1304 - Characterization of Tebipenem Pivoxil Hydrobromide Pharmacokinetics-Pharmacodynamics (PK-PD) in a Neutropenic Murine Acute Pyelonephritis (AP) Model

Background: Tebipenem pivoxil hydrobromide (tebipenem HBr), an orally (PO) bioavailable prodrug of tebipenem, is a carbapenem with broad-spectrum activity against Gram-positive and -negative bacteria that is being developed for the treatment of patients with complicated urinary tract infections, including AP. Data from a one-compartment in vitro infection model demonstrated that the ratio of free-drug plasma area under the curve (AUC) to MIC with adjustment for dosing interval (τ) (AUC:MIC ratio•1/τ) was the PK-PD index most associated with tebipenem HBr efficacy [VanScoy BD et al., IDWeek 2019, Poster  1565]. Studies were undertaken to characterize the magnitude of tebipenem HBr free-drug plasma AUC:MIC ratio•1/τ associated with efficacy for Enterobacteriaceae using a neutropenic murine AP model.

Methods: A single dose pharmacokinetic study was completed in neutropenic mice infected via intra-renal injection with 10⁴ CFU/kidney of Escherichia coli NCTC 13441. Following PO administration of 4 tebipenem HBr doses (1, 15, 45 and 100 mg/kg), plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-treatment initiation and drug concentrations were determined using LC/MS/MS. Dose-ranging studies were completed using a panel of 7 Enterobacteriaceae isolates (tebipenem HBr MIC values of 0.015 to 0.5 mg/L). Mice were infected with 10⁴ CFU/kidney via intra-renal injection. Two hours post-incubation, 8 total daily tebipenem HBr doses (0.3 to 135 mg/kg) were fractionated into regimens given every 8 hours. The relationship between change in log₁₀ CFU/g from baseline at 24 hours and free-drug plasma AUC:MIC ratio•1/τ was fit using a Hill-type model. Free-drug plasma AUC:MIC ratio•1/τ values associated with net bacterial stasis and 1- and 2-log₁₀ CFU/g reductions from baseline at 24 hours were determined.

Results: The relationship between change in log₁₀ CFU/g from baseline at 24 hours and tebipenem HBr free-drug plasma AUC:MIC ratio•1/τ described the data well (r² = 0.833). Free-drug plasma AUC:MIC ratio•1/τ values associated with net bacterial stasis and a 1-log₁₀ CFU/g reduction from baseline were 26.2 and 54.1, respectively. A 2-log₁₀ CFU/g reduction was not achieved.Relationship between change in log10 CFU/g from baseline at 24 hours and tebipenem HBr free-drug plasma AUC:MIC ratio•1/τ based on data for a panel of Enterobacteriaceae isolates evaluated in the dose-ranging studies conducted using a neutropenic murine acute pyelonephritis model


Conclusion: These data will be useful to support tebipenem HBr dose selection for clinical studies in patients with AP.