Pharmacokinetic/Pharmacodynamic Determination and Preclinical Pharmacokinetics of the β-Lactamase Inhibitor ETX1317 and Its Orally Available Prodrug ETX0282

Abstract

Increasingly resistant Enterobacteriaceae have emerged as a health threat in both hospital and community settings. Infections of the urinary tract, once often treated with oral agents in the community, are requiring increased hospitalization and use of intravenously administered agents for effective treatment. These isolates often carry extended spectrum βlactamases (ESBLs) and carbapenemases that necessitate the need for an inhibitor to cover a broad range of β-lactamases. ETX1317 is a novel diazabicyclooctane class serine β-lactamase inhibitor that restores the antibacterial activity of several classes of β-lactams, including third-generation cephalosporins such as cefpodoxime. ETX1317 is currently being developed as an orally available prodrug, ETX0282, to be administered with cefpodoxime proxetil (CPDP). The combination has demonstrated oral efficacy in murine models of infection. Pharmacokinetics established in preclinical species and pharmacokinetic/pharmacodynamic attributes suggest the orally administered combination ETX0282 + CPDP could serve as an effective treatment option against contemporary ESBL and carbapenemase-producing Enterobacteriaceae.

Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine β-Lactamases

“…Cefpodoxime (CPD) emerged as the lead β-lactam candidate. 30 Its approved use as an orally bioavailable proxetil ester prodrug to treat UTI infections was also aligned with our potential target product profile. A fixed 1:2 ratio of cefpodoxime/ETX1317 was utilized as the testing paradigm for antimicrobial susceptibility.…”

“…Liver and intestinal S9 subcellular fractions (Xenotech) from rat and human tissue were diluted to a protein concentration of 0.8 mg/mL in 100 mM potassium phosphate buffer, pH 7.4, and preincubated in a 37 °C water bath for 5 min prior to addition of 10 μM (final) of compound of interest. Serial aliquots were removed at 0, 2, 5, 10, 20, 40, and 60 min and quenched in acetonitrile with internal standard prior to LC/MS/MS 30 to determine concentrations of prodrug. First order degradation half-lives were determined from the slope of the log–linear plots of the depletion data.…”

“…Formulation potency was verified by LC/MS/MS. 30 ETX0282 and CPDP were orally administered via q6h dose intervals in order to achieve targeted unbound exposures. At 24 h after initiation of therapy, animals were euthanized, and thighs (2 separate samples/animal) were aseptically collected and homogenized in 1 mL of sterile saline.…”

Bicyclic Boronate β‐Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens

“…ETX0282 ( 14) in combination with cefpodoxime proxetil, which is a prodrug of cefpodoxime approved for the treatment of antibiotic-resistant Enterobacteriaceae urinary tract infection, is a promising oral therapy for infections caused by ESBLproducing and carbapenem-resistant Enterobacteriaceae. [103][104][105][106] Undoubtedly, the broad-spectrum of activity of durlobactam (13) and ETX0282 ( 14)-or its active form ETX1317 (15)-represents a huge advance in restoring the efficacy of carbapenems in infections caused by the WHO priority pathogens. However, like avibactam these compounds are also inefficient against metallo--lactamases (Table 1).…”

Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections

“…The bioavailability of ETX0282 observed from the phase 1 studies has not been reported. In preclinical species (rat, dog, and monkey) it showed at least 78% bioavailability [ 64 ].…”