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Intensive Care Medicine

, Volume 37, Issue 4, pp 632–638 | Cite as

Optimization of meropenem dosage in the critically ill population based on renal function

  • Jared L. Crandon
  • Robert E. Ariano
  • Sheryl A. Zelenitsky
  • Anthony M. Nicasio
  • Joseph L. Kuti
  • David P. NicolauEmail author
Original

Abstract

Purpose

To develop a meropenem population pharmacokinetic model in critically ill patients with particular focus on optimizing dosing regimens based on renal function.

Methods

Population pharmacokinetic analysis was performed with creatinine clearance (CrCl) and adjusted body weight to predict parameter estimates. Initial modeling was performed on 21 patients (55 samples). Validation was conducted with 12 samples from 5 randomly selected patients excluded from the original model. A 5,000-patient Monte Carlo simulation was used to ascertain optimal dosing regimens for three CrCl ranges.

Results

Mean ± SD age, APACHE, and CrCl were 59.2 ± 16.8 years, 13.6 ± 7, and 78.3 ± 33.7 mL/min. Meropenem doses ranged from 0.5 g every 8 h (q8h)–2 g q8h as 0.5–3 h infusions. Median estimates for volume of the central compartment, K 12, and K 21 were 0.24 L/kg, 0.49 h−1, and 0.65 h−1, respectively. K 10 was described by the equation: K 10 = 0.3922 + 0.0025 × CrCl. Model bias and precision were −1.9 and 8.1 mg/L. R 2, bias, and precision for the validation were 93%, 1.1, and 2.6 mg/L. At minimum inhibitory concentrations (MICs) up to 8 mg/L, the probability of achieving 40% fT > MIC was 96, 90, and 61% for 3 h infusions of 2 g q8h, 1 g q8h, and 1 g q12h in patients with CrCl ≥50, 30–49, and 10–29, respectively. Target attainment was 75, 65, and 44% for these same dosing regimens as 0.5 h infusions.

Conclusions

This pharmacokinetic model is capable of accurately estimating meropenem concentrations in critically ill patients over a range of CrCl values. Compared with 0.5 h infusions, regimens employing prolonged infusions improved target attainment across all CrCl ranges.

Keywords

Meropenem Population pharmacokinetics Prolonged infusion Creatinine clearance Monte Carlo simulation 

Notes

Acknowledgments

We would like to thank Christina Sutherland for her assistance with the analytical determination of meropenem and Aryun Kim, Pharm.D. for her assistance with collection of pharmacokinetic samples.

Supplementary material

134_2010_2105_MOESM01_ESM.doc (28 kb)
Online Resource 1. Covariance matrix for the derived pharmacokinetic parameters. (DOC 28 kb)

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Copyright information

© Copyright jointly held by Springer and ESICM 2010

Authors and Affiliations

  • Jared L. Crandon
    • 1
  • Robert E. Ariano
    • 2
  • Sheryl A. Zelenitsky
    • 2
  • Anthony M. Nicasio
    • 1
  • Joseph L. Kuti
    • 1
  • David P. Nicolau
    • 1
    Email author
  1. 1.Center for Anti-Infective Research and DevelopmentHartford HospitalHartfordUSA
  2. 2.Department of Pharmacy, St. Boniface General Hospital and Faculty of PharmacyUniversity of ManitobaWinnipegCanada

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