Clinical Determinants of Target Non-Attainment of Linezolid in Plasma and Interstitial Space Fluid: A Pooled Population Pharmacokinetic Analysis with Focus on Critically Ill Patients

Abstract

Objectives

We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients.

Methods

Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid. All data were analysed simultaneously by a population approach also considering methodological aspects of microdialysis. The impact of covariates on the attainment of the pharmacokinetic/pharmacodynamic targets, AUC/MIC = 100 (area under the concentration-time curve/minimum inhibitory concentration) and fT>MIC = 99 % (time that unbound concentrations exceed the MIC), was assessed by deterministic and Monte Carlo simulations.

Results

A two-compartment pharmacokinetic model with nonlinear elimination and tissue distribution factors accounting for differences between plasma and ISF concentrations adequately predicted all measurements. Clearance (CL) was highest in septic patients (11.2 L/h vs. CLHealthy/CLCystic fibrosis/CLDiabetic = 7.67/6.87/6.35 L/h). Penetration into subcutaneous adipose ISF was lowest in diabetic patients (−34.9 % compared with healthy volunteers). Creatinine clearance and total body weight further impacted linezolid exposure. To achieve timely efficacious therapy, front-loaded dosing and continuous infusion seemed beneficial in septic patients.

Conclusions

Our analysis suggests that after standard linezolid doses, particularly patients with sepsis and conserved renal function are at risk of not attaining pharmacokinetic/pharmacodynamic targets and would benefit from initial dose intensification.

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Acknowledgements

The authors thank the High-Performance Computing Service at Freie Universitaet Berlin (http://www.zedat.fu-berlin.de/Compute) for providing high-performance computing capacities enabling our modelling activities. We acknowledge the clinical investigators at DRK Kliniken Berlin Westend, Berlin, Germany, the Vienna General Hospital, Vienna, Austria and the Hartford Hospital, Hartford, CT, USA, for the provision of data from previously published studies. Last, Dr. Sebastian Wicha of Uppsala Universitet (Uppsala, Sweden) is gratefully acknowledged for helpful discussions and suggestions.

Parts of this work were presented at the 22nd and 24th Population Approach Group Europe meeting (2013 and 2015) and the 24th European Congress of Clinical Microbiology and Infectious Diseases (2014).

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Correspondence to Charlotte Kloft.

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No sources of funding were used in the preparation of this manuscript.

Conflict of interest

IKM and AS declare that they have no conflicts of interest. JLK has received an honorarium for consulting and speaking by Pfizer Inc. and research grants from Pfizer Inc. MZ received a grant from Pfizer for a research project not involving linezolid. CK reports grants from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grünenthal GmbH, F. Hoffmann-La Roche Ltd, Merck KGaA and Sanofi) and the Innovative Medicines Initiative-Joint Undertaking (“DDMoRe”), both outside the submitted work.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study or respective legal representatives.

Additional information

I. K. Minichmayr and A. Schaeftlein contributed equally to this work.

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Minichmayr, I.K., Schaeftlein, A., Kuti, J.L. et al. Clinical Determinants of Target Non-Attainment of Linezolid in Plasma and Interstitial Space Fluid: A Pooled Population Pharmacokinetic Analysis with Focus on Critically Ill Patients. Clin Pharmacokinet 56, 617–633 (2017). https://doi.org/10.1007/s40262-016-0463-7

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Keywords

  • Linezolid
  • Septic Patient
  • Cystic Fibrosis Patient
  • Unbind Concentration
  • Target Attainment