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Population pharmacokinetics of gentamicin in haemodialysis patients: modelling, simulations and recommendations

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

Abstract

Purpose

The usual recommended dose for gentamicin is 3 to 7 mg/kg/day for patients with a normal renal function while 1.7 mg/kg/day is recommended for patients undergoing chronic haemodialysis. The objectives of this study were to develop a population pharmacokinetics model (POPPK) for gentamicin, designed for patients undergoing dialysis, and to investigate the best dosing scheme for different MIC clinical breakpoints using Monte Carlo simulations.

Methods

In this monocentric prospective interventional open clinical study, 23 patients (141 gentamicin samples) were included. The covariates investigated were weight, creatinine, dialysis (yes/no), dialysis flow and dialysis duration. The POPPK model was developed in Pmetrics and 1000 time-concentration profiles were simulated for 9 doses between 2 and 10 mg/kg/day, with an inter-dose period of 24, 48 or 96 h to predict the probability of having both a serum peak > 8*MIC and a trough < 1 mg/L for MIC values between 0.25 and 4 mg/L.

Results

A two-compartment model including the dialysis on the elimination constant and bodyweight on the volume of distribution best described the data. A 30-min gentamicin infusion of 2 mg/kg/day (for MIC = 1 mg/L) or 8 mg/kg/day (for MIC = 4 mg/L) just before dialysis eliminated by two dialysis sessions before the next administration (dose interval of at least 96 h) led to a peak > 8*MIC for > 90% of the simulations and a trough concentration < 1 mg/L at 96 h for 92% and 34% respectively.

Conclusion

The gentamicin dose generally used to treat infections in dialysis patients is insufficient and might be increased to 3–8 mg/kg/day just before dialysis, taking into account the type of infection.

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Data availability

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

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Acknowledgements

We thank Helene Roussel, Alexandre Garnier and Chloé Barny for their precious help in the study management. We thank Karen Poole for manuscript editing.

Funding

We thank the DRCI of Limoges University Hospital for funding this study.

Author information

Author notes

  1. Caroline Monchaud and Franck Saint-Marcoux contributed equally to this work.

Authors and Affiliations

  1. INSERM, IPPRITT, U1248, F-87000, Limoges, France

    Bénédicte Franck, Caroline Monchaud, Franck Saint-Marcoux, Jean-Philippe Rérolle, Pierre Marquet, Marie Essig & Jean-Baptiste Woillard

  2. Univ. Limoges, IPPRITT, F-87000, Limoges, France

    Bénédicte Franck, Caroline Monchaud, Franck Saint-Marcoux, Jean-Philippe Rérolle, Pierre Marquet, Marie Essig & Jean-Baptiste Woillard

  3. Department of Pharmacology and Toxicology, CHU Limoges, Limoges, France

    Bénédicte Franck, Caroline Monchaud, Franck Saint-Marcoux, Pierre Marquet & Jean-Baptiste Woillard

  4. Department of Nephrology, Haemodialysis and transplantation, CHU Limoges, Limoges, France

    Jean-Philippe Rérolle, Julien Allard, Vincent Allot & Marie Essig

Authors
  1. Bénédicte Franck
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  2. Caroline Monchaud
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  9. Jean-Baptiste Woillard
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Contributions

CM, FSM, ME, JPR, JA, VA and PM conceived or designed the study; BF, JBW, CM, FSM, ME, JPR, JA, VA and PM performed research; and BF and JBW analysed data and wrote the paper.

Corresponding author

Correspondence to Jean-Baptiste Woillard.

Ethics declarations

The ethics committee of Limoges Hospital approved the protocol (no. 201231120). All the patients included in the study gave their written informed consent.

Conflict of interest

The authors declare that they have no conflict of interest.

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Franck, B., Monchaud, C., Saint-Marcoux, F. et al. Population pharmacokinetics of gentamicin in haemodialysis patients: modelling, simulations and recommendations. Eur J Clin Pharmacol 76, 947–955 (2020). https://doi.org/10.1007/s00228-020-02867-3

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