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Evaluation of a non-parametric modelling for meropenem in critically ill patients using Monte Carlo simulation

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Abstract

Purpose

In critically ill patients treated with meropenem, the proposed pharmacokinetics/pharmacodynamics (PK/PD) efficacy index is to keep the free drug concentration 4–5 times above the minimum inhibitory concentration (MIC) of the germ isolated, for 100% of the interval regimen. The objectives were to design a population pharmacokinetics model for meropenem in critically ill patients and to evaluate different dosage schemes that achieve the optimal PK/PD objectives.

Methods

This retrospective, observational, single-centre study included 80 critically ill patients (154 samples) treated with meropenem between May 2011 and December 2017. Patient data, concentrations, treatment and bacteriological variables were collected from electronic medical records. Total and free concentrations of meropenem were modelled in Pmetrics. Monte Carlo simulations were performed to assess the probability of achieving the PK/PD target for different dosage regimens. For patients with available data, the number of patients with a free concentration 4 times higher or lower than the observed MIC for the P. aeruginosa and E. coli was investigated.

Results

A one-compartment model with first-order elimination adequately described serum total and free meropenem concentrations. The only variable that significantly influenced the elimination constant of meropenem was the creatinine clearance (CLcr) calculated using the CKD-EPI formula. The highest probability of achieving the pharmacodynamic objective was with 3-h infusion dosage regimens. Sixty percent and 89% of patients attained a free drug concentration 4 times above the MIC for P. aeruginosa and E. coli respectively.

Conclusions

This study proposed different dosing regimens depending on renal clearance strata and the MIC of the germ targeted.

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Acknowledgements

We are grateful to K. Poole for manuscript editing.

Funding information

The project was supported by FBCN (Fundación Bancaria Caja Navarra) through a “mobility grant for Ph.D. research studies” for Ana Isabel Idoate Grijalba.

Author information

Correspondence to Ana Isabel Idoate Grijalba.

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Conflict of interest

The authors declare that they have no conflict of interest.

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What is already known about this subject (up to three bullet points)

• Meropenem is a time-dependent antibiotic and its bactericidal activity is associated with free concentration (%T > 4 MIC).

• Dosage regimens that have been applied to healthy volunteers or in vitro studies are not appropriate for critically ill patients due to their pathophysiologic changes.

What this study adds

• Dosage regimens recommended in the literature (1 g/6 h, 1 g/8 h) are not always suitable for real-world critically ill populations.

• 60% and 89% of patients attained free drug concentrations 4 times above the MIC for P. aeruginosa and E. coli respectively

• Dosing regimens depending on renal clearance strata and the MIC of the germ targeted are proposed.

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Cite this article

Idoate Grijalba, A.I., Aldaz Pastor, A., Marquet, P. et al. Evaluation of a non-parametric modelling for meropenem in critically ill patients using Monte Carlo simulation. Eur J Clin Pharmacol 75, 1405–1414 (2019). https://doi.org/10.1007/s00228-019-02716-y

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Keywords

  • Meropenem
  • Population pharmacokinetics
  • Pmetrics
  • Probability of target attainment