216. A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of the Beta-lactamase inhibitor Xeruborbactam Alone and in Combination Meropenem in Healthy Adult Subjects

Abstract

Background Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. This report describes the safety and pharmacokinetics of XERU following multiple doses alone and in combination with meropenem. Methods Twenty-four healthy subjects were enrolled into one of 3 cohorts with XERU alone. XERU was administered as a 500 mg loading dose followed by 250 mg q8h or 1000 mg loading dose followed by 500 mg q8h. 15 healthy subjects were enrolled in a single cohort of meropenem alone administered as a 4000 mg loading dose followed by 2000 mg q8h or meropenem in combination with XERU administered as a 500 mg loading dose followed by 250 mg q8h for 10 days. Intensive plasma sampling was obtained after dosing and assayed for drug content using validated LC-MS/MS methods. Results XERU and Meropenem Steady State pharmacokinetic parameters are shown in the table below. No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose. All AEs were mild or moderate in severity. Conclusion XERU was safe and well-tolerated when administered alone and in combination with meropenem. XERU has unique PK properties that includes a long elimination half-life that provides sustained plasma concentrations. The loading dose of XERU allows for rapid achievement of steady state plasma levels of XERU within the first day of treatment. XERU plasma PK properties, along with a broad spectrum of inhibitory activity, facilitates its use with multiple beta-lactam antibiotics including meropenem. Disclosures David Griffith, n/a, Qpex Biopharma: Employee Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Elizabeth Morgan, n/a, Qpex Biopharma: Employee Shawnee Gehrke, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.

In vitro effects of the new oral β-lactamase inhibitor xeruborbactam in combination with oral β-lactams against clinical Mycobacterium abscessus isolates

“…The final drug concentrations were as follows: amoxicillin, tebipenem, cefdinir, and cefuroxime (0.25–256 µg/mL); cefoxitin (0.125–128 µg/mL). Xeruborbactam was used at a final concentration of 4 µg/mL, a level that can be easily attained in human plasma ( 23 – 25 ). The half-life of xeruborbactam is estimated to be approximately 30 h ( 24 , 25 ), while that of avibactam is approximately 2 h ( 26 ).…”

“…Xeruborbactam was used at a final concentration of 4 µg/mL, a level that can be easily attained in human plasma ( 23 – 25 ). The half-life of xeruborbactam is estimated to be approximately 30 h ( 24 , 25 ), while that of avibactam is approximately 2 h ( 26 ). Although some β-lactams, such as imipenem, are unstable during long incubation time, a phenomenon that could potentially result in artificially high MIC values, avibactam is reported to be stable during incubation ( 14 , 27 ).…”

Antibiotic therapy for nonfermenting Gram-negative bacilli infections: future perspectives

“…Currently, the pharmacokinetics and the safety of Xeruborbactam have been evaluated among healthy volunteers. Xeruborbactam proved to have long elimination half-life and sustained plasma concentrations, and was well tolerated both alone and in combination with meropenem [52].…”

Unveiling the Secrets of Acinetobacter baumannii: Resistance, Current Treatments, and Future Innovations

“…Xeruborbactam has completed two phase 1 studies (NCT04380207 and NCT04578873) [105,106]. Being administered by the intravenous or oral route (as a prodrug form), it was found to be safe and well tolerated at doses of 1 g/day or less and resulted in exposures that exceeded non-clinical pharmacokinetic-pharmacodynamic targets [107][108][109]. Another phase 1, randomized, double-blind, single-dose, drug-drug interaction study aimed at determining the impact of co-administration of xeruborbactam on the pharmacokinetics of QPX2014 (an undisclosed β-lactam antibacterial) in healthy adult subjects was completed in 2022, but the results have not yet been published (NCT05072444, [110]).…”