Doripenem population pharmacokinetics and dosing requirements for critically ill patients receiving continuous venovenous haemodiafiltration

Roberts, Jason A.; Udy, Andrew; Bulitta, Jürgen B.; Stuart, Janine; Jarrett, Paul; Starr, Therese; Lassig-Smith, Melissa; Roberts, Natasha; Dunlop, Rachel; Hayashi, Yoshihiko; Wallis, Steven C.; Lipman, Jeffrey

doi:10.1093/jac/dku177

Cited by 30 publications

(36 citation statements)

References 41 publications

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“…Furthermore, concentration drops below 4 mg/liter during steady state could be observed in 15.2% of the cases. (3,4). The sieving coefficients observed in our study differed dramatically from those reported by Cirillo et al A possible explanation for the difference between prefilter/ postfilter clearance and sieving coefficient-dependent clearance could be adsorption of doripenem to the filter membrane.…”

Section: Resultscontrasting

confidence: 92%

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Doripenem Treatment during Continuous Renal Replacement Therapy

Vossen

Wenisch

Maier‐Salamon

et al. 2016

Antimicrob Agents Chemother

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dDoripenem 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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Section: Resultscontrasting

confidence: 92%

“…A two-compartment model with linear elimination was best for describing the pharmacokinetics of doripenem in plasma, which is consistent with findings from previous population pharmacokinetic studies (4,11). The estimated pharmacokinetic parameters, as well as the bootstrap results, are shown in Table 4.…”

Section: Resultssupporting

confidence: 87%

Doripenem Treatment during Continuous Renal Replacement Therapy

Vossen

Wenisch

Maier‐Salamon

et al. 2016

Antimicrob Agents Chemother

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“…First, we did not include patients who had septic shock or who were on continuous renal replacement therapy. Such factors could alter the PK profiles of doripenem (10,46). Second, our data do not include doripenem concentrations at the target site of infection.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Doripenem after Intravenous Infusion in Korean Patients with Acute Infections

Lee

Kim

Jin

et al. 2017

Antimicrob Agents Chemother

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We investigated the population pharmacokinetics (PK) of doripenem in Korean patients with acute infections and determined an appropriate dosing regimen using a Monte Carlo simulation for predicting pharmacodynamics (PD). Patients (n ϭ 37) with a creatinine clearance (CL CR ) of 20 to 50 ml/min or Ͼ50 ml/min who received a 250-mg or 500-mg dose of doripenem over the course of 1 h every 8 h, respectively, were included in this study. Blood samples were taken predosing and 0 h, 0.5 h, and 4 to 6 h after the fourth infusion. A nonlinear mixed-effect modeling tool was used for the PK analysis and pharmacodynamic simulation; doripenem PK were well described by a one-compartment model. The population mean values of the body weight (WT)-normalized clearance (CL/WT) and the body weight-normalized volume of distribution (V/WT) were 0.109 liter/h/kg of body weight (relative standard error, 9.197%) and 0.280 liter/kg (relative standard error, 9.56%), respectively. Doripenem CL was significantly influenced by CL CR . The proposed equation to estimate doripenem CL in Korean patients was CL/WT ϭ 0.109 ϫ WT ϫ (CL CR /57) 0.688 , where CL/WT is in liters per hour per kilogram. CL in Korean patients was expected to be lower than that in Caucasian patients, regardless of renal function. The Monte Carlo simulation showed that 90% attainment of target PK/PD magnitudes could be achieved with the usual dosing regimens when the MIC was Յ1 mg/liter. However, prolonged infusions (4 h) should be considered, especially when patients have augmented renal function and for patients infected with pathogens with a high MIC. Our results provide an individualized doripenem dosing regimen for patients with various renal functions and for patients infected with bacteria with decreased susceptibility.

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“…This enables development of mathematical models that describe PK variability in terms of most relevant RRTrelated and clinical covariates. The more precise estimation of PK parameters enables a more precise prediction of dosing requirements [11,12]. However, even the few available population PK models do not account for the full range of covariates and would require standardization in terms of RRT modalities and operational settings to ensure wide application.…”

Section: Antibiotic Dosing In Critically Ill Patients Receiving Renalmentioning

confidence: 99%

Antibiotic Dosing In Critically Ill Patients Receiving Renal Replacement Therapy

Sime

Roberts

2016

Expert Review of Clinical Pharmacology

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Doripenem population pharmacokinetics and dosing requirements for critically ill patients receiving continuous venovenous haemodiafiltration

Abstract: This is the first paper describing the pharmacokinetics/pharmacodynamics of doripenem in critically ill patients with AKI receiving CVVHDF. A dose of 500 mg intravenously every 8 h was appropriate for our CVVHDF settings for infections caused by susceptible bacteria.

Cited by 30 publications

References 41 publications

Doripenem Treatment during Continuous Renal Replacement Therapy

Doripenem Treatment during Continuous Renal Replacement Therapy

Population Pharmacokinetic Analysis of Doripenem after Intravenous Infusion in Korean Patients with Acute Infections

Antibiotic Dosing In Critically Ill Patients Receiving Renal Replacement Therapy

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