Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Original article

Vol. 154 No. 4 (2024)

Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology – application to amikacin

  • Verena Gotta
  • Julia Anna Bielicki
  • Paolo Paioni
  • Chantal Csajka
  • Dominic Stefan Bräm
  • Christoph Berger
  • Elisabeth Giger
  • Michael Buettcher
  • Klara M. Posfay-Barbe
  • John van den Anker
  • Marc Pfister
DOI
https://doi.org/10.57187/s.3632
Cite this as:
Swiss Med Wkly. 2024;154:3632
Published
08.04.2024

Summary

BACKGROUND AND AIMS: Pharmacometric in silico approaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study.

METHODS: Amikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30–35 weeks and a post-natal age of 0–14 days (“subpopulation of clinical concern”), as potentially oto-/nephrotoxic trough concentrations (Ctrough >5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough (Ctrough <5 mg/l) dosages in most neonates.

RESULTS: In the subpopulation of clinical concern, Ctrough <5 mg/l was predicted in 59% versus 79–99% of cases in all other subpopulations following the current recommendations. Elevated Ctrough values were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctrough below 5 mg/l to >80%.

CONCLUSION: Pharmacometric in silico studies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.

References

  1. Leroux S, Zhao W, Bétrémieux P, Pladys P, Saliba E, Jacqz-Aigrain E; French Society of Neonatology. Therapeutic guidelines for prescribing antibiotics in neonates should be evidence-based: a French national survey. Arch Dis Child. 2015 Apr;100(4):394–8. 10.1136/ARCHDISCHILD-2014-306873 10.1136/archdischild-2014-306873 DOI: https://doi.org/10.1136/archdischild-2014-306873
  2. Kadambari S, Heath PT, Sharland M, Lewis S, Nichols A, Turner MA. Variation in gentamicin and vancomycin dosage and monitoring in UK neonatal units. J Antimicrob Chemother. 2011 Nov;66(11):2647–50. 10.1093/jac/dkr351 DOI: https://doi.org/10.1093/jac/dkr351
  3. Metsvaht T, Nellis G, Varendi H, Nunn AJ, Graham S, Rieutord A, et al. High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination. BMC Pediatr. 2015 Apr;15(1):41. 10.1186/s12887-015-0359-y DOI: https://doi.org/10.1186/s12887-015-0359-y
  4. Liem TB, Slob EM, Termote JU, Wolfs TF, Egberts AC, Rademaker CM. Comparison of antibiotic dosing recommendations for neonatal sepsis from established reference sources. Int J Clin Pharm. 2018 Apr;40(2):436–43. 10.1007/s11096-018-0589-9 DOI: https://doi.org/10.1007/s11096-018-0589-9
  5. Tilen R, Panis D, Aeschbacher S, Sabine T, Meyer Zu Schwabedissen HE, Berger C. Development of the Swiss Database for dosing medicinal products in pediatrics. Eur J Pediatr. 2022 Mar;181(3):1221–31. 10.1007/S00431-021-04304-8 10.1007/s00431-021-04304-8 DOI: https://doi.org/10.1007/s00431-021-04304-8
  6. SwissPedDose Association SwissPedDose. National pediatric drug doses. https://swisspeddose.ch/
  7. Mehrotra N, Bhattaram A, Earp JC, Florian J, Krudys K, Lee JE, et al. Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling. Drug Metab Dispos. 2016 Jul;44(7):924–33. 10.1124/DMD.116.069559 10.1124/dmd.116.069559 DOI: https://doi.org/10.1124/dmd.116.069559
  8. Vinks AA, Emoto C, Fukuda T. Modeling and simulation in pediatric drug therapy: application of pharmacometrics to define the right dose for children. Clin Pharmacol Ther. 2015 Sep;98(3):298–308. 10.1002/cpt.169
  9. Pfiffner M, Berger-Olah E, Vonbach P, Pfister M, Gotta V. Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants. Front Pediatr. 2022 Mar;10:837492. 10.3389/FPED.2022.837492 10.3389/fped.2022.837492 DOI: https://doi.org/10.3389/fped.2022.837492
  10. Pfiffner M, Gotta V, Pfister M, et al (2022) Pharmacokinetics and tolerability of intranasal or intravenous administration of nalbuphine in infants. Arch Dis Child archdischild-2022-323807. https://doi.org/10.1136/archdischild-2022-323807 DOI: https://doi.org/10.1136/archdischild-2022-323807
  11. van Donge T, Samiee-Zafarghandy S, Pfister M, Koch G, Kalani M, Bordbar A, et al. Methadone dosing strategies in preterm neonates can be simplified. Br J Clin Pharmacol. 2019 Jun;85(6):1348–56. 10.1111/BCP.13906 10.1111/bcp.13906 DOI: https://doi.org/10.1111/bcp.13906
  12. van Donge T, Pfister M, Bielicki J, Csajka C, Rodieux F, van den Anker J, et al. Quantitative analysis of gentamicin exposure in neonates and infants calls into question its current dosing recommendations. Antimicrob Agents Chemother. 2018 Mar;62(4):e02004-17. 10.1128/AAC.02004-17 DOI: https://doi.org/10.1128/AAC.02004-17
  13. Darlow CA, da Costa RM, Ellis S, Franceschi F, Sharland M, Piddock L, et al. Potential Antibiotics for the Treatment of Neonatal Sepsis Caused by Multidrug-Resistant Bacteria. Paediatr Drugs. 2021 Sep;23(5):465–84. 10.1007/S40272-021-00465-Z 10.1007/s40272-021-00465-z DOI: https://doi.org/10.1007/s40272-021-00465-z
  14. Ramirez MS, Tolmasky ME. Amikacin: Uses, Resistance, and Prospects for Inhibition. Molecules. 2017 Dec;22(12):2267. 10.3390/MOLECULES22122267 10.3390/molecules22122267 DOI: https://doi.org/10.3390/molecules22122267
  15. Shane AL, Sánchez PJ, Stoll BJ. Neonatal sepsis. Lancet. 2017 Oct;390(10104):1770–80. 10.1016/S0140-6736(17)31002-4 DOI: https://doi.org/10.1016/S0140-6736(17)31002-4
  16. Cristea S, Smits A, Kulo A, Knibbe CA, van Weissenbruch M, Krekels EH, et al. Amikacin Pharmacokinetics To Optimize Dosing in Neonates with Perinatal Asphyxia Treated with Hypothermia. Antimicrob Agents Chemother. 2017 Nov;61(12):e01282–17. 10.1128/AAC.01282-17 DOI: https://doi.org/10.1128/AAC.01282-17
  17. Jenkins A, Thomson AH, Brown NM, Semple Y, Sluman C, MacGowan A, et al.; BSAC Working Party on Therapeutic Drug Monitoring. Amikacin use and therapeutic drug monitoring in adults: do dose regimens and drug exposures affect either outcome or adverse events? A systematic review. J Antimicrob Chemother. 2016 Oct;71(10):2754–9. 10.1093/JAC/DKW250 10.1093/jac/dkw250 DOI: https://doi.org/10.1093/jac/dkw250
  18. Wilbaux M, Fuchs A, Samardzic J, Rodieux F, Csajka C, Allegaert K, et al. Pharmacometric Approaches to Personalize Use of Primarily Renally Eliminated Antibiotics in Preterm and Term Neonates. J Clin Pharmacol. 2016 Aug;56(8):909–35. 10.1002/jcph.705
  19. Illamola SM, Sherwin CM, van Hasselt JG. Clinical Pharmacokinetics of Amikacin in Pediatric Patients: A Comprehensive Review of Population Pharmacokinetic Analyses. Clin Pharmacokinet. 2018 Oct;57(10):1217–28. 10.1007/s40262-018-0641-x DOI: https://doi.org/10.1007/s40262-018-0641-x
  20. Wu Y, Allegaert K, Flint RB, Simons SH, Krekels EH, Knibbe CA, et al. Prediction of glomerular filtration rate maturation across preterm and term neonates and young infants using inulin as marker. AAPS J. 2022 Feb;24(2):38. 10.1208/S12248-022-00688-Z/FIGURES/4 10.1208/s12248-022-00688-z DOI: https://doi.org/10.1208/s12248-022-00688-z
  21. Salem F, Johnson TN, Hodgkinson AB, Ogungbenro K, Rostami-Hodjegan A. Does “Birth” as an Event impact maturation trajectory of renal clearance via glomerular filtration? Reexamining data in preterm and full-term neonates by avoiding the creatinine bias. J Clin Pharmacol. 2021 Feb;61(2):159–71. 10.1002/jcph.1725 DOI: https://doi.org/10.1002/jcph.1725
  22. Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009 Jan;24(1):67–76. 10.1007/s00467-008-0997-5 DOI: https://doi.org/10.1007/s00467-008-0997-5
  23. van Donge T, Allegaert K, Gotta V, Smits A, Levtchenko E, Mekahli D, et al. Characterizing dynamics of serum creatinine and creatinine clearance in extremely low birth weight neonates during the first 6 weeks of life. Pediatr Nephrol. 2021 Mar;36(3):649–59. 10.1007/S00467-020-04749-3 10.1007/s00467-020-04749-3 DOI: https://doi.org/10.1007/s00467-020-04749-3
  24. Bi Y, Liu J, Li L, Yu J, Bhattaram A, Bewernitz M, et al. Role of Model-Informed Drug Development in Pediatric Drug Development, Regulatory Evaluation, and Labeling. J Clin Pharmacol. 2019 Sep;59(S1 Suppl 1):S104–11. 10.1002/jcph.1478 DOI: https://doi.org/10.1002/jcph.1478
  25. Madabushi R, Seo P, Zhao L, Tegenge M, Zhu H. Review: Role of Model-Informed Drug Development Approaches in the Lifecycle of Drug Development and Regulatory Decision-Making. Pharm Res. 2022 Aug;39(8):1669–80. 10.1007/s11095-022-03288-w DOI: https://doi.org/10.1007/s11095-022-03288-w
  26. Hartman SJ, Swaving JG, van Beek SW, van Groen BD, de Hoop M, van der Zanden TM, et al. A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept. Front Pharmacol. 2020 Dec;11:592204. 10.3389/FPHAR.2020.592204 10.3389/fphar.2020.592204 DOI: https://doi.org/10.3389/fphar.2020.592204
  27. Versporten A, Bielicki J, Drapier N, Sharland M, Goossens H; ARPEC project group. The Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children. J Antimicrob Chemother. 2016 Apr;71(4):1106–17. 10.1093/jac/dkv418 DOI: https://doi.org/10.1093/jac/dkv418
  28. Versporten A, Sharland M, Bielicki J, Drapier N, Vankerckhoven V, Goossens H; ARPEC Project Group Members. The antibiotic resistance and prescribing in European Children project: a neonatal and pediatric antimicrobial web-based point prevalence survey in 73 hospitals worldwide. Pediatr Infect Dis J. 2013 Jun;32(6):e242–53. 10.1097/INF.0b013e318286c612 DOI: https://doi.org/10.1097/INF.0b013e318286c612
  29. De Cock RF, Allegaert K, Schreuder MF, Sherwin CM, de Hoog M, van den Anker JN, et al. Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance. Clin Pharmacokinet. 2012 Feb;51(2):105–17. 10.2165/11595640-000000000-00000 DOI: https://doi.org/10.2165/11595640-000000000-00000
  30. Allegaert K, Scheers I, Cossey V, Anderson BJ. Covariates of amikacin clearance in neonates: the impact of postnatal age on predictability. Drug Metab Lett. 2008 Dec;2(4):286–9. 10.2174/187231208786734157 DOI: https://doi.org/10.2174/187231208786734157
  31. Allegaert K, Anderson BJ, Cossey V, Holford NH. Limited predictability of amikacin clearance in extreme premature neonates at birth. Br J Clin Pharmacol. 2006 Jan;61(1):39–48. 10.1111/j.1365-2125.2005.02530.x DOI: https://doi.org/10.1111/j.1365-2125.2005.02530.x
  32. Sherwin CM, Svahn S, Van der Linden A, Broadbent RS, Medlicott NJ, Reith DM. Individualised dosing of amikacin in neonates: a pharmacokinetic/pharmacodynamic analysis. Eur J Clin Pharmacol. 2009 Jul;65(7):705–13. 10.1007/S00228-009-0637-4 10.1007/s00228-009-0637-4 DOI: https://doi.org/10.1007/s00228-009-0637-4
  33. Schreuder MF, Wilhelm AJ, Bökenkamp A, Timmermans SM, Delemarre-van de Waal HA, van Wijk JA. Impact of gestational age and birth weight on amikacin clearance on day 1 of life. Clin J Am Soc Nephrol. 2009 Nov;4(11):1774–8. 10.2215/CJN.02230409 DOI: https://doi.org/10.2215/CJN.02230409
  34. Smits A, De Cock RF, Allegaert K, Vanhaesebrouck S, Danhof M, Knibbe CA. Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice. Antimicrob Agents Chemother. 2015 Oct;59(10):6344–51. 10.1128/AAC.01157-15 DOI: https://doi.org/10.1128/AAC.01157-15
  35. Gotta V, van den Anker J, Pfister M. [Understanding and reducing the risk of adverse drug reactions in pediatric patients]. Ther Umsch. 2015 Dec;72(11-12):679–86. 10.1024/0040-5930/a000737 DOI: https://doi.org/10.1024/0040-5930/a000737
  36. Kaushal R, Bates DW, Landrigan C, McKenna KJ, Clapp MD, Federico F, et al. Medication errors and adverse drug events in pediatric inpatients. JAMA. 2001 Apr;285(16):2114–20. 10.1001/jama.285.16.2114 DOI: https://doi.org/10.1001/jama.285.16.2114
  37. Kaushal R, Goldmann DA, Keohane CA, Abramson EL, Woolf S, Yoon C, et al. Medication errors in paediatric outpatients. Qual Saf Health Care. 2010 Dec;19(6):e30. 10.1136/qshc.2008.031179 DOI: https://doi.org/10.1136/qshc.2008.031179
  38. Vinks AA, Emoto C, Fukuda T. Modeling and simulation in pediatric drug therapy: application of pharmacometrics to define the right dose for children. Clin Pharmacol Ther. 2015 Sep;98(3):298–308. 10.1002/cpt.169 DOI: https://doi.org/10.1002/cpt.169
  39. Hong Y, Kowalski KG, Zhang J, Zhu L, Horga M, Bertz R, et al. Model-based approach for optimization of atazanavir dose recommendations for HIV-infected pediatric patients. Antimicrob Agents Chemother. 2011 Dec;55(12):5746–52. 10.1128/AAC.00554-11 DOI: https://doi.org/10.1128/AAC.00554-11
  40. Wilbaux M, Fuchs A, Samardzic J, Rodieux F, Csajka C, Allegaert K, et al. Pharmacometric Approaches to Personalize Use of Primarily Renally Eliminated Antibiotics in Preterm and Term Neonates. J Clin Pharmacol. 2016 Aug;56(8):909–35. 10.1002/JCPH.705 10.1002/jcph.705 DOI: https://doi.org/10.1002/jcph.705
  41. Dao K, Fuchs A, André P, Giannoni E, Decosterd LA, Marchetti O, et al. Dosing strategies of imipenem in neonates based on pharmacometric modelling and simulation. J Antimicrob Chemother. 2022 Feb;77(2):457–65. 10.1093/JAC/DKAB394 10.1093/jac/dkab394 DOI: https://doi.org/10.1093/jac/dkab394
  42. Dao K, Guidi M, André P, Giannoni E, Basterrechea S, Zhao W, et al. Optimisation of vancomycin exposure in neonates based on the best level of evidence. Pharmacol Res. 2020 Apr;154:104278. 10.1016/J.PHRS.2019.104278 10.1016/j.phrs.2019.104278 DOI: https://doi.org/10.1016/j.phrs.2019.104278
  43. van Donge T, Fuchs A, Leroux S, Pfister M, Rodieux F, Atkinson A, et al. Amoxicillin Dosing Regimens for the Treatment of Neonatal Sepsis: Balancing Efficacy and Neurotoxicity. Neonatology. 2020;117(5):619–27. 10.1159/000509751 DOI: https://doi.org/10.1159/000509751
  44. Bräm DS, Nahum U, Atkinson A, Koch G, Pfister M. Evaluation of machine learning methods for covariate data imputation in pharmacometrics. CPT Pharmacometrics Syst Pharmacol. 2022 Dec;11(12):1638–48. 10.1002/PSP4.12874 10.1002/psp4.12874 DOI: https://doi.org/10.1002/psp4.12874
  45. Wilbaux M, Kasser S, Wellmann S, Lapaire O, van den Anker JN, Pfister M. Characterizing and Forecasting Individual Weight Changes in Term Neonates. J Pediatr. 2016 Jun;173:101–107.e10. 10.1016/J.JPEDS.2016.02.044 10.1016/j.jpeds.2016.02.044 DOI: https://doi.org/10.1016/j.jpeds.2016.02.044
  46. Gotta V, Buclin T, Csajka C, Widmer N. Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes. Ther Drug Monit. 2013 Apr;35(2):150–67. 10.1097/FTD.0b013e318284ef11 DOI: https://doi.org/10.1097/FTD.0b013e318284ef11
  47. Alhadab AA, Ahmed MA, Brundage RC. Amikacin Pharmacokinetic-Pharmacodynamic Analysis in Pediatric Cancer Patients. Antimicrob Agents Chemother. 2018 Mar;62(4):e01781-17. 10.1128/AAC.01781-17 DOI: https://doi.org/10.1128/AAC.01781-17
  48. Rao SC, Srinivasjois R, Moon K. One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev. 2016 Dec;12(12):CD005091. 10.1002/14651858.CD005091.PUB4 10.1002/14651858.CD005091.pub4
  49. Hanberger H, Edlund C, Furebring M, G Giske C, Melhus A, Nilsson LE, et al.; Swedish Reference Group for Antibiotics. Rational use of aminoglycosides—review and recommendations by the Swedish Reference Group for Antibiotics (SRGA). Scand J Infect Dis. 2013 Mar;45(3):161–75. 10.3109/00365548.2012.747694 DOI: https://doi.org/10.3109/00365548.2012.747694
  50. Craig WA. Optimizing aminoglycoside use. Crit Care Clin. 2011 Jan;27(1):107–21. 10.1016/J.CCC.2010.11.006 10.1016/j.ccc.2010.11.006 DOI: https://doi.org/10.1016/j.ccc.2010.11.006
  51. Paioni P, Jäggi VF, Tilen R, Seiler M, Baumann P, Bräm DS, et al. Gentamicin population pharmacokinetics in pediatric patients—a prospective study with data analysis using the saemix package in r. Pharmaceutics. 2021 Oct;13(10):1596. 10.3390/PHARMACEUTICS13101596/S1 10.3390/pharmaceutics13101596 DOI: https://doi.org/10.3390/pharmaceutics13101596
  52. Goers R, Coman Schmid D, Jäggi VF, Paioni P, Okoniewski MJ, Parker A, et al. SwissPKcdw - A clinical data warehouse for the optimization of pediatric dosing regimens. CPT Pharmacometrics Syst Pharmacol. 2021 Dec;10(12):1578–87. 10.1002/PSP4.12723 10.1002/psp4.12723 DOI: https://doi.org/10.1002/psp4.12723
  53. van Donge T, Bielicki JA, van den Anker J, Pfister M. Key Components for Antibiotic Dose Optimization of Sepsis in Neonates and Infants. Front Pediatr. 2018 Oct;6:325. 10.3389/FPED.2018.00325 10.3389/fped.2018.00325 DOI: https://doi.org/10.3389/fped.2018.00325

Most read articles by the same author(s)

<< < 1 2 3