794. Rationale for Dose Selection for  Carbavance (CVC; Meropenem/RPX7009) in Phase 3 Trials
Session: Poster Abstract Session: Antimicrobial Agents: PK/PD Studies
Friday, October 9, 2015
Room: Poster Hall
Background: CVC is a fixed combination of meropenem (MER) and RPX7009, a novel broad-spectrum serine beta-lactamase inhibitor optimized for inhibition of the KPC beta-lactamase and the potentiation of carbapenems (CARBs) against Enterobacteriaceae (ENT). It is being developed to treat serious gram-negative infections, including those infections caused by bacteria resistant to currently available CARBs. The objective of these studies was to select the appropriate clinical dose for the pivotal clinical trials of CVC.

Methods: MICs for MER alone and with RPX7009 at various concentrations (CONs) were examined against 315 KPC producing strains of ENT (KPC-ENT).  Resistance development (RD) studies with 10 KPC-ENT were performed at multiple CONs of both MER and RPX7009.  Efficacy in a mouse thigh infection model against 12 KPC-ENT were determined at different exposures (EXPs) of MER and RPX7009. Prevention of RD was examined with 10 strains in an in vitro hollow fiber pharmacodynamics (HF-PD) model using various EXPs of both MER and RPX7009 simulated based on human PK determined in Phase 1 studies.  

Results: 96% of KPC-ENT were inhibited by MER 2 mg/L with RPX7009 at 8 mg/L. Previously described porin-based resistance to MER was prevented by RPX7009 at 8 mg/L combined with 8 mg/L of MER.  Both mouse and in vitro HF-PD models showed maximal bacterial killing and prevention of RD against strains with MER MIC’s up to 8 mg/L with MER/RPX7009 EXPs with doses of 2g q8h by 3 hr infusion.

Conclusion: Based on the non-clinical studies of RD and PK-PD studies along with Phase 1 studies in healthy volunteers, a dose of 2g MER plus 2g of RPX7009 by 3 hr infusion every 8 hours was selected for pivotal studies with CVC. MER MICs determined with 8 mg/L of RPX7009 were the best predictor of efficacy in the in vitro HF-PD model.

Olga Lomovskaya, PhD, David Griffith, BS, Jeff Loutit, MBChB and Michael Dudley, PharmD, FIDSA, The Medicines Company, San Diego, CA

Disclosures:

O. Lomovskaya, The Medicines Company: Employee , Salary

D. Griffith, The Medicines Company: Employee , Salary

J. Loutit, The Medicines Company: Employee , Salary

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