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

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 (<i>N</i> = 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 (<i>Pseudomonas aeruginosa</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter calcoaceticus-baumannii</i> complex, and <i>Escherichia coli</i>). Most participants (82.0%; <i>n</i> = 168/205) achieved the imipenem exposure target, and 83.9% (<i>n</i> = 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 similar across the overall exposure range and by key pathogens. There were no apparent trends in ACM rates by imipenem or relebactam exposure distributions overall or by individual key pathogens, suggesting an exposure-efficacy plateau. These results further support the recommended and currently approved IMI/REL 500/500/250 mg dosing regimen for patients with HABP/VABP.