Imipenem/cilastatin/relebactam dosing regimen justification using exposure–efficacy analyses in participants with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia in the RESTORE-IMI 2 phase 3 study
Abstract
ABSTRACT An exposure–efficacy analysis of the phase 3 RESTORE-IMI 2 study (NCT02493764) evaluated the relationship between plasma exposure of imipenem and relebactam and key efficacy endpoints (primary: 28-day all-cause mortality [ACM]; secondary: clinical response at early follow-up [EFU; 7–14 days after the end of treatment]) in adult participants with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) who received imipenem/cilastatin/relebactam 500/500/250 mg (IMI/REL). Participants from the IMI/REL treatment group in the microbiological-modified intent-to-treat population who had pharmacokinetic (PK) data and relevant baseline pathogen susceptibility data available were included (N = 211). Previously developed population PK models were used to derive steady-state imipenem and relebactam exposures. Exposures were analyzed against the primary and secondary endpoints overall and by the most common key pathogens identified during RESTORE-IMI 2 (Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter calcoaceticus–baumannii complex, and Escherichia coli). Most participants (82.0%; n = 168/205) achieved the imipenem exposure target, and 83.9% (n = 177/211) achieved the relebactam exposure target. ACM was 16.1% overall; 11% among participants who met the imipenem exposure target, and 18% among those who met the relebactam exposure target. At EFU, 62.1% of participants experienced a favorable clinical response. Efficacy was…
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