1304. Characterization of Tebipenem Pivoxil Hydrobromide Pharmacokinetics-Pharmacodynamics (PK-PD) in a Neutropenic Murine Acute Pyelonephritis (AP) Model. (31st December 2020)

• Record Type: Journal Article
• Authors: VanScoy, Brian D; Fikes, Steven; Rubino, Christopher M; Bhavnani, Sujata M; Cotroneo, Nicole S; Critchley, Ian A; Parr, Thomas R; Ambrose, Paul G
• Is Part Of: Open forum infectious diseases. Volume 7:Number 1(2020) Supplement
• Page Start: S666
• Page End: S666
• Publication Date: 2020-12-31
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofaa439.1487
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: 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 ratio1/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 ratio1/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 10 4 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 10 4 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 ratio1/τ was fit using a Hill-type model. Free-drug plasma AUC:MIC ratio1/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 ratio1/τ described the data well (r 2 = 0.833). Free-drug plasma AUC:MIC ratio1/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 ratio1/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. Disclosures: Brian D. VanScoy, B.S., Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Steven Fikes, BA, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Christopher M. Rubino, PharMD, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Sujata M. Bhavnani, PharMD, MS, FIDSA, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Nicole S. Cotroneo, BS, Spero Therapeutics (Employee, Shareholder) Ian A. Critchley, PhD, Spero Therapeutics (Employee, Shareholder) Thomas R. Parr, PhD, Spero Therapeutics (Employee, Shareholder) Paul G. Ambrose, PharMD, FIDSA, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support)