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

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 × CL_CR for septic patients and CL = 6.63 + 0.72 × CL_CR 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. 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.