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Population Pharmacokinetics of Meropenem in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

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Abstract

Background and objective: Meropenem is a carbapenem antibacterial frequently prescribed for the treatment of severe infections in critically ill patients, including those receiving continuous renal replacement therapy (CRRT). The objective of this study was to develop a population pharmacokinetic model of meropenem in critically ill patients undergoing CRRT.

Patients and methods: A prospective, open-label study was conducted in 20 patients undergoing CRRT. Blood and dialysate-ultrafiltrate samples were obtained after administration of 500 mg, 1000 mg or 2000 mg of meropenem every 6 or 8 hours by intravenous infusion. The data were analysed under the population approach using NONMEM version V software. Age, bodyweight, dialysate plus ultrafiltrate flow, creatinine clearance (CLCR), the unbound drug fraction in plasma, the type of membrane, CRRT and the patient type (whether septic or severely polytraumatized) were the covariates studied.

Results: The pharmacokinetics of meropenem in plasma were best described by a two-compartment model. CLCR was found to have a significant correlation with the apparent total clearance (CL) of the drug during the development of the covariate model. However, the influence of CLCR on CL differed between septic and polytraumatized patients (CL = 6.63 + 0.064 × CLCR for septic patients and CL = 6.63 + 0.72 × CLCR for polytraumatized patients). The volume of distribution of the central compartment (V1) was also dependent on the patient type, with values of 15.7 L for septic patients and 69.5 L for polytraumatized patients. The population clearance was 15 L/h, and the population apparent volume of distribution of the peripheral compartment was 19.8 L. From the base to the final model, the interindividual variabilities in CL and the V1 were significantly reduced. When computer simulations were carried out and efficacy indexes were calculated, it was shown that polytraumatized patients and septic patients with conserved renal function may not achieve adequate efficacy indexes to deal with specific infections. Continuous infusion of meropenem is recommended for critically septic patients and polytraumatized patients when pathogens with a minimum inhibitory concentration (MIC) of ≥4 mg/L are isolated. Infections caused by pathogens with an MIC of ≥8 mg/L should not be treated with meropenem in polytraumatized patients without or with moderate renal failure because excessive doses of meropenem would be necessary.

Conclusion: A population pharmacokinetic model of meropenem in intensive care patients undergoing CRRT was developed and validated. CLCR and the patient type (whether septic or polytraumatized) were identified as significant covariates. The population pharmacokinetic model developed in the present study has been employed to recommend continuous infusion protocols in patients treated with CRRT.

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Acknowledgements

The authors would like to thank the Basque Government for the pre-doctoral research grant to Arantxazu Isla. No sources of funding were used to assist in the preparation of this study. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country, Vitoria-Gasteiz, Spain

    Arantxazu Isla, Alicia Rodríguez-Gascón, María Ángeles Solinís &  José Luis Pedraz

  2. Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona, Spain

    Iñaki F. Trocóniz & Lorea Bueno

  3. Intensive Care Unit, Santiago Apóstol Hospital, Vitoria-Gasteiz, Spain

    Javier Maynar

  4. Intensive Care Unit, Doce de Octubre Hospital, Madrid, Spain

    José Ángel Sánchez-Izquierdo

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  1. Arantxazu Isla
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  2. Alicia Rodríguez-Gascón
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  3. Iñaki F. Trocóniz
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  4. Lorea Bueno
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  5. María Ángeles Solinís
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  8. José Luis Pedraz
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Correspondence to José Luis Pedraz.

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Isla, A., Rodríguez-Gascón, A., Trocóniz, I.F. et al. Population Pharmacokinetics of Meropenem in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy. Clin Pharmacokinet 47, 173–180 (2008). https://doi.org/10.2165/00003088-200847030-00003

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