{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:54:06Z","timestamp":1790279646551,"version":"4.1.0"},"reference-count":58,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,5,30]],"date-time":"2022-05-30T00:00:00Z","timestamp":1653868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union Seventh Framework Program","award":["FP7\/2007-2013"],"award-info":[{"award-number":["FP7\/2007-2013"]}]},{"name":"European Union Seventh Framework Program","award":["602295"],"award-info":[{"award-number":["602295"]}]},{"DOI":"10.13039\/501100000780","name":"grant agreement","doi-asserted-by":"publisher","award":["FP7\/2007-2013"],"award-info":[{"award-number":["FP7\/2007-2013"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"grant agreement","doi-asserted-by":"publisher","award":["602295"],"award-info":[{"award-number":["602295"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II\/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule. The primary objective was to describe PK parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (t-max)) of enalapril and its active metabolite enalaprilat. Of 102 patients, 89 patients (n = 26, DCM; n = 63 CHD) were included in the primary PK endpoint analysis. Rate and extent of enalapril and its active metabolite enalaprilat were described and etiology and age could be identified as potential PK modifying factors. The dosing schedule appeared to be tolerated well and did not result in any significant drug-related serious adverse events. The PK analysis and the lack of severe safety events supports the applied age-appropriate dosing schedule for the enalapril ODMTs.<\/jats:p>","DOI":"10.3390\/pharmaceutics14061163","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:25:12Z","timestamp":1653956712000},"page":"1163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies)"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5597-6973","authenticated-orcid":false,"given":"Stephanie","family":"Laeer","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-Universitaet D\u00fcsseldorf, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0581-843X","authenticated-orcid":false,"given":"Willi","family":"Cawello","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-Universitaet D\u00fcsseldorf, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1782-9937","authenticated-orcid":false,"given":"Bjoern B.","family":"Burckhardt","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-Universitaet D\u00fcsseldorf, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"Ablonczy","sequence":"additional","affiliation":[{"name":"Goettsegen Gy\u00f6rgy Hungarian Institute of Cardiology (HPHC), 1450 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milica","family":"Bajcetic","sequence":"additional","affiliation":[{"name":"Univerzitetska De\u010dja Klinika (UDK), University Children Hospital, School of Medicine, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes M. P. J.","family":"Breur","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht, Wilhelmina Children\u2019s Hospital, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel","family":"Dalinghaus","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Erasmus MC Sophia Children\u2019s Hospital, 3000 CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Male","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia N.","family":"de Wildt","sequence":"additional","affiliation":[{"name":"Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia Children\u2019s Hospital, 3015 GJ Rotterdam, The Netherlands"},{"name":"Department of Pharmacology and Toxicology, Radboud Institute of Health Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3982-9823","authenticated-orcid":false,"given":"J\u00f6rg","family":"Breitkreutz","sequence":"additional","affiliation":[{"name":"Ethicare GmbH, 45721 Haltern am See, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammed","family":"Faisal","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-Universitaet D\u00fcsseldorf, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Keatley-Clarke","sequence":"additional","affiliation":[{"name":"The Children\u2019s Heart Federation, London EC2A 3NW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0733-0454","authenticated-orcid":false,"given":"Ingrid","family":"Klingmann","sequence":"additional","affiliation":[{"name":"Pharmaplex Bvba, B-1970 Wezembeek-Oppem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian B.","family":"Lagler","sequence":"additional","affiliation":[{"name":"Paracelsus Medizinische Privatuniversit\u00e4t, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,30]]},"reference":[{"key":"ref_1","unstructured":"EMA (2022, March 31). Committee for Proprietary Medicinal Products (CPMP) Summary Information of Referral Opinion Pursuant to Article 30 of Council Directive 2001\/83\/EC for Renitec and associated names (See Annex I), London 4 December 2003. Available online: https:\/\/www.ema.europa.eu\/documents\/referral\/summary-information-referral-opinion-pursuant-article-30-council-directive-2001\/83\/ec-renitec-associated-names-see-annex-i-international-non-proprietary-name-inn-enalapril-background_en.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1136\/hrt.54.3.305","article-title":"Effects of enalapril in heart failure: A double blind study of effects on exercise performance, renal function, hormones, and metabolic state","volume":"54","author":"Cleland","year":"1985","journal-title":"Heart"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.jacc.2005.08.022","article-title":"ACC\/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: A report of the American College of Cardiology\/American Heart Association Task Force on Practice Guidelines (Writing Committee to update the 2001 Guidelines for the Evaluation and Management of Heart Failure)","volume":"46","author":"Hunt","year":"2005","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","unstructured":"EMA (2022, March 31). Report on the Expert Group Meeting of Paediatric Heart Failure, London 29 November 2010. Available online: https:\/\/www.ema.europa.eu\/documents\/other\/report-expert-group-meeting-paediatric-heart-failure-london-29-november-2010_en.pdf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/S0022-3476(89)80715-2","article-title":"Orally administered enalapril for infants with congestive heart failure: A dose-finding study","volume":"114","author":"Lloyd","year":"1989","journal-title":"J. Pediatrics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/clpt.1994.119","article-title":"The kinetic profiles of enalapril and enalaprilat and their possible developmental changes in pediatric patients with congestive heart failure","volume":"56","author":"Nakamura","year":"1994","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1177\/00912700122012661","article-title":"The pharmacokinetics of enalapril in children and infants with hypertension","volume":"41","author":"Wells","year":"2001","journal-title":"J. Clin. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100393","DOI":"10.1016\/j.conctc.2019.100393","article-title":"Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study","volume":"15","author":"Bajcetic","year":"2019","journal-title":"Contemp. Clin. Trials Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105812","DOI":"10.1016\/j.ejps.2021.105812","article-title":"Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review","volume":"162","author":"Vinarov","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/pr.2015.237","article-title":"Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin","volume":"79","author":"Sethi","year":"2016","journal-title":"Pediatr. Res."},{"key":"ref_11","first-page":"S10","article-title":"Developmental Changes in Pharmacokinetics and Pharmacodynamics","volume":"58","author":"Reed","year":"2018","journal-title":"J. Clin. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1124\/dmd.116.072652","article-title":"Age-Dependent Absolute Abundance of Hepatic Carboxylesterases (CES1 and CES2) by LC-MS\/MS Proteomics: Application to PBPK Modeling of Oseltamivir In Vivo Pharmacokinetics in Infants","volume":"45","author":"Boberg","year":"2017","journal-title":"Drug Metab. Dispos."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/j.1365-2125.1982.tb01991.x","article-title":"Enalapril maleate and a lysine analog (MK-521): Disposition in man","volume":"14","author":"Ulm","year":"1982","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1007\/s40262-015-0298-7","article-title":"Effect of Kidney Function on Drug Kinetics and Dosing in Neonates, Infants, and Children","volume":"54","author":"Rodieux","year":"2015","journal-title":"Clin. Pharmacokinet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3109\/00365599009180363","article-title":"Initial effect of enalapril on kidney function in patients with moderate to severe chronic nephropathy","volume":"24","author":"Kamper","year":"1990","journal-title":"Scand. J. Urol. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/bcp.13760","article-title":"The influence of heart failure on the pharmacokinetics of cardiovascular and non-cardiovascular drugs: A critical appraisal of the evidence","volume":"85","author":"Mangoni","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.2165\/00003088-197601060-00001","article-title":"Pharmacokinetics in patients with cardiac failure","volume":"1","author":"Benowitz","year":"1976","journal-title":"Clin. Pharmacokinet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s40262-012-0029-2","article-title":"Clinical Pharmacokinetics of Drugs in Patients with Heart Failure","volume":"52","author":"Ogawa","year":"2013","journal-title":"Clin. Pharmacokinet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/j.1365-2125.1987.tb03069.x","article-title":"The pharmacokinetics of enalapril in hospitalized patients with congestive heart failure","volume":"23","author":"Dickstein","year":"1987","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1097\/00005344-198507000-00023","article-title":"Pharmacokinetics and pharmacodynamics of enalapril in patients with congestive heart failure and patients with hypertension","volume":"7","author":"Schwartz","year":"1985","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1161\/CIRCHEARTFAILURE.108.820217","article-title":"Heart failure in children, part I: History, etiology, and pathophysiology","volume":"2","author":"Hsu","year":"2009","journal-title":"Circ. Heart Fail."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1067\/mhj.2002.121265","article-title":"Carvedilol therapy in pediatric patients with congestive heart failure: A study investigating clinical and pharmacokinetic parameters","volume":"143","author":"Mir","year":"2002","journal-title":"Am. Heart J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.ejpb.2011.02.005","article-title":"Orally disintegrating mini-tablets (ODMTs)\u2013A novel solid dosage form for paediatric use","volume":"78","author":"Stoltenberg","year":"2011","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/cpdd.728","article-title":"Relative Bioavailability of Enalapril Administered as Orodispersible Minitablets in Healthy Adults","volume":"9","author":"Burckhardt","year":"2020","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"481","DOI":"10.2147\/DDDT.S188417","article-title":"Model-dependent pharmacokinetic analysis of enalapril administered to healthy adult volunteers using orodispersible mini-tablets for use in paediatrics","volume":"13","author":"Faisal","year":"2019","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1097\/FJC.0b013e3182676f06.","article-title":"An integrated physiology-based model for the interaction of RAA system biomarkers with drugs","volume":"60","author":"Ramusovic","year":"2012","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_27","first-page":"431","article-title":"Tailored Assays for Pharmacokinetic and Pharmacodynamic Investigations of Aliskiren and Enalapril in Children: An Application in Serum, Urine, and Saliva","volume":"20","author":"Burckhardt","year":"2015","journal-title":"J. Pediatric Pharmacol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"281","DOI":"10.3389\/fped.2019.00281","article-title":"Simultaneous Semi-Mechanistic Population Pharmacokinetic Modeling Analysis of Enalapril and Enalaprilat Serum and Urine Concentrations From Child Appropriate Orodispersible Minitablets","volume":"7","author":"Faisal","year":"2019","journal-title":"Front. Pediatrics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ijpharm.2018.02.037","article-title":"Flexible and precise dosing of enalapril maleate for all paediatric age groups utilizing orodispersible minitablets","volume":"541","author":"Thabet","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_30","first-page":"907461","article-title":"Physiologically based pharmacokinetic modeling: Methodology, applications, and limitations with a focus on its role in pediatric drug development","volume":"2011","author":"Khalil","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1208\/s12248-013-9555-6","article-title":"Physiologically based pharmacokinetic models in the prediction of oral drug exposure over the entire pediatric age range\u2014Sotalol as a model drug","volume":"16","author":"Khalil","year":"2014","journal-title":"AAPS J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1021\/mp0600182","article-title":"A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan","volume":"3","author":"Takagi","year":"2006","journal-title":"Mol. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"133","DOI":"10.2478\/s11696-007-0010-y","article-title":"Acidity, lipophilicity, solubility, absorption, and polar surface area of some ACE inhibitors","volume":"61","author":"Remko","year":"2007","journal-title":"Chem. Pap."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1021\/mp034006h","article-title":"Molecular properties of WHO essential drugs and provisional biopharmaceutical classification","volume":"1","author":"Kasim","year":"2004","journal-title":"Mol. Pharm."},{"key":"ref_35","first-page":"324","article-title":"Intracellular and not intraluminal esterolysis of enalapril in kidney. Studies with the single pass perfused nonfiltering rat kidney","volume":"26","author":"Sirianni","year":"1998","journal-title":"Drug Metab. Dispos."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1111\/j.1365-2125.1986.tb05205.x","article-title":"Age and the pharmacokinetics of angiotensin converting enzyme inhibitors enalapril and enalaprilat","volume":"21","author":"Hockings","year":"1986","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1124\/dmd.112.045054","article-title":"Simultaneous absolute protein quantification of carboxylesterases 1 and 2 in human liver tissue fractions using liquid chromatography-tandem mass spectrometry","volume":"40","author":"Sato","year":"2012","journal-title":"Drug Metab. Dispos."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0928-0987(01)00190-7","article-title":"pH-metric solubility. 3. Dissolution titration template method for solubility determination","volume":"14","author":"Avdeef","year":"2001","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1002\/jps.20322","article-title":"Physiologically based pharmacokinetic modeling 1: Predicting the tissue distribution of moderate-to-strong bases","volume":"94","author":"Rodgers","year":"2005","journal-title":"J. Pharm. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1002\/jps.20502","article-title":"Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions","volume":"95","author":"Rodgers","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1007\/s11095-006-9210-3","article-title":"Mechanistic approaches to volume of distribution predictions: Understanding the processes","volume":"24","author":"Rodgers","year":"2007","journal-title":"Pharm. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1124\/dmd.109.028209","article-title":"Age- and sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver","volume":"37","author":"Zhu","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1093\/infdis\/jiq145","article-title":"Surge in expression of carboxylesterase 1 during the post-neonatal stage enables a rapid gain of the capacity to activate the anti-influenza prodrug oseltamivir","volume":"203","author":"Shi","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_44","unstructured":"Khalil, F., and L\u00e4er, S. (2016, January 1\u20134). Development of a physiologically based model to support the choice of paediatric enalapril dosing regimen for orodispersible minitablets. Proceedings of the 50th Annual Meeting of the AEPC, Rome, Italy."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1136\/adc.64.2.219","article-title":"Enalapril for severe heart failure in infancy","volume":"64","author":"Frenneaux","year":"1989","journal-title":"Arch. Dis. Child."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1136\/adc.70.1.35","article-title":"Efficacy and dosage of enalapril in congenital and acquired heart disease","volume":"70","author":"Leversha","year":"1994","journal-title":"Arch. Dis. Child."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1111\/j.1651-2227.1995.tb13581.x","article-title":"Use of enalapril in neonatal hypertension","volume":"84","author":"Schilder","year":"1995","journal-title":"Acta Paediatr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1007\/s00467-003-1121-5","article-title":"Enalapril-induced acute renal failure in a newborn infant","volume":"18","author":"Dutta","year":"2003","journal-title":"Pediatric Nephrol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"603042","DOI":"10.3389\/fphar.2020.603042","article-title":"Simulation Training to Improve Informed Consent and Pharmacokinetic\/Pharmacodynamic Sampling in Pediatric Trials","volume":"11","author":"Burckhardt","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.conctc.2018.08.008","article-title":"A feasibility study prior to an international multicentre paediatric study to assess pharmacokinetic\/pharmacodynamic sampling and sample preparation procedures, logistics and bioanalysis","volume":"12","author":"Ciplea","year":"2018","journal-title":"Contemp. Clin. Trials Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1208\/s12248-019-0375-1","article-title":"Fit-for-Purpose Quality Control System in Continuous Bioanalysis During Long-Term Pediatric Studies","volume":"21","author":"Ali","year":"2019","journal-title":"AAPS J."},{"key":"ref_52","unstructured":"Cawello, W. (2003). Parameters for compartment-free pharmacokinetics. Standardisation of Study Design, Data Analysis and Reporting, Shaker Verlag."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0022-3476(84)80479-5","article-title":"A simple estimate of glomerular filtration rate in full-term infants during the first year of life","volume":"104","author":"Schwartz","year":"1984","journal-title":"J. Pediatrics"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/S0022-3476(85)80697-1","article-title":"A simple estimate of glomerular filtration rate in adolescent boys","volume":"106","author":"Schwartz","year":"1985","journal-title":"J. Pediatrics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"611322","DOI":"10.3389\/fped.2021.611322","article-title":"LENA Consortium. Clinical Pharmacokinetics of Enalapril and Enalaprilat in Pediatric Patients-A Systematic Review","volume":"9","author":"Faisal","year":"2021","journal-title":"Front. Pediatrics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1001\/jama.298.10.1171","article-title":"Carvedilol for children and adolescents with heart failure: A randomized controlled trial: Pediatric Carvedilol Study Group","volume":"298","author":"Shaddy","year":"2007","journal-title":"JAMA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/bdd.1937","article-title":"Does age affect gastric emptying time? A model-based meta-analysis of data from premature neonates through to adults","volume":"36","author":"Bonner","year":"2015","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1124\/dmd.115.068700","article-title":"Examining Small Intestinal Transit Time as a Function of Age: Is There Evidence to Support Age-Dependent Differences among Children?","volume":"44","author":"Maharaj","year":"2016","journal-title":"Drug Metab. Dispos."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/6\/1163\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:21:50Z","timestamp":1760138510000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/6\/1163"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,30]]},"references-count":58,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["pharmaceutics14061163"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14061163","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,30]]}}}