Clinical Pharmacokinetics of Amikacin in Pediatric Patients: A Comprehensive Review of Population Pharmacokinetic Analyses

  • Sílvia M. Illamola
  • Catherine M. Sherwin
  • J. G. Coen van Hasselt
Review Article

Abstract

Amikacin plays a key role in the treatment of severe hospital-acquired infections with Gram-negative bacteria. Therapeutic use of amikacin is challenged by high inter-individual variability (IIV) combined with a narrow therapeutic spectrum. Pediatric patients represent a particularly fragile population where adequate dosing is crucial yet challenging to achieve due significant IIV associated with developmental processes and other factors. The current review provides an overview of parametric population pharmacokinetic analyses of amikacin in pediatric patients and associated patient-specific determinants of IIV. We searched PubMed for parametric population pharmacokinetic analyses of amikacin in pediatric patients. Information on patient population, study design, pharmacokinetic model characteristics, and identified patient-specific predictors of IIV was collected. Comparative analyses across studies were conducted to characterize quantitative differences reported for different studies and patient populations. Eight eligible publications were identified, of which six analyses involved neonates up to 3 months of age and two studies investigated older pediatric patients (age 2–17 years). Most commonly included covariates were current body weight for both clearance and volume of distribution, followed by age-related covariates on clearance in neonatal studies (four of six models). Quantitative comparisons of different models reported generally showed similar developmental effects in neonatal populations. The present review provides a comprehensive overview of parametric population pharmacokinetic studies for amikacin. Future studies could address the knowledge gap of patients between 3 months and 2 years of age. Furthermore, systematic studies of additional potential predictors for IIV (e.g., sepsis, inflammatory markers, renal function biomarkers) could be of relevance to address the significant IIV remaining after inclusion of the most commonly identified covariates.

Notes

Compliance with Ethical Standards

Funding

No sources of funding were used to assist with the preparation of this review.

Conflict of interest

Sílvia M. Illamola, Catherine M. Sherwin, and J. G. Coen van Hasselt have no conflicts of interest that are relevant to the content of this review.

References

  1. 1.
    Boehr DD, Draker KA, Wright GD. Aminoglycoside and aminocyclitols. In: Finch RG, Greenwood D, Norrby SR, Whitley RJ, editors. Antibiotic and chemotherapy: anti-infective agents and their use in therapy. New York: Churchill Livingstone; 2003. pp. 155–84.Google Scholar
  2. 2.
    Spitzer AR, Ellsbury DL, Handler D, Clark RH. The Pediatrix BabySteps® Data Warehouse and the Pediatrix QualitySteps Improvement Project System–tools for “meaningful use” in continuous quality improvement. Clin Perinatol. 2010;37(1):49–70.  https://doi.org/10.1016/j.clp.2010.01.016.CrossRefPubMedGoogle Scholar
  3. 3.
    BMS. Amikacin. Summary of product characteristics. Princeton, NJ: BMS; 2014.Google Scholar
  4. 4.
    Young DC, Zobell JT, Stockmann C, Waters CD, Ampofo K, Sherwin CM, et al. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: V. Aminoglycosides. Pediatr Pulmonol. 2013;48(11):1047–61.  https://doi.org/10.1002/ppul.22813.CrossRefPubMedGoogle Scholar
  5. 5.
    Prescott WA Jr. National survey of extended-interval aminoglycoside dosing in pediatric cystic fibrosis pulmonary exacerbations. J Pediatr Pharmacol Ther. 2011;16(4):262–9.  https://doi.org/10.5863/1551-6776-16.4.262.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Downes KJ, Hahn A, Wiles J, Courter JD, Vinks AA. Dose optimisation of antibiotics in children: application of pharmacokinetics/pharmacodynamics in paediatrics. Int J Antimicrob Agents. 2014;43(3):223–30.  https://doi.org/10.1016/j.ijantimicag.2013.11.006.CrossRefPubMedGoogle Scholar
  7. 7.
    Sumpter A, Anderson BJ. Pediatric pharmacology in the first year of life. Curr Opin Anesthesiol. 2009;22(4):469–75.  https://doi.org/10.1097/ACO.0b013e32832bc7ff.CrossRefGoogle Scholar
  8. 8.
    Zaske D. Applied pharmacokinetics. Principles of therapeutic drug monitoring. 3rd ed. Vancouver: Applied Therapeutics; 1992.Google Scholar
  9. 9.
    Krekels EHJ, van Hasselt JC, van den Ander JN, Allegaert K, Tibboel D, Knibbe CAJ. Evidence-based drug treatment for special patient populations through model-based approaches. Eur J Pharm Sci. 2017;109S:S22–6.  https://doi.org/10.1016/j.ejps.2017.05.022.CrossRefPubMedGoogle Scholar
  10. 10.
    Treluyer JM, Merle Y, Tonnelier S, Rey E, Pons G. Nonparametric population pharmacokinetic analysis of amikacin in neonates, infants, and children. Antimicrob Agents Chemother. 2002;46(5):1381–7.  https://doi.org/10.1128/Aac.46.5.1381-1387.2002.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Labaune JM, Bleyzac N, Maire P, Jelliffe RW, Boutroy MJ, Aulagner G, et al. Once-a-day individualized amikacin dosing for suspected infection at birth based on population pharmacokinetic models. Biol Neonate. 2001;80(2):142–7.  https://doi.org/10.1159/000047133.CrossRefPubMedGoogle Scholar
  12. 12.
    Schreuder MF, Wilhelm AJ, Bokenkamp A, Timmermans SMH, Delemaxre-van de Waal HA, van Wijk JAE. Impact of gestational age and birth weight on amikacin clearance on day 1 of life. Clin J Am Soc Nephrol. 2009;4(11):1774–8.  https://doi.org/10.2215/Cjn.02230409.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang J, Liang WQ, Wu JJ, Pan CM. Population pharmacokinetic analysis of amikacin and validation on neonates using Monte Carlo method. Acta Pharmacol Sin. 2000;21(10):954–60.PubMedGoogle Scholar
  14. 14.
    Padovani EM, Pistolesi C, Fanos V, Messori A, Martini N. Pharmacokinetics of amikacin in neonates. Dev Pharmacol Therap. 1993;20(3–4):167–73.CrossRefGoogle Scholar
  15. 15.
    Golenz MR, Wilson WD, Carlson GP, Craychee TJ, Mihalyi JE, Knox L. Effect of route of administration and age on the pharmacokinetics of amikacin administered by the intravenous and intraosseous routes to 3-day-old and 5-day-old foals. Equine Vet J. 1994;26(5):367–73.CrossRefPubMedGoogle Scholar
  16. 16.
    Petersen PO, Wells TG, Kearns GL. Amikacin dosing in neonates - evaluation of a dosing chart based on population pharmacokinetic data. Dev Pharmacol Ther. 1991;16(4):203–11.PubMedGoogle Scholar
  17. 17.
    Smits A, De Cock RFW, Allegaert K, Vanhaesebrouck S, Danhof M, Knibbe CAJ. Prospective evaluation of a model-based dosing regimen for amikacin in preterm and term neonates in clinical practice. Antimicrob Agents Chemother. 2015;59(10):6344–51.  https://doi.org/10.1128/Aac.01157-15.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Zhao W, Biran V, Jacqz-Aigrain E. Amikacin maturation model as a marker of renal maturation to predict glomerular filtration rate and vancomycin clearance in neonates. Clin Pharmacokinet. 2013;52(12):1127–34.  https://doi.org/10.1007/s40262-013-0101-6.CrossRefPubMedGoogle Scholar
  19. 19.
    Allegaert K, Anderson BJ, Cossey V, Holford NHG. Limited predictability of amikacin clearance in extreme premature neonates at birth. Br J Clin Pharmacol. 2006;61(1):39–48.  https://doi.org/10.1111/j.1365-2125.2005.02530.x.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Sherwin CMT, Wead S, Stockmann C, Healy D, Spigarelli MG, Neely A, et al. Amikacin population pharmacokinetics among paediatric burn patients. Burns. 2014;40(2):311–8.  https://doi.org/10.1016/j.burns.2013.06.015.CrossRefPubMedGoogle Scholar
  21. 21.
    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;65(7):705–13.  https://doi.org/10.1007/s00228-009-0637-4.CrossRefPubMedGoogle Scholar
  22. 22.
    De Cock RFW, Allegaert K, Schreuder MF, Sherwin CMT, 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;51(2):105–17.CrossRefPubMedGoogle Scholar
  23. 23.
    Botha JH, du Preez M, Miller R, Adhikari M. Determination of population pharmacokinetic parameters for amikacin in neonates using mixed-effect models. Eur J Clin Pharmacol. 1998;53(5):337–41.  https://doi.org/10.1007/s002280050389.CrossRefPubMedGoogle Scholar
  24. 24.
    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;2(4):286–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Illamola SM, Colom H, van Hasselt JGC. Evaluating renal function and age as predictors of amikacin clearance in neonates: model-based analysis and optimal dosing strategies. Br J Clin Pharmacol. 2016;82(3):793–805.  https://doi.org/10.1111/bcp.13016.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm. 1993;21(6):735–50.CrossRefPubMedGoogle Scholar
  27. 27.
    Nguyen THT, Mouksassi MS, Holford N, Al-Huniti N, Freedman I, Hooker AC, et al. Model evaluation of continuous data pharmacometric models: metrics and graphics. CPT Pharmacometrics Syst Pharmacol. 2017;6(2):87–109.  https://doi.org/10.1002/psp4.12161.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yu T, Stockmann C, Healy DP, Olson J, Wead S, Neely AN, et al. Determination of optimal amikacin dosing regimens for pediatric patients with burn wound sepsis. J Burn Care Res. 2015;36(4):E244–52.  https://doi.org/10.1097/Bcr.0000000000000159.CrossRefPubMedGoogle Scholar
  29. 29.
    Garraffo R, Drugeon HB, Dellamonica P, Bernard E, Lapalus P. Determination of optimal dosage regimen for amikacin in healthy-volunteers by study of pharmacokinetics and bactericidal activity. Antimicrob Agents Chemother. 1990;34(4):614–21.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Holford NH. A size standard for pharmacokinetics. Clin Pharmacokinet. 1996;30(5):329–32.CrossRefPubMedGoogle Scholar
  31. 31.
    Guignard JP, Drukker A. Why do newborn infants have a high plasma creatinine? Pediatrics. 1999;103(4):e49.  https://doi.org/10.1542/peds.103.4.e49.CrossRefPubMedGoogle Scholar
  32. 32.
    Weinbren MJ. Pharmacokinetics of antibiotics in burn patients. J Antimicrob Chemother. 1999;44(3):319–27.  https://doi.org/10.1093/jac/44.3.319.CrossRefPubMedGoogle Scholar
  33. 33.
    Boucher BA, Kuhl DA, Hickerson WL. Pharmacokinetics of systemically administered antibiotics in patients with thermal-injury. Clin Infect Dis. 1992;14(2):458–63.CrossRefPubMedGoogle Scholar
  34. 34.
    Jaehde L, Sorgel F. Clinical pharmacokinetics in patients with burns. Clin Pharmacokinet. 1995;29(1):15–28.CrossRefPubMedGoogle Scholar
  35. 35.
    van Hasselt JG, van Eijkelenburg NK, Beijnen JH, Schellens JH, Huitema AD. Optimizing drug development of anti-cancer drugs in children using modelling and simulation. Br J Clin Pharmacol. 2013;76(1):30–47.  https://doi.org/10.1111/bcp.12062.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Clinical Pharmacology, Department of PediatricsUniversity of Utah School of MedicineSalt Lake CityUSA
  2. 2.Department of Pharmacy and Pharmaceutical Technology, School of PharmacyUniversitat de BarcelonaBarcelonaSpain
  3. 3.Biochemistry ServiceHospital Universitari Vall d’Hebron, Universitat Autònoma de BarcelonaBarcelonaSpain
  4. 4.Division of Systems Biomedicine and PharmacologyLeiden Academic Centre for Drug Research, Leiden UniversityLeidenThe Netherlands

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