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Grading the level of evidence of neonatal pharmacotherapy: midazolam and phenobarbital as examples

Pediatric Research volume 95, pages 75–83 (2024)Cite this article

Abstract

Background

Many drugs are used off-label or unlicensed in neonates. This does not mean they are used without evidence or knowledge. We aimed to apply and evaluate the Grading and Assessment of Pharmacokinetic–Pharmacodynamic Studies (GAPPS) scoring system for the level of evidence of two commonly used anti-epileptic drugs.

Methods

Midazolam and phenobarbital as anti-epileptics were evaluated with a systematic literature search on neonatal pharmacokinetic (PK) and/or pharmacodynamic [PD, (amplitude-integrated) electroencephalography effect] studies. With the GAPPS system, two evaluators graded the current level of evidence. Inter-rater agreement was assessed for dosing evidence score (DES), quality of evidence (QoE), and strength of recommendation (REC).

Results

Seventy-two studies were included. DES scores 4 and 9 were most frequently used for PK, and scores 0 and 1 for PD. Inter-rater agreements on DES, QoE, and REC ranged from moderate to very good. A final REC was provided for all PK studies, but only for 25% (midazolam) and 33% (phenobarbital) of PD studies.

Conclusions

There is a reasonable level of evidence concerning midazolam and phenobarbital PK in neonates, although using a predefined target without integrated PK/PD evaluation. Further research is needed on midazolam use in term neonates with therapeutic hypothermia, and phenobarbital treatment in preterms.

Impact

  • There is a reasonable level of evidence concerning pharmacotherapy of midazolam and phenobarbital in neonates. Most evidence is however based on PK studies, using a predefined target level or concentration range without integrated, combined PK/PD evaluation.

  • Using the GAPPS system, final strength of recommendation could be provided for all PK studies, but only for 25% (midazolam) to 33% (phenobarbital) of PD studies.

  • Due to the limited PK observations of midazolam in term neonates with therapeutic hypothermia, and of phenobarbital in preterm neonates these subgroups can be identified for further research.

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Fig. 1: Flowcharts of the included papers for the four literature searches.
Fig. 2: The GAPPS (Grading and Assessment of Pharmacokinetic–Pharmacodynamic Studies) system, reused from Gastine et al. with permission from RightsLink.
Fig. 3: Relative frequency of dosing evidence scores (DES).
Fig. 4: Relative frequency of strength of recommendations (REC).

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Data availability

All data generated or analyzed during this study are included in this published article and its Supplementary Information files. For additional information concerning these data, the corresponding author can be contacted.

References

  1. Flint, R. B. et al. Large differences in neonatal drug use between nicus are common practice: time for consensus? Br. J. Clin. Pharmacol. 84, 1313–1323 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Slater, R., Moultrie, F., Bax, R., van den Anker, J. & Bhatt, A. Preterm health: time to bridge the evidence gap. Lancet 396, 872–873 (2020).

    Article  PubMed  Google Scholar 

  3. van den Anker, J., Reed, M. D., Allegaert, K. & Kearns, G. L. Developmental changes in pharmacokinetics and pharmacodynamics. J. Clin. Pharmacol. 58, S10–S25 (2018).

    PubMed  Google Scholar 

  4. Smits, A. et al. Current knowledge, challenges and innovations in developmental pharmacology: a combined Conect4children Expert Group and European Society for Developmental, Perinatal and Paediatric Pharmacology White Paper. Br. J. Clin. Pharmacol. 88, 4965–4984 (2022).

  5. Smits, A. et al. Prospective evaluation of a model-based dosing regimen for amikacin in preterm and term neonates in clinical practice. Antimicrob. Agents Chemother. 59, 6344–6351 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Smits, A., Kulo, A., van den Anker, J. & Allegaert, K. The amikacin research program: a stepwise approach to validate dosing regimens in neonates. Expert Opin. Drug Metab. Toxicol. 13, 157–166 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Atkins, D. et al. Grading quality of evidence and strength of recommendations. BMJ 328, 1490 (2004).

    Article  PubMed  Google Scholar 

  8. Gastine, S. et al. GAPPS (Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies) a critical appraisal system for antimicrobial PKPD studies - development and application in pediatric antibiotic studies. Expert Rev. Clin. Pharmacol. 12, 1091–1098 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Cohen, J. Weighted Kappa: nominal scale agreement with provision for scaled disagreement or partial credit. Psychol. Bull. 70, 213–220 (1968).

    Article  CAS  PubMed  Google Scholar 

  10. Altman, D. G. Practical Statistics for Medical Research (Chapman & Hall/CRC, 1991).

    Google Scholar 

  11. Engbers, A. G. J. et al. Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus. Br. J. Clin. Pharmacol. 86, 2028–2039 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Engbers, A. G. J. et al. The pharmacokinetics of caffeine in preterm newborns: no influence of doxapram but important maturation with age. Neonatology 118, 106–113 (2021).

    Article  CAS  PubMed  Google Scholar 

  13. Voller, S. et al. Recently registered midazolam doses for preterm neonates do not lead to equal exposure: a population pharmacokinetic model. J. Clin. Pharmacol. 59, 1300–1308 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Shaniv, D. et al. Neonatal drug formularies-a global scope. Children 10, 848 (2023).

  15. Barker, C. I. S. et al. Pharmacokinetic studies in children: recommendations for practice and research. Arch. Dis. Child. 103, 695–702 (2018).

    PubMed  Google Scholar 

  16. van den Broek, M. P. et al. Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach. Clin. Pharmacokinet. 51, 671–679 (2012).

    Article  PubMed  Google Scholar 

  17. Nijstad, A. L. et al. Clinical pharmacology of cytotoxic drugs in neonates and infants: providing evidence-based dosing guidance. Eur. J. Cancer 164, 137–154 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. van der Zanden, T. M. et al. Developing a paediatric drug formulary for the Netherlands. Arch. Dis. Child. 102, 357–361 (2017).

    Article  PubMed  Google Scholar 

  19. van der Zanden, T. M. et al. Extending the Dutch Paediatric Formulary across Europe: successful development of country specific, parallel, paediatric drug formularies. Abstract ESDPPP Congres Basel, Switserland. Arch. Dis. Child. 104, e59–e60 (2019).

    Google Scholar 

  20. van der Zanden, T. M. et al. Off-label, but on-evidence? A review of the level of evidence for pediatric pharmacotherapy. Clin. Pharmacol. Ther. 112, 1243–1253 (2022).

  21. Kanji, S. et al. Reporting guidelines for clinical pharmacokinetic studies: the ClinPK Statement. Clin. Pharmacokinet. 54, 783–795 (2015).

    Article  PubMed  Google Scholar 

  22. Schmidt, B. et al. Long-term effects of caffeine therapy for apnea of prematurity. N. Engl. J. Med. 357, 1893–1902 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Schmidt, B. et al. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA 307, 275–282 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Koch, G. et al. Caffeine citrate dosing adjustments to assure stable caffeine concentrations in preterm neonates. J. Pediatr. 191, 50.e1–56.e1 (2017).

    Article  Google Scholar 

  25. Allegaert, K. Rational use of medicines in neonates: current observations, areas for research and perspectives. Healthcare 6, 115 (2018).

  26. Allegaert, K., Smits, A., Simons, S. & den Anker, J. V. Perspectives in neonatal pharmacology: drug discovery, knowledge integration and structured prioritization. Curr. Pharm. Des. 24, 4839–4841 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Soul, J. S. et al. Recommendations for the design of therapeutic trials for neonatal seizures. Pediatr. Res. 85, 943–954 (2019).

    Article  PubMed  Google Scholar 

  28. Young, L., Berg, M. & Soll, R. Prophylactic barbiturate use for the prevention of morbidity and mortality following perinatal asphyxia. Cochrane Database Syst. Rev. 2016, CD001240 (2016).

    PubMed  PubMed Central  Google Scholar 

  29. Glass, H. C. et al. Safety of early discontinuation of antiseizure medication after acute symptomatic neonatal seizures. JAMA Neurol. 78, 817–825 (2021).

    Article  PubMed  Google Scholar 

  30. Kumar, J., Meena, J., Yadav, J. & Saini, L. Efficacy and safety of phenobarbitone as first-line treatment for neonatal seizure: a systematic review and meta-analysis. J. Trop. Pediatr. 67, fmab008 (2021).

  31. FDA. U.S. Food and Drug Administration. NDA approval letter phenobarbital sodium. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/215910Orig1s000ltr.pdf (2022).

  32. Sun Pharmaceutical Industries. Sezaby (phenobarbital sodium) for injection. https://sezaby.com/ (2023).

  33. Sharpe, C. et al. Levetiracetam versus phenobarbital for neonatal seizures: a randomized controlled trial. Pediatrics 145, e20193182 (2020).

  34. Cuzzolin, L. & Agostino, R. Off-label and unlicensed drug treatments in neonatal intensive care units: an Italian multicentre study. Eur. J. Clin. Pharmacol. 72, 117–123 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Costa, H., Costa, T. X., Martins, R. R. & Oliveira, A. G. Use of off-label and unlicensed medicines in neonatal intensive care. PLoS ONE 13, e0204427 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The research activities of A.S. are supported by the Clinical Research and Education Council of the University Hospitals Leuven.

Funding

No funding was used for the development of this paper.

Author information

Authors and Affiliations

  1. University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK

    Liam Mahoney

  2. Department of Clinical Sciences and Community Health, Università Degli Studi Di Milano, Milan, Italy

    Genny Raffaeli

  3. Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    Genny Raffaeli & Giacomo Cavallaro

  4. Section of Neonatology, Department of Pediatrics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey

    Serdar Beken

  5. Department of Neonatology, Ankara Etlik City Hospital, University of Health Sciences, Ankara, Turkey

    Sezin Ünal

  6. Department of Women’s and Children’s Health, University of Liverpool, Liverpool Health Partners, Liverpool, UK

    Charalampos Kotidis

  7. University of Liverpool, Liverpool Womens Hospital, Liverpool, UK

    Charalampos Kotidis

  8. Clínica Universidad de Navarra, Madrid, Spain

    Felipe Garrido

  9. Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK

    Aomesh Bhatt

  10. INFANT Research Centre, University College Cork, Cork, Ireland

    Eugene M. Dempsey

  11. Department of Neonatology, Cork University Maternity Hospital, Cork, Ireland

    Eugene M. Dempsey

  12. Department of Paediatrics and Child Health, University College Cork, Cork, Ireland

    Eugene M. Dempsey

  13. Department of Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands

    Karel Allegaert & Robert B. Flint

  14. Department of Development and Regeneration, KU Leuven, Leuven, Belgium

    Karel Allegaert & Anne Smits

  15. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

    Karel Allegaert

  16. Division of Neonatology, Department of Neonatal and Pediatric Intensive Care, Erasmus University Medical Center - Sophia Children’s Hospital, Rotterdam, The Netherlands

    Sinno H. P. Simons & Robert B. Flint

  17. Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium

    Anne Smits

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on behalf of the ESPR Pharmacology Section

Contributions

Concept and design: L.M., G.R., S.B., R.B.F., S.Ü., H.K., G.C., F.G., A.B., E.M.D., K.A., S.H.P.S., A.S. Acquisition of data: L.M., G.R., S.B., R.B.F., S.Ü., G.C., F.G., K.A., S.H.P.S., A.S. Analysis and interpretation of data: L.M., G.R., S.B., R.B.F., S.Ü., H.K., G.C., F.G., A.B., E.M.D., K.A., S.H.P.S., A.S. Drafting the article: L.M., G.R., R.B.F., G.C., F.G., K.A., S.H.P.S., A.S. Critical revision of the article: L.M., G.R., S.B., R.B.F., S.Ü., H.K., G.C., F.G., A.B., E.M.D., K.A., S.H.P.S., A.S. Final approval of the version to be published: L.M., G.R., S.B., R.B.F., S.Ü., H.K., G.C., F.G., A.B., E.M.D., K.A., S.H.P.S., A.S.

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Correspondence to Sinno H. P. Simons.

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Mahoney, L., Raffaeli, G., Beken, S. et al. Grading the level of evidence of neonatal pharmacotherapy: midazolam and phenobarbital as examples. Pediatr Res 95, 75–83 (2024). https://doi.org/10.1038/s41390-023-02779-9

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