Population pharmacokinetic/pharmacodynamic assessment of imipenem/cilastatin/relebactam in patients with hospital‐acquired/ventilator‐associated bacterial pneumonia

Abstract

In the phase III RESTORE‐IMI 2 study (ClinicalTrials.gov: NCT02493764), the combination antibacterial agent imipenem/cilastatin/relebactam (IMI/REL) demonstrated noninferiority to piperacillin/tazobactam for the end points of all‐cause mortality at day 28 and favorable clinical response at the early follow‐up visit in adult participants with gram‐negative hospital‐acquired bacterial pneumonia/ventilator‐associated bacterial pneumonia (HABP/VABP). Existing population pharmacokinetic models for imipenem (IPM) and REL were updated using data from patients with HABP/VABP from RESTORE‐IMI 2. Creatinine clearance (CrCl), body weight, infection type, and ventilation status were significant covariates in the updated model. The following simulations were performed to calculate the pharmacokinetic/pharmacodynamic joint probability of target attainment among patients with HABP/VABP and varying degrees of renal function: augmented renal clearance (CrCl ≥150 ml/min), normal renal function (CrCl ≥90 to <150 ml/min), renal impairment (mild, CrCl ≥60 to <90 ml/min; moderate, CrCl ≥30 to <60 ml/min; or severe, CrCl ≥15 to <30 ml/min), and end‐stage renal disease (CrCl <15 ml/min). At the recommended IMI/REL dosing regimens across renal categories, greater than 90% of patients in all renal function groups were predicted to achieve joint pharmacokinetic/pharmacodynamic targets at a minimum inhibitory concentration breakpoint of ≤2 μg/ml, regardless of ventilation status. This modeling and simulation analysis supports use of the recommended IMI/REL dosing regimens, adjusted based on renal function, in patients with HABP/VABP.

In Vitro Antibacterial Activity of Imipenem/Relebactam against Clinical Isolates in Japan

“…Of these isolates, the MIC of 1 K. pneumoniae isolate and 1 S. marcescens isolate was 2 μg/mL, which is considered intermediate susceptibility according to the CLSI breakpoint for IMR (MIC of 2 μg/mL). However, it has been reported that at the recommended IMI/REL dosing regimens, >90% of patients were predicted to achieve joint pharmacokinetic/pharmacodynamic targets at an MIC breakpoint of ≤2 μg/mL, which aligns with the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint for IMR ( 16 , 17 ). Taking this into consideration, IMR may be effective for 2/3 and 2/2 of imipenem-nonsusceptible isolates of K. pneumoniae and S. marcescens collected in this study, respectively, and thus, these isolates would be considered susceptible by EUCAST breakpoints but of intermediate susceptibility by CLSI breakpoints.…”

Imipenem/cilastatin/relebactam efficacy, safety and probability of target attainment in adults with hospital-acquired or ventilator-associated bacterial pneumonia among patients with baseline renal impairment, normal renal function, and augmented renal clearance

“…PK/PD methodology previously described. 28 MIC of 2 µg/mL is EUCAST breakpoint for Enterobacterales and P. aeruginosa . 32 NRF, normal renal function.…”

“…Existing population PK models for concentration–time profiles for imipenem and relebactam were updated using data from the RESTORE-IMI 2 study; 28 simulations were performed to calculate the PK/PD joint PTA (unbound or free drug levels above PK/PD targets) and to confirm current dosing schedules in patients with variable renal function and HABP/VABP. The details of model development, validation and qualification, as well as the virtual population pool used for the Monte Carlo simulations, which included 1000 patients with HABP/VABP in each renal category, have been previously reported.…”

“…The details of model development, validation and qualification, as well as the virtual population pool used for the Monte Carlo simulations, which included 1000 patients with HABP/VABP in each renal category, have been previously reported. 28 …”

Simulation to minimise patient self-inflicted lung injury: are we almost there?

“…They provide information on the optimal drug dosing according to PK/PD data, which are then validated in clinical practice through phase 3 studies. 10 , 11 …”