PII-025 - UNDERSTANDING THE PK/PD RELATIONSHIP FOR THE METALLO-BETA-LACTAMASE (MBL) INHIBITOR MK-3402 AND PRELIMINARY DOSE PROJECTION FOR PATIENTS WITH MDR GRAM-NEGATIVE INFECTIONS.

D. Li¹, L. Liang¹, K. Young¹, D. Hilbert¹, G. Gillespie¹, A. Pasternak¹, E. Feng², R. Vargo¹; ¹Merck & Co., Rahway, NJ, USA, ²GlaxoSmithKline, Collegeville, PA, USA.

Background: Currently, there are limited effective treatment options for MDR gram-negative infections that address the rapid dissemination of metallo-β-lactamases (MBLs) in Enterobacteriales and Pseudomonas aeruginosa. MK-3402 was developed in combination with the serine β-lactamase inhibitor relebactam (REL) as a free-standing β-lactamase inhibitor combination to be co-administered with multiple β-lactam antibiotics. It may be a significant advance in the treatment of infections caused by MBL-expressing gram-negative bacteria.

Methods: In vitro hollow fiber studies and in vivo mouse studies were conducted with K. pneumoniae and P. aeruginosa strains with various minimum inhibitory concentrations (MICs) treated with the β-lactam antibiotics imipenem (IMI) or cefepime (FEP) in combination with REL/MK-3402. The data from these studies were used in PK/PD analyses to understand the PK driver and PK target. Single ascending dose (SAD) and multiple ascending dose (MAD) studies were conducted in healthy participants to characterize MK-3402 PK in humans. A preliminary population pharmacokinetics model was developed, and probability of target attainment analysis (PTA) was performed to project the dose for patients with MBL-expressing gram-negative infections based on PK target and clinical PK profile.

Results: Based on HF and in vivo animal dose titration and dose ranging studies, fAUC/MIC was identified as the PK driver for efficacy. The PK target for MK-3402 was determined as fAUC/MIC=13.6 with IMI and fAUC/MIC= 2.3 with FEP as the partner antibiotic. PTA simulation predicts 75 mg q6h dosing regimen achieves 90% PTA in patients and is used to inform future clinical development.

Conclusion: With understanding of the PK/PD driver and target for MK-3402, a preliminary dosing regimen was projected to support clinical development.