{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T11:27:56Z","timestamp":1775215676134,"version":"3.50.1"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T00:00:00Z","timestamp":1646179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>The objective of this pharmacometric (PMX) study was to (i) characterize population pharmacokinetics (PPK) and exposure-pain response associations following intranasal (0.1 mg\/kg) or intravenous (IV, 0.05 mg\/kg) administration of nalbuphine, with the goal to (ii) evaluate strategies for optimized dosing and timing of painful interventions in infants 1\u20133 months old.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>PPK analysis of nalbuphine serum concentrations, prospectively collected 15, 30, and between 120 and 180 min post-dose, utilizing the software package Monolix. The final PPK model was applied to derive individual time-matched concentration predictions for each pain assessment (Neonatal Infant Pain Score, NIPS) after establishment of venous access and urinary catheterization or lumbar puncture. Drug exposure-pain response simulations were performed to evaluate potential benefits of higher doses with respect to a previously proposed target concentration of 12 mcg\/L (efficacy threshold).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty-eight of 52 study subjects receiving nalbuphine had at least one concentration measurement and were included in the pharmacometric analysis. A two-compartment model with allometric scaling was applied to describe population PK data, with intranasal bioavailability estimated to be 41% (95%CI: 26\u201356%). Model-based simulations showed that the proposed efficacy threshold (12 mcg\/L) is expected to be exceeded with an IV dose of 0.05 mg\/kg for 6 min, with 0.1 mg\/kg for 30 min and with 0.2 mg\/kg for 80 min. This efficacy threshold is not achieved with intranasal doses of 0.1 and 0.2 mg\/kg, whereas an intranasal dose of 0.4 mg\/kg is expected to exceed such threshold for 30 to 100 min.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This PMX study confirmed that bioavailability of intranasal nalbuphine is close to 50%. Exposure-pain response simulations indicated that an intranasal dose of 0.4 mg\/kg is required to provide a comparable pain control as achieved with an IV dose of 0.1\u20130.2 mg\/kg. The optimal time window for painful procedures appears to be within the first 30 min after IV administration of 0.1 mg\/kg nalbuphine, whereas such procedures should be scheduled 30 min after an intranasal dose of 0.4 mg\/kg nalbuphine. Additional clinical studies are warranted to confirm these PMX based recommendations and to further optimize pain management in this vulnerable infant population.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2022.837492","type":"journal-article","created":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T06:05:51Z","timestamp":1646201151000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants"],"prefix":"10.3389","volume":"10","author":[{"given":"Miriam","family":"Pfiffner","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Berger-Olah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priska","family":"Vonbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Pfister","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"Gotta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,2]]},"reference":[{"key":"B1","year":"","journal-title":"Fachinformation Nalbuphin"},{"key":"B2","unstructured":"Reference ID: 4500827Silver Spring, MDU.S. Food and Drug Administration2019"},{"key":"B3","unstructured":"Nubain \u00ae 10 mg \/ ml Injektionsl\u00f6sung13\n            FachinformationsverzeichnisDeutschland\n          2020"},{"key":"B4","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1093\/bja\/aer001","article-title":"Population pharmacokinetics of nalbuphine after surgery in children","volume":"106","author":"Bressolle","year":"2011","journal-title":"Br J Anaesth."},{"key":"B5","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1185\/146300903774115793","article-title":"Population Pharmacokinetics of Nalbuphine in Neonates","volume":"5","author":"Jacqz-Aigrain","year":"","journal-title":"Paediat Perinat Drug Ther"},{"key":"B6","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1038\/clpt.1989.130","article-title":"Pharmacokinetics of nalbuphine in infants, young healthy volunteers, and elderly patients","volume":"46","author":"Jaillon","year":"1989","journal-title":"Clin Pharmacol Ther."},{"key":"B7","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1111\/j.1365-2125.1988.tb03300.x","article-title":"The pharmacokinetics of oral and intravenous nalbuphine in healthy volunteers","volume":"25","author":"Aitkenhead","year":"1988","journal-title":"Br J Clin Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S0378-4347(96)00369-6","article-title":"Modified method of nalbuphine determination in plasma: validation and application to pharmacokinetics of the rectal route","volume":"690","author":"Nicolle","year":"1997","journal-title":"J Chromatogr B Biomed Appl."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1002\/bmc.1601","article-title":"Validated LC-MS\/MS assay for the quantitative determination of nalbuphine in human plasma and its application to a pharmacokinetic study","volume":"25","author":"Cai","year":"2011","journal-title":"Biomed Chromatogr."},{"key":"B10","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1007\/s13318-019-00552-0","article-title":"Opioids : a review of pharmacokinetics and pharmacodynamics in neonates , infants , and children","volume":"44","author":"Thigpen","year":"2019","journal-title":"Eur J Drug Metab Pharmacokinet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"105093","DOI":"10.1016\/j.ejps.2019.105093","article-title":"European journal of pharmaceutical sciences a dual system platform for drug metabolism : nalbuphine as a model compound","volume":"141","author":"Liang","year":"2020","journal-title":"Eur J Pharm Sci"},{"key":"B12","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1097\/MOP.0000000000000347","article-title":"Management of acute pediatric pain in the emergency department","volume":"28","author":"Ruest","year":"2016","journal-title":"Curr Opin Pediatr."},{"key":"B13","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1097\/PEC.0000000000000171","article-title":"Intranasal medications in pediatric emergency medicine","volume":"30","author":"Del Pizzo","year":"2014","journal-title":"Pediatr Emerg Care."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.2146\/ajhp140630","article-title":"Safety and efficacy of intranasally administered medications in the emergency department and prehospital settings","volume":"72","author":"Corrigan","year":"2015","journal-title":"Am J Heal Pharm."},{"key":"B15","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.pharmthera.2012.03.003","article-title":"Intranasal drug delivery: an efficient and non-invasive route for systemic administration-focus on opioids","volume":"134","author":"Grassin-Delyle","year":"2012","journal-title":"Pharmacol Ther"},{"key":"B16","doi-asserted-by":"publisher","first-page":"189","DOI":"10.21037\/atm-20-5177","article-title":"Intranasal drugs for analgesia and sedation in children admitted to pediatric emergency department: a narrative review","volume":"9","author":"Pansini","year":"2021","journal-title":"Ann Transl Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1007\/s00228-019-02720-2","article-title":"Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study","volume":"75","author":"Ziesenitz","year":"2019","journal-title":"Eur J Clin Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1007\/s40272-017-0235-3","article-title":"Efficacy and Safety of Ibuprofen in Infants Aged Between 3 and 6 Months","volume":"19","author":"Ziesenitz","year":"2017","journal-title":"Pediatr Drugs."},{"key":"B19","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ejpb.2014.03.004","article-title":"Intranasal delivery of systemic-acting drugs: small-molecules and biomacromolecules","volume":"88","author":"Fortuna","year":"2014","journal-title":"Eur J Pharm Biopharm"},{"key":"B20","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1159\/000323699","article-title":"Blood Loss Related to Participation in Pharmacokinetic Study in Preterm","volume":"100","author":"Heidmets","year":"2011","journal-title":"Neonatology"},{"key":"B21","unstructured":"Neonatal Infant Pain Scale (NIPS)1272015"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1001\/jamapediatrics.2019.3351","article-title":"Pain and sedation scales for neonatal and pediatric patients in a preverbal stage of development a systematic review","volume":"173","author":"Giordano","year":"2019","journal-title":"JAMA Pediatr"},{"key":"B23","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1007\/s10928-007-9066-0","article-title":"Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies","volume":"34","author":"Savic","year":"2007","journal-title":"J Pharmacokinet Pharmacodyn."},{"key":"B24","author":"Utesch","year":"","journal-title":"Allometrie und Skalierung von Modellparametern \u00dcbersicht Einleitung Allometrie ( Populations- ) Pharmakokinetik Zusammenfassung"},{"key":"B25","author":"Pfiffner","year":"","journal-title":"Pharmacokinetics and tolerability of intranasal or intravenous administration of nalbuphine in infants"},{"key":"B26","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/s40262-018-0659-0","article-title":"Pharmacokinetic\u2013pharmacodynamic modeling in pediatric drug development, and the importance of standardized scaling of clearance","volume":"58","author":"Germovsek","year":"2019","journal-title":"Clin Pharmacokinet"},{"key":"B27","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1111\/j.1472-8206.1997.tb00180.x","article-title":"Pharmacokinetics of intrarectal nalbuphine in children undergoing general anaesthesia","volume":"11","author":"Bessard","year":"1997","journal-title":"Fundam Clin Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"439","DOI":"10.2165\/00003088-199936060-00005","article-title":"Glucuronidation in humans pharmacogenetic and developmental aspects","volume":"36","author":"Wildt SN","year":"1999","journal-title":"Clin Pharmacokinet"},{"key":"B29","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1002\/j.1552-4604.1987.tb05581.x","article-title":"The disposition and bioavailability of intravenous and oral nalbuphine in healthy volunteers","volume":"27","author":"Lo","year":"1987","journal-title":"J Clin Pharmacol."}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.837492\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T06:05:58Z","timestamp":1646201158000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.837492\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,2]]},"references-count":29,"alternative-id":["10.3389\/fped.2022.837492"],"URL":"https:\/\/doi.org\/10.3389\/fped.2022.837492","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,2]]},"article-number":"837492"}}