Skip to main content
SpringerLink
Log in

Individualised dosing of amikacin in neonates: a pharmacokinetic/pharmacodynamic analysis

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To examine the pharmacokinetics of amikacin and its pharmacokinetic pharmacodynamic (PKPD) relationship in neonates. To develop an alternative dosing strategy for amikacin in neonates.

Methods

A population PKPD analysis was performed using data collected from 80 neonates with gestational ages from 24 to 41 weeks. The final pharmacokinetic model analysed 358 amikacin concentrations. All neonates were > 72 hours postnatal age. Simulations were performed to develop a new dosing strategy.

Results

The final covariate model was clearance = 0.23 × (current weight/2)0.691 × (postmenstrual age/40)3.23 and volume of distribution = 0.957 × (current weight/2)0.89. Following the logistic regression analysis of treatment failure, new amikacin target concentrations were estimated and used in development of an alternative dosing strategy.

Conclusion

Simulation of a new dosing regimen yielded the following recommendations: 15 mg/kg at 36-h intervals, 14 mg/kg at 24-h intervals and 15 mg/kg at 24-h intervals for neonates ≤28 weeks, 29–36 weeks and ≥37 weeks postmenstrual age respectively.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Clapp DW (2006) Developmental regulation of the immune system. Semin Perinatol 30:69–72

    Article  PubMed  Google Scholar 

  2. Petersen PO, Wells TG, Kearns GL (1991) Amikacin dosing in neonates: evaluation of a dosing chart based on population pharmacokinetic data. Dev Pharmacol Ther 16:203–211

    PubMed  CAS  Google Scholar 

  3. Zaske DE, Strate RG, Kohls PR (1991) Amikacin pharmacokinetics—wide interpatient variation in 98 patients. J Clin Pharmacol 31:158–163

    PubMed  CAS  Google Scholar 

  4. Bristol-Meyers S (2001) Amikin. Bristol-Myers Squibb Pharmaceuticals, Noble Park, Australia

    Google Scholar 

  5. Bleyzac N, Varnier V, Labaune JM, Corvaisier S, Maire P, Jelliffe RW, Putet G, Aulagner G (2001) Population pharmacokinetics of amikacin at birth and interindividual variability in renal maturation. Eur J Clin Pharmacol 57:499–504

    Article  PubMed  CAS  Google Scholar 

  6. Young TE, Mangum B (2002) Neofax, 15 ed. Acorn Publishing, Raleigh

  7. Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–12

    Article  PubMed  CAS  Google Scholar 

  8. Langhendries JP, Battisti O, Bertrand JM, Francois A, Kalenga M, Darimont J, Scalais E, Wallemacq P (1998) Adaptation in neonatology of the once-daily concept of aminoglycoside administration: evaluation of a dosing chart for amikacin in an intensive care unit. Biol Neonate 74:351–362

    Article  PubMed  CAS  Google Scholar 

  9. Cookson B, Tripp J, Leung T, Williams JD (1980) Evaluation of amikacin dosage regimes in the low and very low birthweight newborn. Infection 8(Suppl 3):239–242

    Article  Google Scholar 

  10. Ette EL, Williams PJ, Kim YH, Lane JR, Liu MJ, Capparelli EV (2003) Model appropriateness and population pharmacokinetic modeling. J Clin Pharmacol 43:610–623

    PubMed  CAS  Google Scholar 

  11. Pagano M, Gauvreau K (1993) Principles of biostatistics. Wadsworth Publishing, Belmont, CA

    Google Scholar 

  12. Kotze A, Bartel PR, Sommers DK (1999) Once versus twice daily amikacin in neonates: prospective study on toxicity. J Paediatr Child Health 35:283–286

    Article  PubMed  CAS  Google Scholar 

  13. Langhendries JP, Battisti O, Bertrand JM, Francois A, Darimont J, Ibrahim S, Tulkens PM, Bernard A, Buchet JP, Scalais E (1993) Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity. Dev Pharmacol Ther 20:220–230

    PubMed  CAS  Google Scholar 

  14. Botha FJH, van der Bijl P, Seifart HI, Parkin DP (1996) Fluctuation of the volume of distribution of amikacin and its effect on once-daily dosage and clearance in a seriously ill patient. Intensive Care Med 22:443–446

    Article  PubMed  CAS  Google Scholar 

  15. Assael BM, Parini R, Rusconi F, Cavanna G (1982) Influence of intrauterine maturation on the pharmacokinetics of amikacin in the neonatal period. Pediatr Res 16:810–815

    Article  PubMed  CAS  Google Scholar 

  16. Botha JH, du Preez M, Miller R, Adhikari M (1998) Determination of population pharmacokinetic parameters for amikacin in neonates using mixed-effect models. Eur J Clin Pharmacol 53:337–341

    Article  PubMed  CAS  Google Scholar 

  17. Kenyon CF, Knoppert DC, Lee SK, Vandenberghe HM, Chance GW (1990) Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant. Antimicrob Agents Chemother 34:265–268

    PubMed  CAS  Google Scholar 

  18. Berger A, Kretzer V, Gludovatz P, Heinze G, Haiden N, Pollak A (2004) Evaluation of an amikacin loading dose for nosocomial infections in very low birthweight infants. Acta Paediatrica 93:356–360

    Article  PubMed  CAS  Google Scholar 

  19. Savic RM, Karlsson MO (2007) Importance of shrinkage in empirical bayes estimates for diagnostics and estimation: problems and solutions. Abstracts of the Annual Meeting of the Population Approach Group in Europe, p. 16

  20. Allegaert K, Cossey V, Langhendries JP, Naulaers G, Vanhole C, Devlieger H, Van Overmeire B (2004) Effects of co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin in preterm infants during the first days of life. Biol Neonate 86:207–211

    Article  PubMed  CAS  Google Scholar 

  21. Treluyer JM, Merle Y, Tonnelier S, Rey E, Pons G (2002) Nonparametric population pharmacokinetic analysis of amikacin in neonates, infants, and children. Antimicrob Agents Chemother 46:1381–1387

    Article  PubMed  CAS  Google Scholar 

  22. Koren G, James A, Perlman M (1985) Simple method for the estimation of glomerular filtration rate by gentamicin pharmacokinetics during routine drug monitoring in the newborn. Clin Pharmacol Ther 38:680–685

    PubMed  CAS  Google Scholar 

  23. Allegaert K, Anderson BJ, Cossey V, Holford NHG (2005) Limited predictability of amikacin clearance in extreme premature neonates at birth. Br J Clin Pharmacol 61:39–48

    Article  CAS  Google Scholar 

  24. Bueva A, Guignard JP (1994) Renal function in preterm neonates. Pediatr Res 36:572–577

    PubMed  CAS  Google Scholar 

  25. Kenyon CF, Knoppert DC, Lee SK, Vandenberghe HM, Chance GW (1990) Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant. Antimicrob Agents Chemother 34:265–268

    PubMed  CAS  Google Scholar 

  26. Lingvall M, Reith DM, Broadbent R (2005) The effect of sepsis upon gentamicin pharmacokinetics in neonates. Br J Clin Pharmacol 59:54–61

    Article  PubMed  CAS  Google Scholar 

  27. Mann HJ, Fuhs DW, Awang R, Ndemo FA, Cerra FB (1987) Altered aminoglycoside pharmacokinetics in critically ill patients with sepsis. Clin Pharm 6:148–153

    PubMed  CAS  Google Scholar 

  28. Padovani EM, Pistolesi C, Fanos V, Messori A, Martini N (1993) Pharmacokinetics of amikacin in neonates. Dev Pharmacol Ther 20:167–173

    PubMed  CAS  Google Scholar 

  29. Besunder JB, Reed MD, Blumer JL (1988) Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (part ii). Clin Pharmacokinet 14:261–286

    Article  PubMed  CAS  Google Scholar 

  30. van den Anker JN (1996) Pharmacokinetics and renal function in preterm infants. Acta Paediatr 85:1393–1399

    Article  PubMed  Google Scholar 

  31. Aperia A, Broberger O, Elinder G, Herin P, Zetterstrom R (1981) Postnatal development of renal function in pre-term and full-term infants. Acta Paediatr Scand 70:183–187

    Article  PubMed  CAS  Google Scholar 

  32. Moore RD, Smith CR, Lietman PS (1984) Association of aminoglycosides plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med 77:657–662

    Article  PubMed  CAS  Google Scholar 

  33. Moore RD, Lietman PS, Smith CR (1987) Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 155:93–99

    PubMed  CAS  Google Scholar 

  34. Noone P, Parsons TM, Pattison JR, Slack RC, Garfield-Davies D, Hughes K (1974) Experience in monitoring gentamicin therapy during treatment of serious gram-negative sepsis. Br Med J 1:477–481

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge Professor Stephen Duffull, School of Pharmacy, University of Otago, Dunedin, New Zealand, for his assistance with the PK modelling and the simulations. Catherine Sherwin is supported by a Freemasons Postgraduate Fellowship in Paediatrics and Child Health from the Freemasons of New Zealand.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH, 45229-3039, USA

    Catherine M. T. Sherwin

  2. Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, P.O. Box 913, Dunedin, New Zealand

    David M. Reith

  3. University of Uppsala, Uppsala, Sweden

    Sofia Svahn

  4. Department of Pathology, Dunedin School of Medicine, Dunedin, New Zealand

    Antje Van Der Linden

  5. Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Roland S. Broadbent

  6. New Zealand’s National School of Pharmacy, University of Otago, Dunedin, New Zealand

    Natalie J. Medlicott

Authors
  1. Catherine M. T. Sherwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sofia Svahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antje Van Der Linden
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roland S. Broadbent
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Natalie J. Medlicott
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David M. Reith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Catherine M. T. Sherwin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sherwin, C.M.T., Svahn, S., Van Der Linden, A. et al. Individualised dosing of amikacin in neonates: a pharmacokinetic/pharmacodynamic analysis. Eur J Clin Pharmacol 65, 705–713 (2009). https://doi.org/10.1007/s00228-009-0637-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-009-0637-4

Keywords

Search

Navigation