Tebipenem Pivoxil | ScienceGate

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 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. 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)

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In Vitro and In Vivo Characterization of Tebipenem, an Oral Carbapenem

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02240-19 ◽

2020 ◽

Vol 64 (8) ◽

Author(s):

Nicole Cotroneo ◽

Aileen Rubio ◽

Ian A. Critchley ◽

Chris Pillar ◽

Michael J. Pucci

Keyword(s):

Bacterial Resistance ◽

Unmet Need ◽

Multidrug Resistant ◽

Oral Agent ◽

Gram Negative ◽

Improved Stability ◽

Tebipenem Pivoxil ◽

Tract Infections

ABSTRACT The continued evolution of bacterial resistance to the β-lactam class of antibiotics has necessitated countermeasures to ensure continued effectiveness in the treatment of infections caused by bacterial pathogens. One relatively successful approach has been the development of new β-lactam analogs with advantages over prior compounds in this class. The carbapenems are an example of such β-lactam analogs possessing improved stability against β-lactamase enzymes and, therefore, a wider spectrum of activity. However, all carbapenems currently marketed for adult patients are intravenous agents, and there is an unmet need for an oral agent to treat patients that otherwise do not require hospitalization. Tebipenem pivoxil hydrobromide (tebipenem-PI-HBr or SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. Tebipenem-PI-HBr is currently in development for the treatment of complicated urinary tract infections (cUTI). Microbiological data are presented here that demonstrate equivalency of tebipenem with intravenous carbapenems such as meropenem and support its use in infections in which the potency and spectrum of a carbapenem are desired. The results from standard in vitro microbiology assays as well as efficacy in several in vivo mouse infection models suggest that tebipenem-PI-HBr could be a valuable oral agent available to physicians for the treatment of infections, particularly those caused by antibiotic-resistant Gram-negative pathogens.

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Sodium valproate/tebipenem pivoxil interaction

Reactions Weekly ◽

10.1007/s40278-015-8123-5 ◽

2015 ◽

Vol 1540 (1) ◽

pp. 275-275

Keyword(s):

Sodium Valproate ◽

Tebipenem Pivoxil

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Investigation of pneumonia-causing pathogenic organisms in children and the usefulness of tebipenem pivoxil for their treatment

Journal of Infection and Chemotherapy ◽

10.1007/s10156-010-0053-9 ◽

2010 ◽

Vol 16 (4) ◽

pp. 280-287 ◽

Cited By ~ 6

Author(s):

Haruo Kuroki ◽

Noriko Tateno ◽

Hiroyuki Ikeda ◽

Naoko Saito

Keyword(s):

Pathogenic Organisms ◽

Tebipenem Pivoxil

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In Vitro and In Vivo Characterization of Tebipenem (TBP), an Orally Active Carbapenem, against Biothreat Pathogens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02385-20 ◽

2021 ◽

Author(s):

Nicholas P. Clayton ◽

Akash Jain ◽

Stephanie A. Halasohoris ◽

Lisa M. Pysz ◽

Sanae Lembirik ◽

...

Keyword(s):

Survival Rates ◽

Multidrug Resistant ◽

Positive Control ◽

Vehicle Control ◽

Control Group ◽

Post Challenge ◽

Vehicle Control Group ◽

Tebipenem Pivoxil

Bacillus anthracis and Yersinia pestis, causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and B. pseudomallei are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr, formerly SPR994), is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. We evaluated the in vitro activity and in vivo efficacy of tebipenem against biothreat pathogens. Tebipenem was active in vitro against 30-strain diversity sets of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei with minimum inhibitory concentration (MIC) values of 0.001 – 0.008 μg/ml for B. anthracis, ≤0.0005 – 0.03 μg/ml for Y. pestis, 0.25 – 1 μg/ml for B. mallei, and 1 – 4 μg/ml for B. pseudomallei. In a B. anthracis murine model, all control animals died within 52 h post challenge. The survival rates in the groups treated with tebipenem were 75% and 73% when dosed at 12 h and 24 h post challenge, respectively. The survival rates in the positive control groups treated with ciprofloxacin were 75% and when dosed 12 h and 25% when dosed 24 h post challenge, respectively. Survival rates were significantly (p=0.0009) greater in tebipenem groups treated at 12 h and 24 h post challenge and in the ciprofloxacin group 12 h post-challenge vs. the vehicle-control group. For Y. pestis, survival rates for all animals in the tebipenem and ciprofloxacin groups were significantly (p<0.0001) greater than the vehicle-control group. These results support further development of tebipenem for treating biothreat pathogens.

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A Randomized, Double-blind, Placebo- and Positive-controlled Crossover Study of the Effects of Tebipenem Pivoxil Hydrobromide on QT/QTc Intervals in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00145-21 ◽

2021 ◽

Author(s):

Vipul K. Gupta ◽

Gary Maier ◽

Paul Eckburg ◽

Lisa Morelli ◽

Yang Lei ◽

...

Keyword(s):

Heart Rate ◽

Crossover Study ◽

Qt Interval ◽

Dependent Manner ◽

Double Blind ◽

Assay Sensitivity ◽

Double Blind Placebo ◽

Corrected Qt Interval ◽

Tebipenem Pivoxil

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an orally available prodrug of TBP, a carbapenem with in vitro activity against multidrug-resistant gram-negative pathogens. This study evaluated the effects of single therapeutic and supratherapeutic doses of TBP-PI-HBr on the heart rate corrected QT interval (QTc) by assessing the concentration-QT (C-QT) relationship using exposure-response modeling. This was a randomized, double-blind, placebo- and active-controlled, single dose, 4-way, crossover study. Subjects received single oral doses of TBP-PI-HBr 600 and 1200 mg, placebo, and positive control, moxifloxacin 400 mg. Cardiodynamic electrocardiograms (ECGs) and blood samples were collected in each period. Twenty-four subjects were enrolled. TBP-PI-HBr had no clinically significant adverse effects on heart rate or ECG parameters. The model-predicted slope suggests that ddHR was not importantly affected by plasma tebipenem concentrations, supporting the use of QTcF as an appropriate correction method. The model predicted difference in corrected QT interval (ddQTcF) at mean peak concentration (Cmax) for TBP had negative predicted values for each dose, and no QTc prolongation was detected following TBP-PI-HBr 600 mg or 1200 mg. Assay sensitivity was established following moxifloxacin 400 mg. Exposure to TBP increased in a dose-dependent manner with 600 and 1200 mg doses. TBP area under the concentration curve from time 0 to infinity (AUC0-inf) and Cmax at the 1200 mg dose level were 1.8- and 1.3-fold higher than with the 600 mg dose. TBP-PI-HBr was generally safe and well tolerated with no effect on QT prolongation.

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