Imipenem/cilastatin/relebactam pharmacokinetics in critically ill patients with augmented renal clearance.

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.