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Population pharmacokinetics of meropenem in critically ill patients undergoing continuous renal replacement therapy
Arantxazu Isla1, Alicia Rodríguez-Gascón, Iñaki F Trocóniz
1Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country, Paseo de la Universidad no. 7, Vitoria-Gasteiz, Spain.
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 (CL(CR)), 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. CL(CR) 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 CL(CR) on CL differed between septic and polytraumatized patients (CL = 6.63 + 0.064 x CL(CR) for septic patients and CL = 6.63 + 0.72 x CL(CR) for polytraumatized patients). The volume of distribution of the central compartment (V(1)) 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 V(1) 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 > or =4 mg/L are isolated. Infections caused by pathogens with an MIC of > or =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. CL(CR) 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.
Insights
This study developed a population pharmacokinetic model for meropenem in critically ill patients on continuous renal replacement therapy (CRRT). Results show that creatinine clearance and patient type significantly impact meropenem dosing, guiding optimized treatment protocols.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Critical Care Medicine
- Infectious Diseases
Background:
- Meropenem is crucial for severe infections in critically ill patients.
- Continuous renal replacement therapy (CRRT) alters drug pharmacokinetics.
- Optimizing meropenem dosing in CRRT patients is essential for effective treatment.
Purpose of the Study:
- To develop a population pharmacokinetic model for meropenem in critically ill patients undergoing CRRT.
- To identify key covariates influencing meropenem pharmacokinetics in this population.
- To provide evidence-based recommendations for meropenem dosing strategies.
Main Methods:
- A prospective, open-label study involving 20 critically ill patients on CRRT.
- Meropenem administered at various doses (500-2000 mg) every 6 or 8 hours.
- Population pharmacokinetic analysis using NONMEM software, assessing covariates like creatinine clearance and patient type.
Main Results:
- A two-compartment model best described meropenem plasma pharmacokinetics.
- Creatinine clearance (CL(CR)) and patient type (septic vs. polytraumatized) significantly influenced meropenem clearance (CL) and volume of distribution (V(1)).
- Simulations indicated potential for inadequate drug exposure in certain patient groups, necessitating adjusted dosing.
Conclusions:
- A validated population pharmacokinetic model for meropenem in CRRT patients was established.
- Creatinine clearance and patient type are critical covariates for meropenem dosing.
- The model supports recommendations for continuous meropenem infusion to optimize efficacy in critically ill patients on CRRT.
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