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. 2023 Apr 18;67(4):e0150922.
doi: 10.1128/aac.01509-22. Epub 2023 Mar 30.

Absorption, Metabolism, and Excretion of [14C]-Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Male Subjects

Vipul K Gupta  1 , Gary Maier  2 , Leanne Gasink  3 , Amanda Ek  4 , Mary Fudeman  5 , Praveen Srivastava  6 , Angela Talley  1
Affiliations

Absorption, Metabolism, and Excretion of [14C]-Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Male Subjects

Vipul K Gupta et al. Antimicrob Agents Chemother. .

Abstract

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug of pharmacologically active moiety tebipenem (TBP), which is a carbapenem with activity against multidrug-resistant Gram-negative pathogens. Conversion from the prodrug to the active moiety, namely, TBP, occurs in the enterocytes of the gastrointestinal tract via intestinal esterases. The absorption, metabolism, and excretion in humans were evaluated, following the administration of a single oral dose of [14C]-TBP-PI-HBr. Healthy male subjects (n = 8) received a single 600 mg oral dose of TBP-PI-HBr containing approximately 150 μCi of [14C]-TBP-PI-HBr. Blood, urine, and fecal samples were collected to determine the total radioactivity, concentrations of TBP (plasma only), and metabolite profiling and identification. The overall mean recovery of the total radioactivity in urine (38.7%) and feces (44.6%) combined was approximately 83.3% of the administered dose, with individual recoveries ranging from 80.1% to 85.0%. Plasma TBP LC-MS/MS and metabolite profiling data suggest that TBP was the main circulating component in plasma and that it accounts for approximately 54% of the total plasma radioactivity, based on the plasma AUC ratio of TBP/total radioactivity. The ring-open metabolite LJC 11562 was another major component in plasma (>10%). TBP (M12), LJC 11562, and four trace to minor metabolites were identified/characterized in the urine. TBP-PI, TBP (M12), and 11 trace to minor metabolites were identified/characterized in the feces. The renal and fecal routes are major clearance pathways in the elimination of [14C]-TBP-PI-HBr, with a mean combined recovery of 83.3%. TBP and its inactive ring-open metabolite LJC 11562 were the major circulating metabolites in the plasma.

Keywords: absorption; excretion; mass balance; metabolism; tebipenem.

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Conflict of interest statement

The authors declare a conflict of interest. G.M. and L.G. are consultants to Spero Therapeutics, Inc. All other authors were paid employees of Spero Therapeutics, Cambridge, MA at the time of this study.

Figures

FIG 1
FIG 1
Structure of TBP and metabolites and proposed biotransformation pathway.
FIG 2
FIG 2
Arithmetic mean plasma concentrations of TBP and total radioactivity in plasma and whole blood, following a single oral dose of TBP-PI-HBr (linear and semilogarithmic scales). A 600 mg dose of TBP-PI-HBr contained approximately 150 μCi of [14C]-TBP-PI-HBr.
FIG 3
FIG 3
Arithmetic mean (±SD) cumulative percentage of the radioactive dose that was recovered in feces at specified intervals after a single 600 mg (150 μCi) oral dose of [14C]-TBP-PI-HBr.
FIG 4
FIG 4
Radiochromatogram from blank plasma spiked with TBP and an analysis of plasma and feces samples after a single oral dose of [14C]-TBP-PI-HBr to male human subjects.
FIG 5
FIG 5
Radiochromatograms from an analysis of 0.25 h to 6 h AUC-pooled plasma samples after a single oral dose of [14C]-TBP-PI-HBr to male human subjects (600 mg/subject, 150 μCi/subject).
FIG 6
FIG 6
Radiochromatograms from an analysis of fecal samples after a single oral dose of [14C]-TBP-PI-HBr to male human subjects.
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