Safety and Pharmacokinetics of Taniborbactam (VNRX-5133) with Cefepime in Subjects with Various Degrees of Renal Impairment

Abstract

Taniborbactam, an investigational β-lactamase inhibitor that is active against both serine- and metallo-β-lactamases, is being developed in combination with cefepime to treat serious infections caused by multidrug-resistant Gram-negative bacteria. Anticipating the use of cefepime-taniborbactam in patients with impaired renal function, an open-label, single-dose clinical study was performed to examine the pharmacokinetics of both drugs in subjects with various degrees of renal function. Hemodialysis-dependent subjects were also studied to examine the amounts of cefepime and taniborbactam dialyzed. Single intravenous infusions of 2 g cefepime and 0.5 g taniborbactam coadministered over 2 h were examined, with hemodialysis-dependent subjects receiving doses both on- and off-dialysis. No subjects experienced serious adverse events or discontinued treatment due to adverse events. The majority of adverse events observed were mild in severity, and there were no trends in the safety of cefepime-taniborbactam related to declining renal function or the timing of hemodialysis. Clinically significant and similar decreases in drug clearance with declining renal function were observed for both cefepime and taniborbactam. The respective decreases in geometric mean clearance for subjects with mild, moderate, and severe renal impairment compared to subjects with normal renal function were 18%, 63%, and 78% for cefepime and 15%, 63%, and 81% for taniborbactam, respectively. Decreases in clearance were similar for both drugs and were shown to be proportional to decreases in renal function. Both cefepime and taniborbactam were dialyzable, with similar amounts removed during 4 h of hemodialysis. This study is registered at ClinicalTrials.gov as NCT03690362.

Keywords: VNRX-5133; beta-lactamase inhibitor; cefepime; cefepime-taniborbactam; drug safety; pharmacokinetics; renal impairment; taniborbactam.

Conflict of interest statement

The authors declare a conflict of interest. J.A.D. is a principal at Pharmacology Development Services, LLC (Collegeville, PA), T.C.M. is an employee and equity owner of the Orlando Clinical Research Center (Orlando, FL), and W.B.S. is an employee of the Alliance for Multispecialty Research, University of Tennessee Medical Center (Knoxville, TN); all three authors performed work as paid contractors for Venatorx Pharmaceuticals, Inc., Malvern, PA. T.H. is an employee of Venatorx Pharmaceuticals, Inc., Malvern, PA.

Figures

FIG 1

Mean cefepime and taniborbactam plasma concentrations across renal groups (nondialysis). (a) Cefepime, logarithmic concentration scale. (b) Taniborbactam, logarithmic concentration scale.

FIG 2

Cefepime and taniborbactam CL versus eCLCR, showing linear regression. (a) Cefepime. (b) Taniborbactam.

FIG 3

Comparison of mean cefepime and taniborbactam plasma concentrations in the on-dialysis and off-dialysis treatment periods (dialysis subjects). (a) Cefepime, logarithmic concentration scale. (b) Taniborbactam, logarithmic concentration scale.