Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects

Abstract

Tebipenem pivoxil hydrobromide (TBPM-PI-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 Enterobacteriaceae. The safety and pharmacokinetics (PK) of tebipenem were studied after administration of single and multiple ascending oral doses of TBPM-PI-HBr in fed and fasted states. Healthy adults received single oral doses of TBPM-PI-HBr at 100 mg to 900 mg or placebo (n = 108) or multiple doses of 300 mg or 600 mg every 8 h or placebo (n = 16) for 14 days. In the single-ascending-dose (SAD) phase, mean tebipenem plasma concentrations increased in a linear and dose proportional manner for doses of 100 to 900 mg and were comparable in the fasted and fed states for the 300- and 600-mg doses. In the MAD phase, tebipenem maximum concentration (Cmax) was reached within 1.5 h and was dose proportional on day 1 and higher than dose proportional (2.7-fold) on day 14. AUC was more than 2-fold greater on day 1 (2.7-fold) and day 14 (2.5-fold) for 600 mg q8h than for 300 mg q8h. Approximately 55% to 60% of tebipenem was recovered in the urine. TBPM-PI-HBr was well tolerated; mild, transient diarrhea was the most commonly reported adverse event. TBPM-PI-HBr provides an orally bioavailable carbapenem option to treat serious infections caused by MDR Enterobacteriaceae and has the potential to decrease the need for intravenous antibiotic therapy in the hospital or outpatient setting. (This study has been registered at ClinicalTrials.gov under identifier NCT03395249.)

Pharmacokinetics, Urinary Excretion, and Pharmaco-Metabolomic Study of Tebipenem Pivoxil Granules After Single Escalating Oral Dose in Healthy Chinese Volunteers

“…The current work reproduced parameters of T max , C max , AUC 0-∞ , and MRT 0-t previously reported in healthy Chinese or Australian subjects (Eckburg, et al, 2019;Xue, et al, 2019). However, inconsistencies were also noticed; although t 1/2 in our study was close to that in previous report in Chinese volunteers (Xue, et al, 2019), it was observed as 1.0 h in Australian volunteers (Eckburg, et al, 2019).…”

“…Limited studies aiming at exploring the pharmacokinetics of TBPM have been documented ( Eckburg et al, 2019 ; Nakashima, et al, 2009b ; Xue, et al, 2019 ). These studies provided pharmacokinetic parameters of TBPM either in a single dose or in single gender.…”

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

“…In the Phase 1 SAD/MAD study, TBP-PI-HBr 300 mg and 600 mg administered q8h produced a C max ranging from 6.5-7.8 µg/mL and 13.4 to 15.1 µg/mL, respectively. 15 The supratherapeutic 1200 mg dose used in this study was expected to produce a C max that was 1.3-fold higher and an AUC 0-inf that was 1.8-fold higher than the 600 mg dose. Nine of 24 subjects had C max values greater than the target (at least 1.5fold C max ) with no effect on the QTc interval.…”

“…15 Because of short half-life of TBP (<1 h) in humans, no evidence for accumulation was observed with TBP-PI-HBr 600 mg q8h for 14 days. 15 Further, TBP has no active metabolites that could contribute to adverse effects on the QT interval. In the Phase 1 SAD/MAD study, TBP-PI-HBr 300 mg and 600 mg administered q8h produced a C max ranging from 6.5-7.8 µg/mL and 13.4 to 15.1 µg/mL, respectively.…”

“…13,14 Previously, the PK of TBP were evaluated in a single-and multipleascending dose study in healthy subjects. 15 The PK profile of TBP generally was dose proportional and linear after single doses of 100 to 900 mg. After multiple daily doses of on May 2, 2021 by guest http://aac.asm.org/ Downloaded from 4 300 and mg q8h, TBP demonstrated dose-proportionality PK with no accumulation over 14 days. 15 The objective of this study was to evaluate the effects of single therapeutic (600 mg) and supratherapeutic (1200 mg) doses of TBP-PI-HBr on the heart rate corrected QT interval (QTc) by assessing the concentration-QT (C-QT) relationship using exposureresponse modeling.…”