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Published on: August 30, 2018
Imipenem/cilastatin/relebactam pharmacokinetics in critically ill patients with augmented renal clearance
Andrew J Fratoni1, John W Mah2, David P Nicolau1
1Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT 06102, USA.
Background:
Imipenem and relebactam are predominantly excreted via glomerular filtration. Augmented renal clearance (ARC) is a common syndrome in critically-ill patients with sepsis, and sub-therapeutic antibiotic concentrations are of concern. Herein, we describe the pharmacokinetics of imipenem/relebactam in critically-ill patients with ARC.
Methods:
Infected patients in the ICU with ARC (CLCR ≥ 130 mL/min) received a single dose of imipenem/cilastatin/relebactam 1.25 g as a 30 min infusion. Blood samples were collected over 6 h for concentration determination. Protein binding was assessed by ultrafiltration. An 8 h urine creatinine collection confirmed ARC. Population pharmacokinetic models with and without covariates were fit using the non-parametric adaptive grid algorithm in Pmetrics. A 5000 patient Monte Carlo simulation assessed joint PTA using relebactam fAUC/MIC ≥8 and imipenem ≥40% fT>MIC.
Results:
Eight patients with ARC completed the study. A base population pharmacokinetic model with two-compartments fitted the data best. The mean ± SD parameters were: CL, 17.31 ± 5.76 L/h; Vc, 16.15 ± 7.75 L; k12, 1.62 ± 0.99 h-1; and k21, 3.53 ± 3.31 h-1 for imipenem, and 11.51 ± 4.79 L/h, 16.54 ± 7.43 L, 1.59 ± 1.12 h-1, and 2.83 ± 2.91 h-1 for relebactam. Imipenem/cilastatin/relebactam 1.25 g as a 30 min infusion every 6 h achieved 100% and 93% PTA at MICs of 1 and 2 mg/L, respectively.
Conclusions:
Despite enhanced clearance of both imipenem and relebactam, the currently approved dosing regimen for normal renal function was predicted to achieve optimal exposure in critically-ill patients with ARC sufficient to treat most susceptible pathogens.
Insights
Critically-ill patients with augmented renal clearance (ARC) receiving imipenem/relebactam achieved therapeutic drug concentrations. Standard dosing regimens are effective for treating infections in these patients.
Area of Science:
- Pharmacology
- Critical Care Medicine
- Infectious Diseases
Background:
- Imipenem and relebactam are primarily eliminated by glomerular filtration.
- Augmented renal clearance (ARC) is prevalent in critically-ill sepsis patients, raising concerns about sub-therapeutic antibiotic levels.
- This study investigates the pharmacokinetics of imipenem/relebactam in critically-ill patients with ARC.
Purpose of the Study:
- To evaluate the pharmacokinetic profile of imipenem/relebactam in critically-ill patients with augmented renal clearance.
- To determine if standard dosing regimens achieve adequate drug exposure in patients with ARC.
- To assess the probability of target attainment (PTA) for imipenem and relebactam.
Main Methods:
- Eight critically-ill patients with ARC (CLCR ≥ 130 mL/min) received a single 1.25g dose of imipenem/cilastatin/relebactam.
- Blood samples were collected for 6 hours to determine drug concentrations.
- Population pharmacokinetic modeling and Monte Carlo simulations were used to assess PTA.
Main Results:
- The population pharmacokinetic model with two compartments best described the data for both imipenem and relebactam.
- The mean clearance (CL) for imipenem was 17.31 ± 5.76 L/h and for relebactam was 11.51 ± 4.79 L/h.
- The standard 1.25g dose every 6 hours achieved 100% and 93% PTA at MICs of 1 and 2 mg/L, respectively.
Conclusions:
- Despite enhanced clearance in patients with ARC, the standard dosing regimen of imipenem/relebactam is predicted to achieve optimal drug exposure.
- The approved dosing regimen is likely sufficient to treat most susceptible pathogens in critically-ill patients with ARC.
- This suggests that current dosing recommendations are appropriate for this patient population.
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