Phenobarbital is a first-line treatment of various seizure types in newborns. Dosage individualization maximizing the proportion of patients with drug levels in therapeutic range or sufficient treatment response is still challenging. The aim of this review was to summarize the available evidence on phenobarbital pharmacokinetics in neonates and to identify its possible covariates suitable for individualization of initial drug dosing. Several covariates have been considered: body weight and height, body surface area, gestational and postnatal age, laboratory parameters of renal and hepatic functions, asphyxia, therapeutic hypothermia, extracorporeal membrane oxygenation (ECMO), drug interactions, and genetic polymorphisms. The most frequently studied and well-founded covariate for the estimation of phenobarbital dosing is actual body weight. Loading dose of 15-20 mg/kg followed by a maintenance dose of 3-5 mg/kg/day seems to be accurate. However, the evidence for the other covariates with respect to dosing individualization is not sufficient. Doses at the lower limit of suggested range should be preferred in patients with severe asphyxia, while the upper limit of the range should be targeted in neonates receiving ECMO support.

Department of Pharmacology 1st Faculty of Medicine Charles University 110 00 Prague Czech Republic

General University Hospital Prague 128 00 Prague Czech Republic

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Evans D., Levene M. Neonatal seizures. Arch. Dis. Child Fetal Neonatal Ed. 1998;78:F70–F75. doi: 10.1136/fn.78.1.F70. PubMed DOI PMC

El-Dib M., Soul J.S. The use of phenobarbital and other anti-seizure drugs in newborns. Semin. Fetal Neonatal Med. 2017;22:321–327. doi: 10.1016/j.siny.2017.07.008. PubMed DOI

Krishna S., Hutton A., Aronowitz E., Moore H., Vannucci S.J. The effects of adding prophylactic phenobarbital to therapeutic hypothermia in the term-equivalent hypoxic-ischemic rat. Pediatr. Res. 2018;83:506–513. doi: 10.1038/pr.2017.266. PubMed DOI

Papile L.A., Baley J.E., Benitz W., Cummings J., Carlo W.A., Eichenwald E., Kumar P., Polin R.A., Tan R.C., Committee on Fetus and Newborn et al. Hypothermia and neonatal encephalopathy. Pediatrics. 2014;133:1146–1150. PubMed

Falsaperla R., Mauceri L., Pavone P., Barbagallo M., Vitaliti G., Ruggieri M., Pisani F., Corsello G. Short-Term Neurodevelopmental Outcome in Term Neonates Treated with Phenobarbital versus Levetiracetam: A Single-Center Experience. Behav. Neurol. 2019;2019:3683548. doi: 10.1155/2019/3683548. PubMed DOI PMC

Spagnoli C., Seri S., Pavlidis E., Mazzotta S., Pelosi A., Pisani F. Phenobarbital for Neonatal Seizures: Response Rate and Predictors of Refractoriness. Neuropediatrics. 2016;47:318–326. PubMed

Zeller B., Giebe J. Pharmacologic Management of Neonatal Seizures. Neonatal Netw. 2015;34:239–344. doi: 10.1891/0730-0832.34.4.239. PubMed DOI

Reinisch J.M., Sanders S.A., Mortensen E.L., Rubin D.B. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA. 1995;274:1518–1525. doi: 10.1001/jama.1995.03530190032031. PubMed DOI

Farwell J.R., Lee Y.J., Hirtz D.G., Sulzbacher S.I., Ellenberg J.H., Nelson K.B. Phenobarbital for febrile seizures-effects on intelligence and on seizure recurrence. N. Engl. J. Med. 1990;322:364–369. doi: 10.1056/NEJM199002083220604. PubMed DOI

Sulzbacher S., Farwell J.R., Temkin N., Lu A.S., Hirtz D.G. Late cognitive effects of early treatment with phenobarbital. Clin. Pediatr. (Phila) 1999;38:387–394. doi: 10.1177/000992289903800702. PubMed DOI

Pacifici G.M. Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics. Curr. Pediatr. Rev. 2016;12:48–54. doi: 10.2174/1573397111666151026223914. PubMed DOI

Marsot A., Brevaut-Malaty V., Vialet R., Boulamery A., Bruguerolle B., Simon N. Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach. Fundam. Clin. Pharmacol. 2014;28:465–471. doi: 10.1111/fcp.12042. PubMed DOI

Lutz I.C., Allegaert K., de Hoon J.N., Marynissen H. Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: A literature review. BMJ. Paediatr. Open. 2020;4 doi: 10.1136/bmjpo-2020-000685. PubMed DOI PMC

Yozawitz E., Stacey A., Pressler R.M. Pharmacotherapy for Seizures in Neonates with Hypoxic Ischemic Encephalopathy. Paediatr. Drugs. 2017;19:553–567. PubMed

Taburet A.M., Chamouard C., Aymard P., Chevalier J.Y., Costil J. Phenobarbital protein binding in neonates. Dev. Pharmacol. Ther. 1982;4:129–134. doi: 10.1159/000457368. PubMed DOI

Ehrnebo M., Agurell S., Jalling B., Boréus L.O. Age differences in drug binding by plasma proteins: Studies on human foetuses, neonates and adults. Eur. J. Clin. Pharmacol. 1971;3:189–193. doi: 10.1007/BF00565004. PubMed DOI

Kwan P., Brodie M.J. Phenobarbital for the treatment of epilepsy in the 21st century: A critical review. Epilepsia. 2001;45:1141–1149. doi: 10.1111/j.0013-9580.2004.12704.x. PubMed DOI

Methaneethorn J., Leelakanok L. Pharmacokinetic variability of phenobarbital: A systematic review of population pharmacokinetic analysis. Eur. J. Clin. Pharmacol. 2020 doi: 10.1007/s00228-020-03011-x. PubMed DOI

Anderson B.J., Holford N.H. Understanding dosing: Children are small adults, neonates are immature children. Arch Dis Child. 2013;98:737–744. doi: 10.1136/archdischild-2013-303720. PubMed DOI

Queensland Governmen Queensland Clinical Guidelines. [(accessed on 28 December 2020)]; Available online: https://www.health.qld.gov.au/__data/assets/pdf_file/0030/143697/g-seizures.pdf.

Gilman M.E., Toback J.W., Gal P., Erkan N.V. Individualizing phenobarbital dosing in neonates. Clin. Pharm. 1983;2:258–262. PubMed

Gherpelli J.L., Cruz A.M., Tsanaclis L.M., Costa H.P., Garcia T.G., Segre C.A., Spina-Franca A. Phenobarbital in newborns with neonatal seizures. A study of plasma levels after intravenous administration. Brain Dev. 1993;15:258–262. doi: 10.1016/0387-7604(93)90020-9. PubMed DOI

Nahata M.C., Masuoka T., Edwards R.C. Developmental aspects of phenobarbital dosage requirements in newborn infants with seizures. J. Perinatol. 1988;8:318–320. doi: 10.1203/00006450-198704010-00434. PubMed DOI

Pauwels S., Allegaert K. Therapeutic drug monitoring in neonates. Arch. Dis. Child. 2016;101:377–381. doi: 10.1136/archdischild-2013-305309. PubMed DOI

Jalling B. Plasma concentrations of phenobarbital in the treatment of seizures in newborns. Acta. Paediatr. Scand. 1975;64:514–524. doi: 10.1111/j.1651-2227.1975.tb03873.x. PubMed DOI

Touw D.J., Graafland O., Cranendonk A., Vermeulen R.J., van Weissenbruch M.M. Clinical pharmacokinetics of phenobarbital in neonates. Eur. J. Pharm. Sci. 2000;12:111–116. doi: 10.1016/S0928-0987(00)00145-7. PubMed DOI

Turhan A.H., Atici A., Okuyaz C., Uysal S. Single enteral loading dose of phenobarbital for achieving its therapeutic serum levels in neonates. Croat. Med. J. 2010;51:215–218. doi: 10.3325/cmj.2010.51.215. PubMed DOI PMC

Alonso Gonzalez A.C., Ortega Valin L., Santos Buelga D., Garcia Sanchez M.J., Santos Borbujo J., Monzon Corral L., Dominguez-Gil Hurle A. Dosage programming of phenobarbital in neonatal seizures. J. Clin. Pharm. Ther. 1993;18:267–270. doi: 10.1111/j.1365-2710.1993.tb00586.x. PubMed DOI

Fischer J.H., Lockman L.A., Zaske D., Kriel R. Phenobarbital maintenance dose requirements in treating neonatal seizures. Neurology. 1981;31:1042–1044. doi: 10.1212/WNL.31.8.1042. PubMed DOI

Filippi L., la Marca G., Cavallaro G., Fiorini P., Favelli F., Malvagia S., Donzelli G., Guerrini R. Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: A pharmacokinetic study during whole body hypothermia. Epilepsia. 2011;52:794–801. doi: 10.1111/j.1528-1167.2011.02978.x. PubMed DOI

Oztekin O., Kalay S., Tezel G., Akcakus M., Oygur N. Can we safely administer the recommended dose of phenobarbital in very low birth weight infants? Childs Nerv. Syst. 2013;29:1353–1357. doi: 10.1007/s00381-013-2094-8. PubMed DOI

Yukawa M., Yukawa E., Suematsu F., Takiguchi T., Ikeda H., Aki H., Mimemoto M. Population pharmacokinetics of phenobarbital by mixed effect modelling using routine clinical pharmacokinetic data in Japanese neonates and infants: An update. J. Clin. Pharm. Ther. 2011;36:704–710. doi: 10.1111/j.1365-2710.2010.01220.x. PubMed DOI

Sima M., Pokorna P., Hartinger J., Slanar O. Estimation of initial phenobarbital dosing in term neonates with moderate-to-severe hypoxic ischaemic encephalopathy following perinatal asphyxia. J. Clin. Pharm. Ther. 2018;43:196–201. doi: 10.1111/jcpt.12632. PubMed DOI

Shellhaas R.A., Ng C.M., Dillon C.H., Barks J.D., Bhatt-Mehta V. Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia. Pediatr. Crit. Care. Med. 2013;14:194–202. doi: 10.1097/PCC.0b013e31825bbbc2. PubMed DOI PMC

Pitlick W., Painter M., Pippenger C. Phenobarbital pharmacokinetics in neonates. Clin. Pharmacol. Ther. 1978;23:346–350. doi: 10.1002/cpt1978233346. PubMed DOI

Thibault C., Massey S.L., Naim M.Y., Abend N.S., Zuppa A.F. Population Pharmacokinetics of IV Phenobarbital in Neonates After Congenital Heart Surgery. Pediatr. Crit. Care Med. 2020;21:e557–e565. doi: 10.1097/PCC.0000000000002341. PubMed DOI PMC

Grasela T.H., Jr., Donn S.M. Neonatal population pharmacokinetics of phenobarbital derived from routine clinical data. Dev. Pharmacol. Ther. 1985;8:374–383. doi: 10.1159/000457062. PubMed DOI

Voller S., Flint R.B., Stolk L.M., Degraeuwe P.L.J., Simons S.H.P., Pokorna P., Burger D.M., de Groot R., Tibboel D., DINO study group Model-based clinical dose optimization for phenobarbital in neonates: An illustration of the importance of data sharing and external validation. Eur. J. Pharm. Sci. 2017;109S:S90–S97. doi: 10.1016/j.ejps.2017.05.026. PubMed DOI

Moffett B.S., Weingarten M.M., Galati M., Placencia J.L., Rodman E.A., Riviello J.J., Kayyal S.Y. Phenobarbital population pharmacokinetics across the pediatric age spectrum. Epilepsia. 2018;59:1327–1333. doi: 10.1111/epi.14447. PubMed DOI

Gal P., Boer H.R., Toback J., Erkan N.V. Phenobarbital dosing in neonates and asphyxia. Neurology. 1982;32:788–789. doi: 10.1212/WNL.32.7.788. PubMed DOI

Van den Broek M.P., Groenendaal F., Toet M.C., van Straaten H.L., van Hasselt J.G., Huitema A.D., de Vries L.S., Egberts A.C., Rademaker C.M. Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: A thermopharmacological approach. Clin. Pharmacokinet. 2012;51:671–679. doi: 10.1007/s40262-012-0004-y. PubMed DOI

Favie L.M.A., de Haan T.R., Bijleveld Y.A., Rademaker C.M.A., Egberts T.C.G., Nuytemans D., Mathot R.A.A., Groenendaal F., Huitema A.D.R. Prediction of Drug Exposure in Critically Ill Encephalopathic Neonates Treated with Therapeutic Hypothermia Based on a Pooled Population Pharmacokinetic Analysis of Seven Drugs and Five Metabolites. Clin. Pharmacol. Ther. 2020;108:1098–1106. doi: 10.1002/cpt.1917. PubMed DOI PMC

Pokorna P., Posch L., Sima M., Klement P., Slanar O., van den Anker J., Tibboel D., Allegaert K. Severity of asphyxia is a covariate of phenobarbital clearance in newborns undergoing hypothermia. J. Matern. Fetal. Neonatal Med. 2018;32:2302–2309. doi: 10.1080/14767058.2018.1432039. PubMed DOI

Pokorna P., Sima M., Vobruba V., Tibboel D., Slanar O. Phenobarbital pharmacokinetics in neonates and infants during extracorporeal membrane oxygenation. Perfusion. 2018;33:80–86. doi: 10.1177/0267659118766444. PubMed DOI

Michalickova D., Pokorna P., Tibboel D., Slanar O., Knibbe C.A.J., Krekels E.H.J. Rapid Increase in Clearance of Phenobarbital in Neonates on Extracorporeal Membrane Oxygenation: A Pilot Retrospective Population Pharmacokinetic Analysis. Pediatr. Crit. Care Med. 2020;21:e707–e715. doi: 10.1097/PCC.0000000000002402. PubMed DOI

Sima M., Pokorna P., Hronova K., Slanar O. Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns. Physiol. Res. 2015;64:S513–S519. doi: 10.33549/physiolres.933213. PubMed DOI

Lee S.M., Chung J.Y., Lee Y.M., Park M.S., Namgung R., Park K.I., Lee C. Effects of cytochrome P450 (CYP)2C19 polymorphisms on pharmacokinetics of phenobarbital in neonates and infants with seizures. Arch. Dis. Child. 2012;97:569–572. doi: 10.1136/archdischild-2011-300538. PubMed DOI

Pokorna P., Michalickova D., Voller S., Hronova K., Tibboel D., Slanar O., Krekels E.H. Severity parameters for asphyxia or hypoxic-ischemic encephalopathy do not explain interindividual variability in the pharmacokinetics of phenobarbital in newborns treated with therapeutic hypothermia. Minerva Pediatr. 2020 doi: 10.23736/S0026-4946.20.05740-0. PubMed DOI

Favie L.M.A., Groenendaal F., van den Broek M.P.H., Rademaker C.M.A., de Haan T.R., van Straaten H.L.M., Dijk P.H., van Heijst A., Simons S.H.P., Dijkman K.P., et al. Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia. Neonatology. 2019;116:154–162. doi: 10.1159/000499330. PubMed DOI PMC

Thibault C., Massey S.L., Abend N.S., Naim M.Y., Zorian A., Zuppa A.F. Population Pharmacokinetics of Phenobarbital in Neonates and Infants on Extracorporeal Membrane Oxygenation and the Influence of Concomitant Renal Replacement Therapy. J. Clin. Pharmacol. 2020;61:378–387. doi: 10.1002/jcph.1743. PubMed DOI PMC

Back H.M., Lee J.B., Han N., Goo S., Jung E., Kim J., Song B., An S.H., Kim J.T., Rhie S.J., et al. Application of Size and Maturation Functions to Population Pharmacokinetic Modeling of Pediatric Patients. Pharmaceutics. 2019;11:259. doi: 10.3390/pharmaceutics11060259. PubMed DOI PMC

Gal P., Toback J., Erkan N.V., Boer H.R. The influence of asphyxia on phenobarbital dosing requirements in neonates. Dev. Pharmacol. Ther. 1984;7:145–152. doi: 10.1159/000457157. PubMed DOI

Dillman N.O., Messinger M.M., Dinh K.N., Placencia J.L., Moffett B.S., Guaman M.C., Erklauer J.C., Kaiser J.R., Wilfong A.A. Evaluation of the Effects of Extracorporeal Membrane Oxygenation on Antiepileptic Drug Serum Concentrations in Pediatric Patients. J. Pediatr. Pharmacol. Ther. 2017;22:352–357. doi: 10.5863/1551-6776-22.5.352. PubMed DOI PMC

Sima M., Slanar O. Impact of drug-drug interactions on phenobarbital pharmacokinetics in pediatric patients. Epilepsia. 2019;60:1266–1267. doi: 10.1111/epi.14704. PubMed DOI

Moffett B.S. Impact of drug-drug interactions on phenobarbital pharmacokinetics in pediatric patients—Response. Epilepsia. 2019;60:1268. doi: 10.1111/epi.15542. PubMed DOI

Ouvrier R.A., Goldsmith R. Phenobarbitone dosage in neonatal convulsions. Arch. Dis. Child. 1982;57:653–657. doi: 10.1136/adc.57.9.653. PubMed DOI PMC

Smits A., Annaert P., Van Cruchten S., Allegaert K. A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision during Therapeutic Hypothermia in Neonates. Front. Pharmacol. 2020 doi: 10.3389/fphar.2020.00587. PubMed DOI PMC

Green B., Duffull S.B. What is the best size descriptor to use for pharmacokinetic studies in the obese? Br. J. Clin. Pharmacol. 2004;58:119–133. doi: 10.1111/j.1365-2125.2004.02157.x. PubMed DOI PMC

Sima M., Hartinger J., Cikankova T., Slanar O. Estimation of once-daily amikacin dose in critically ill adults. J. Chemother. 2018;30:37–43. doi: 10.1080/1120009X.2017.1376818. PubMed DOI

Al-Sallami H.S., Goulding A., Grant A., Taylor R., Holford N., Duffull S.B. Prediction of Fat-Free Mass in Children. Clin. Pharmacokinet. 2015;54:1169–1178. doi: 10.1007/s40262-015-0277-z. PubMed DOI

Pokorna P., Sima M., Cerna O., Allegaert K., Tibboel D., Slanar O. Actual body weight-based vancomycin dosing in neonates. J. Chemother. 2019;31:307–312. doi: 10.1080/1120009X.2019.1599574. PubMed DOI

Pokorna P., Sima M., Cerna O., Slanar O. Nomogram based on actual body weight for estimation of vancomycin maintenance dose in infants. Infect. Dis. (Lond.) 2019;51:334–339. doi: 10.1080/23744235.2018.1541250. PubMed DOI

Martinkova J., Pokorna P., Zahora J., Chladek J., Vobruba V., Selke-Krulichova I., Chladkova J. Tolerability and outcomes of kinetically guided therapy with gentamicin in critically ill neonates during the first week of life: An open-label, prospective study. Clin. Ther. 2010;32:2400–2414. doi: 10.1016/j.clinthera.2011.01.013. PubMed DOI

Calvier E.A., Krekels E.H.J., Välitalo P.A.J., Rostami-Hodjegan A., Tibboel D., Danhof M., Knibbe C.A.J. Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade? Clin. Pharmacokinet. 2017;56:273–285. doi: 10.1007/s40262-016-0436-x. PubMed DOI PMC

Morselli P.L. Clincial pharmacokinetics in neonates. Clin. Pharmacokinet. 1976;1:81–98. doi: 10.2165/00003088-197601020-00001. PubMed DOI

Greenberg J.H., Parikh C.R. Biomarkers for Diagnosis and Prognosis of AKI in Children: One Size Does Not Fit All. Clin. J. Am. Soc. Nephrol. 2017;12:1551–1557. doi: 10.2215/CJN.12851216. PubMed DOI PMC

D’Agata I.D., Balistreri W.F. Evaluation of liver disease in the pediatric patient. Pediatr. Rev. 1999;20:376–390. doi: 10.1542/pir.20-11-376. PubMed DOI

Wandel C., Böcker R., Böhrer H., Browne A., Rügheimer E., Martin E. Midazolam is metabolized by at least three different cytochrome P450 enzymes. Br. J. Anaesth. 1994;73:658–661. doi: 10.1093/bja/73.5.658. PubMed DOI

Meyer U.A. Interaction of proton pump inhibitors with cytochromes P450: Consequences for drug interactions. Yale J. Biol. Med. 1996;69:203–209. PubMed PMC

Pokorna P., Wildschut E.D., Vobruba V., van den Anker J.N., Tibboel D. The Impact of Hypothermia on the Pharmacokinetics of Drugs Used in Neonates and Young Infants. Curr. Pharm. Des. 2015;21:5705–5724. doi: 10.2174/1381612821666150901110929. PubMed DOI

Ahearne C.E., Boylan G.B., Murray D.M. Short and long term prognosis in perinatal asphyxia: An update. World. J. Clin. Pediatr. 2016;5:67–74. doi: 10.5409/wjcp.v5.i1.67. PubMed DOI PMC