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; V-c, 16.15 +/- 7.75 L; k(12), 1.62 +/- 0.99 h(-1); and k(21), 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.