111","key":"1052_CR3","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1183\/09059180.00011109","volume":"18","author":"M Beghetti","year":"2009","unstructured":"Beghetti M. Paediatric pulmonary hypertension: monitoring progress and identifying unmet needs. Eur Respir Rev. 2009;18(111):18\u201323.","journal-title":"Eur Respir Rev"},{"issue":"22","key":"1052_CR4","doi-asserted-by":"publisher","first-page":"2894","DOI":"10.1161\/CIRCULATIONAHA.108.839274","volume":"119","author":"N Gali\u00e8","year":"2009","unstructured":"Gali\u00e8 N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119(22):2894\u2013903.","journal-title":"Circulation"},{"issue":"10","key":"1052_CR5","doi-asserted-by":"publisher","first-page":"2302","DOI":"10.1111\/bcp.14039","volume":"85","author":"D Small","year":"2019","unstructured":"Small D, Ferguson-Sells L, Dahdah N, Bonnet D, Landry J, Li B. Pharmacokinetics and safety of tadalafil in a paediatric population with pulmonary arterial hypertension: a multiple ascending-dose study. Br J Clin Pharmacol. 2019;85(10):2302\u20139.","journal-title":"Br J Clin Pharmacol"},{"issue":"5","key":"1052_CR6","doi-asserted-by":"publisher","first-page":"329","DOI":"10.2165\/00003088-199630050-00001","volume":"30","author":"NH Holford","year":"1996","unstructured":"Holford NH. A size standard for pharmacokinetics. Clin Pharmacokinet. 1996;30(5):329\u201332.","journal-title":"Clin Pharmacokinet"},{"issue":"1","key":"1052_CR7","doi-asserted-by":"publisher","first-page":"25","DOI":"10.2133\/dmpk.24.25","volume":"24","author":"BJ Anderson","year":"2009","unstructured":"Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24(1):25\u201336.","journal-title":"Drug Metab Pharmacokinet"},{"key":"1052_CR8","unstructured":"Adcirca [prescribing information]. Indianapolis: Eli Lilly and Company; 2009. Available at: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2009\/022332lbl.pdf."},{"issue":"5","key":"1052_CR9","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1177\/0091270008315315","volume":"48","author":"RE Wrishko","year":"2008","unstructured":"Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol. 2008;48(5):610\u20138.","journal-title":"J Clin Pharmacol"},{"issue":"12","key":"1052_CR10","doi-asserted-by":"publisher","first-page":"4962","DOI":"10.1002\/jps.21789","volume":"98","author":"R Spence","year":"2009","unstructured":"Spence R, Mandagere A, Harrison B, Dufton C, Boinpally R. No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers. J Pharm Sci. 2009;98(12):4962\u201374.","journal-title":"J Pharm Sci"},{"key":"1052_CR11","volume-title":"NONMEM 7.3.0 users guides (1989, 2013)","year":"2013","unstructured":"Beal S, Sheiner LB, Boeckmann A, Bauer RJ, editors. NONMEM 7.3.0 users guides (1989, 2013). Ellicott City: Icon Development Solutions; 2013."},{"issue":"3","key":"1052_CR12","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.cmpb.2005.04.005","volume":"79","author":"L Lindbom","year":"2005","unstructured":"Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit\u2014a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Progr Biomed. 2005;79(3):241\u201357.","journal-title":"Comput Methods Progr Biomed"},{"issue":"5","key":"1052_CR13","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1007\/BF02353864","volume":"22","author":"TM Ludden","year":"1994","unstructured":"Ludden TM, Beal SL, Sheiner LB. Comparison of the Akaike Information Criterion, the Schwarz criterion and the F test as guides to model selection. J Pharmacokinet Biopharm. 1994;22(5):431\u201345.","journal-title":"J Pharmacokinet Biopharm"},{"issue":"2","key":"1052_CR14","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.cmpb.2003.11.003","volume":"75","author":"L Lindbom","year":"2004","unstructured":"Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN)\u2014a Perl module for NONMEM related programming. Comput Methods Progr Biomed. 2004;75(2):85\u201394.","journal-title":"Comput Methods Progr Biomed"},{"issue":"2","key":"1052_CR15","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1208\/s12248-011-9255-z","volume":"13","author":"M Bergstrand","year":"2011","unstructured":"Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143\u201351.","journal-title":"AAPS J"},{"issue":"2","key":"1052_CR16","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1111\/j.1432-1033.1997.00625.x","volume":"247","author":"D Lacroix","year":"1997","unstructured":"Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3A in the human liver\u2014evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem. 1997;247(2):625\u201334.","journal-title":"Eur J Biochem"},{"key":"1052_CR17","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1124\/jpet.103.054841","volume":"307","author":"J Stevens","year":"2003","unstructured":"Stevens J, Hines R, Gu C, et al. Developmental expression of the major human hepatic CYP3A enzymes. J Pharmacol Exp Ther. 2003;307:573\u201382.","journal-title":"J Pharmacol Exp Ther"},{"issue":"8","key":"1052_CR18","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1124\/dmd.30.8.883","volume":"30","author":"JA Williams","year":"2002","unstructured":"Williams JA, Ring BJ, Cantrell VE, et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos. 2002;30(8):883\u201391.","journal-title":"Drug Metab Dispos"},{"issue":"1","key":"1052_CR19","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1248\/bpb.b14-00566","volume":"38","author":"R Takahiro","year":"2015","unstructured":"Takahiro R, Nakamura S, Kohno H, et al. Contribution of CYP3A isoforms to dealkylation of PDE5 inhibitors: a comparison between sildenafil N-demethylation and tadalafil demethylenation. Biol Pharm Bull. 2015;38(1):58\u201365.","journal-title":"Biol Pharm Bull"},{"key":"1052_CR20","doi-asserted-by":"publisher","first-page":"S1767","DOI":"10.21037\/jtd.2019.09.14","volume":"11","author":"V Parikh","year":"2019","unstructured":"Parikh V, Bhardwaj A, Nair A. Pharmacotherapy for pulmonary arterial hypertension. J Thorac Dis. 2019;11(12):S1767\u201381.","journal-title":"J Thorac Dis"},{"key":"1052_CR21","unstructured":"Tracleer [prescribing information]. South San Francisco: Actelion Pharmaceuticals US, Inc; 2009. Available at: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2017\/209279s000lbl.pdf."}],"container-title":["Clinical Pharmacokinetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40262-021-01052-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40262-021-01052-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40262-021-01052-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T01:16:27Z","timestamp":1643937387000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40262-021-01052-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,11]]},"references-count":21,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["1052"],"URL":"https:\/\/doi.org\/10.1007\/s40262-021-01052-8","relation":{},"ISSN":["0312-5963","1179-1926"],"issn-type":[{"value":"0312-5963","type":"print"},{"value":"1179-1926","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,11]]},"assertion":[{"value":"11 June 2021","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2021","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was funded by Eli Lilly and Company.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"Lisa Ferguson-Sells and Baohui Li are employees of Eli Lilly and Company and own stocks. David Small and Nieves Velez de Mendizabal are former employees of Eli Lilly and Company. NVM is an employee of Metrum Research Group, Tariffville, CT, USA, and DS is an employee of Karuna Therapeutics, Boston, MA, USA.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Both studies (LVIG and PHIRST-1) were conducted in accordance with consensus ethics principles derived from international ethics guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines; the International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guideline [E6]; and applicable local laws and regulations. The local Ethics Review Committees approved the protocols, and written informed consent was obtained from patients or legal guardians prior to a patient\u2019s participation.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Eli Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of PK or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU, and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at .","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of data and material"}},{"value":"Not applicable.","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability"}},{"value":"LF-S, BL, and DS conceptualized and designed the study; LF-S and BL acquired data for the study; and LF-S, NVM, BL, and DS analyzed and interpreted the data, drafted the paper, and critically revised the paper.","order":9,"name":"Ethics","group":{"name":"EthicsHeading","label":"Author contributions"}}]}}