Skip to main content
SpringerLink
Log in

Pharmacokinetics of Gentamicin Components C1, C1a, and C2/C2a/C2b and Subsequent Decline in Glomerular Filtration Rate in Neonates

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Gentamicin is a commonly used antibiotic in neonates. Its components C1, C1a, C2, C2a, and C2b may have different nephrotoxic potential. We aimed to describe pharmacokinetics and nephrotoxic potential of gentamicin components in a joint model in neonates. Neonates with gestational age ≥ 32 weeks treated with gentamicin blood samples were collected at a steady state. Pharmacokinetics of C1, C1a, and C2/C2a/C2b were modelled in NONMEM and included competitive uptake into kidney proximal tubular cells and decrease in glomerular filtration rate. The nephrotoxic potential of total gentamicin, C1, C1a, and C2/C2a/C2b was evaluated by simulations. A total of 30 neonates (median (range) gestational age 36.4 (32–42) weeks, postnatal age 3 (1–5) days, creatinine value 47.5 (17–78) µmol/L) were included. Pharmacokinetics of all components was best described by a two-compartment model. Clearance of C1 was smaller than clearances of C1a and C2/C2a/C2b, and other parameters were similar. The model with different Km (concentration for which half-maximal uptake into kidney proximal tubular cells is achieved) for C1, C1a, and C2/C2a/C2b (37.5, 18, 15 mg/L) provided a better fit than the model with equal Km (15 mg/L). According to simulations, decrease in glomerular filtration rate in the case of once-daily dosing of 4 mg/kg/day was the largest for C2/C2a/C2b (median (5th and 95th percentile) 0.22% (0.00–8.12%)), followed by total gentamicin (0.20% (0.00–4.10%)), C1a (0.11% (0.00–7.57%)), and C1 (0.04% (0.00–1.55%)). Different gentamicin components C1, C1a, and C2/C2a/C2b exhibited different pharmacokinetic profiles. Once-daily dosing of 4 mg/kg/day results in low nephrotoxicity in neonates, in line with previous studies.

Graphical Abstract

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
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

The data of this study are available from the corresponding author upon reasonable request.

References

  1. 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;15:41.

    Article  Google Scholar 

  2. Garrido F, Allegaert K, Arribas C, Villamor E, Raffaeli G, Paniagua M, et al. Variations in antibiotic use and sepsis management in neonatal intensive care units: a European Survey. Antibiotics (Basel). 2021;10(9):1046.

    Article  CAS  Google Scholar 

  3. Kent A, Turner MA, Sharland M, Heath PT. Aminoglycoside toxicity in neonates: something to worry about? Expert Rev Anti Infect Ther. 2014;12(3):319–31.

    Article  CAS  Google Scholar 

  4. Jansen D, Peters E, Heemskerk S, Koster-Kamphuis L, Bouw MP, Roelofs HM, et al. Tubular injury biomarkers to detect gentamicin-induced acute kidney injury in the neonatal intensive care unit. Am J Perinatol. 2016;33(2):180–7.

    Article  Google Scholar 

  5. Rougier F, Claude D, Maurin M, Sedoglavic A, Ducher M, Corvaisier S, et al. Aminoglycoside nephrotoxicity: modeling, simulation, and control. Antimicrob Agents Chemother. 2003;47(3):1010–6.

    Article  CAS  Google Scholar 

  6. Llanos-Paez CC, Staatz C, Hennig S. Balancing antibacterial efficacy and reduction in renal function to optimise initial gentamicin dosing in paediatric oncology patients. AAPS J. 2017;20(1):14.

    Article  Google Scholar 

  7. White LO, Lovering A, Reeves DS. Variations in gentamicin C1, C1a, C2, and C2a content of some preparations of gentamicin sulphate used clinically as determined by high-performance liquid chromatography. Ther Drug Monit. 1983;5(1):123–6.

    Article  CAS  Google Scholar 

  8. Barreiro EJ, Kümmerle AE, Fraga CA. The methylation effect in medicinal chemistry. Chem Rev. 2011;111(9):5215–46.

    Article  CAS  Google Scholar 

  9. Bulman ZP, Cirz R, Hildebrandt D, Kane T, Rosario Z, Wlasichuk K, et al. Unraveling the gentamicin drug product complexity reveals variation in microbiological activities and nephrotoxicity. Antimicrob Agents Chemother. 2020;64(9).

  10. Williams PD, Bennett DB, Gleason CR, Hottendorf GH. Correlation between renal membrane binding and nephrotoxicity of aminoglycosides. Antimicrob Agents Chemother. 1987;31(4):570–4.

    Article  CAS  Google Scholar 

  11. Sandoval RM, Reilly JP, Running W, Campos SB, Santos JR, Phillips CL, et al. A non-nephrotoxic gentamicin congener that retains antimicrobial efficacy. J Am Soc Nephrol. 2006;17(10):2697–705.

    Article  CAS  Google Scholar 

  12. Mosegaard A, Welling PG, Madsen PO. Gentamicin and gentamicin C1 in the treatment of complicated urinary tract infections: comparative study of efficacy, tolerance, and pharmacokinetics. Antimicrob Agents Chemother. 1975;7(3):328–32.

    Article  CAS  Google Scholar 

  13. Forrey AW, Meijsen-Ludwick BT, O’Neill MA, Maxwell BM, Blair AD, Cutler RE. Nephrotoxicity: a comparison in humans of gentamicin and gentamicin C1 administration. Toxicol Appl Pharmacol. 1978;44(3):453–62.

    Article  CAS  Google Scholar 

  14. O’Sullivan ME, Song Y, Greenhouse R, Lin R, Perez A, Atkinson PJ, et al. Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes. Proc Natl Acad Sci U S A. 2020;117(51):32423–32.

    Article  Google Scholar 

  15. Padari H, Metsvaht T, Germovsek E, Barker CI, Kipper K, Herodes K, et al. Pharmacokinetics of penicillin G in preterm and term neonates. Antimicrob Agents Chemother. 2018;62(5).

  16. Padari H, Soeorg H, Tasa T, Metsvaht T, Kipper K, Herodes K, et al. Ampicillin pharmacokinetics during first week of life in preterm and term neonates. Pediatr Infect Dis J. 2021;40(5):464–72.

    Article  Google Scholar 

  17. United States Pharmacopeial Convention. (United States Pharmacopeial Convention, Rockville, Maryland, United States, 2011).

  18. European Medicines Agency. (European Medicines Agency, London, United Kingdom, 2011).

  19. Croes S, Koop AH, van Gils SA, Neef C. Efficacy, nephrotoxicity and ototoxicity of aminoglycosides, mathematically modelled for modelling-supported therapeutic drug monitoring. Eur J Pharm Sci. 2012;45(1–2):90–100.

    Article  CAS  Google Scholar 

  20. Contrepois A, Brion N, Garaud JJ, Faurisson F, Delatour F, Levy JC, et al. Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans. Antimicrob Agents Chemother. 1985;27(4):520–4.

    Article  CAS  Google Scholar 

  21. Hurst AK, Iseri KT, Gill MA, Noguchi JK, Gilman TM, Jelliffe RW. Comparison of four methods for predicting serum gentamicin concentrations in surgical patients with perforated or gangrenous appendicitis. Clin Pharm. 1987;6(3):234–8.

    CAS  PubMed  Google Scholar 

  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 (Berlin, Germany). 2009;24(1):67–76.

    Article  Google Scholar 

  23. Giuliano RA, Verpooten GA, Verbist L, Wedeen RP, De Broe ME. In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp Ther. 1986;236(2):470–5.

    CAS  PubMed  Google Scholar 

  24. Jeleazcov C, Ihmsen H, Schmidt J, Ammon C, Schwilden H, Schüttler J, et al. Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children. Br J Anaesth. 2008;100(4):509–16.

    Article  CAS  Google Scholar 

  25. Koch G, Schropp J, Jusko WJ. Assessment of non-linear combination effect terms for drug-drug interactions. J Pharmacokinet Pharmacodyn. 2016;43(5):461–79.

    Article  CAS  Google Scholar 

  26. Luft FC, Kleit SA. Renal parenchymal accumulation of aminoglycoside antibiotics in rats. J Infect Dis. 1974;130(6):656–9.

    Article  CAS  Google Scholar 

  27. Moestrup SK, Cui S, Vorum H, Bregengård C, Bjørn SE, Norris K, et al. Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest. 1995;96(3):1404–13.

    Article  CAS  Google Scholar 

  28. Christensen EI, Moskaug JO, Vorum H, Jacobsen C, Gundersen TE, Nykjaer A, et al. Evidence for an essential role of megalin in transepithelial transport of retinol. J Am Soc Nephrol. 1999;10(4):685–95.

    Article  CAS  Google Scholar 

  29. Smith GC, Winterborn MH, Taylor CM, Lawson N, Guy M. Assessment of retinol-binding protein excretion in normal children. Pediatr Nephrol. 1994;8(2):148–50.

    Article  CAS  Google Scholar 

  30. Charlton JR, Harer MW, Swan C, Nielsen R. Immature megalin expression in the preterm neonatal kidney is associated with urinary loss of vitamin carrier proteins. Pediatr Res. 2019;85(3):405–11.

    Article  CAS  Google Scholar 

  31. Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother. 1999;43(5):1003–12.

    Article  CAS  Google Scholar 

  32. Shimizu D, Ichikawa S, Hoshina T, Kawase M, Tanaka K, Araki S, et al. The evaluation of the appropriate gentamicin use for preterm infants. Eur J Clin Microbiol Infect Dis. 2019;38(12):2365–9.

    Article  CAS  Google Scholar 

  33. Chiara A, Chirico G, Barbarini M, De Vecchi E, Rondini G. Ultrasonic evaluation of kidney volume in term and preterm infants. Am J Perinatol. 1993;10(2):109–11.

    Article  CAS  Google Scholar 

  34. Cheong B, Muthupillai R, Rubin MF, Flamm SD. Normal values for renal length and volume as measured by magnetic resonance imaging. Clin J Am Soc Nephrol. 2007;2(1):38–45.

    Article  Google Scholar 

  35. Provoost AP, Adejuyigbe O, Wolff ED. Nephrotoxicity of aminoglycosides in young and adult rats. Pediatr Res. 1985;19(11):1191–6.

    Article  CAS  Google Scholar 

  36. Lindbom L, Pihlgren P, Jonsson EN, Jonsson N. PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 2005;79(3):241–57.

    Article  Google Scholar 

  37. Chevalier RL. The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction. Am J Physiol Renal Physiol. 2016;311(1):F145–61.

    Article  CAS  Google Scholar 

  38. Kohlhepp SJ, Loveless MO, Kohnen PW, Houghton DC, Bennett WM, Gilbert DN. Nephrotoxicity of the constituents of the gentamicin complex. J Infect Dis. 1984;149(4):605–14.

    Article  CAS  Google Scholar 

  39. Nation RL, Peng GW, Chiou WL, Malow J. Comparison of gentamicin C1 and (Cla, C2)-levels in patients. Eur J Clin Pharmacol. 1978;13:459–62.

    Article  Google Scholar 

  40. Steinman A, Isoherranen N, Ashoach O, Soback S. Pharmacokinetics of gentamicin C1, C1a and C2 in horses after single intravenous dose. Equine Vet J. 2002;34(6):615–8.

    Article  CAS  Google Scholar 

  41. Isoherranen N, Lavy E, Soback S. Pharmacokinetics of gentamicin C(1), C(1a), and C(2) in beagles after a single intravenous dose. Antimicrob Agents Chemother. 2000;44(6):1443–7.

    Article  CAS  Google Scholar 

  42. Abu-Basha EA, Al-Shunnaq AF, Gehring R. Pharmacokinetics of gentamicin C1, C1a, C2 and C2a in broiler chickens after IV, IM, SC and oral administration. Journal of Bioequivalence & Bioavailability. 2013;5:129–35.

    Article  Google Scholar 

  43. Kastl JT. Renal function in the fetus and neonate - the creatinine enigma. Semin Fetal Neonatal Med. 2017;22(2):83–9.

    Article  Google Scholar 

  44. Neeli H, Hanna N, Abduljalil K, Cusumano J, Taft DR. Application of physiologically based pharmacokinetic-pharmacodynamic modeling in preterm neonates to guide gentamicin dosing decisions and predict antibacterial effect. J Clin Pharmacol. 2021;61(10):1356–65.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the study participants.

Funding

This study was supported by the Estonian Research Council (PUT1197, IUT34-24), the Archimedes Foundation (project no. 3.2.1001.11–0032) and the European Regional Development Fund.

Author information

Authors and Affiliations

  1. Department of Microbiology, University of Tartu, Ravila 19, 50411, Tartu, Estonia

    Hiie Soeorg & Irja Lutsar

  2. Pediatric Intensive Care Unit, Tartu University Hospital, Tartu, Estonia

    Helgi Padari & Tuuli Metsvaht

  3. Institute of Chemistry, University of Tartu, Tartu, Estonia

    Karin Kipper

  4. Pediatric Intensive Care Unit, Tallinn Children’s Hospital, Tallinn, Estonia

    Mari-Liis Ilmoja

Authors
  1. Hiie Soeorg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helgi Padari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karin Kipper
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mari-Liis Ilmoja
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Irja Lutsar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tuuli Metsvaht
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TM, IL, MLI, and HP designed the study; TM, MLI, and HP recruited the patients; KK developed the assay to measure gentamicin components and performed the analysis; HS designed the pharmacokinetic analysis study, performed the analysis, and wrote the manuscript; all authors read and approved the manuscript.

Corresponding author

Correspondence to Hiie Soeorg.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 18 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Soeorg, H., Padari, H., Kipper, K. et al. Pharmacokinetics of Gentamicin Components C1, C1a, and C2/C2a/C2b and Subsequent Decline in Glomerular Filtration Rate in Neonates. AAPS J 24, 77 (2022). https://doi.org/10.1208/s12248-022-00727-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-022-00727-9

KEY WORDS

Search

Navigation