Doripenem Treatment during Continuous Renal Replacement Therapy

Abstract

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

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Figures

FIG 1

Mean pre- and postfilter concentrations of doripenem in plasma and mean concentrations in the ultrafiltrate (n = 12). Prefilter values at 8.5, 16.5, 32.5, and 40.5 h were extrapolated (marked by open circles).

FIG 2

Simulated concentration-time profiles (means ± standard deviations) based on 1,000 hypothetical patients receiving a doripenem dose of 1,000 mg/8 h (A), 750 mg/8 h (B), or 500 mg/8 h (C) continuously over 7 days. The horizontal dashed lines represent the desired concentrations of 4 mg/liter and 8 mg/liter in plasma.

FIG 3

Comparison of mean prefilter carbapenem concentrations during the first dosing interval (1 g doripenem versus 1 g meropenem) during continuous renal replacement therapy (13).