Pharmacokinetics of Oral Tebipenem Pivoxil Hydrobromide in Subjects with Various Degrees of Renal Impairment

Gina Patel, Keith A Rodvold, Vipul K Gupta, Jon Bruss, Leanne Gasink, Floni Bajraktari, Yang Lei, Akash Jain, Praveen Srivastava, Angela K Talley, Gina Patel, Keith A Rodvold, Vipul K Gupta, Jon Bruss, Leanne Gasink, Floni Bajraktari, Yang Lei, Akash Jain, Praveen Srivastava, Angela K Talley

Abstract

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug antimicrobial agent with broad-spectrum activity that includes multidrug-resistant (MDR) Enterobacterales. This study evaluated the safety, tolerability, and pharmacokinetics of TBP-PI-HBr in healthy subjects with normal renal function (cohort 1) and subjects with various degrees of renal impairment (RI [cohorts 2 to 4]) or end-stage renal disease (ESRD) receiving hemodialysis (HD) (cohort 5). Subjects in cohorts 1 to 4 received a single oral dose of TBP-PI-HBr (600 mg). Subjects in cohort 5 received single-dose administration (600 mg) in 2 separate periods: pre-HD (period 2) and post-HD (period 1). Pharmacokinetic (PK) parameters for TBP, the active moiety, were determined using noncompartmental analysis. Compared with cohort 1, the TBP plasma area under the curve (AUC) increased 1.4- to 4.5-fold among cohorts 2 to 4, the maximum concentration of drug in plasma (Cmax) increased up to 1.3-fold and renal clearance (CLR) decreased from 13.4 L/h to 2.4 L/h as the severity of RI increased. Plasma TBP concentrations decreased over 8 to 12 h in cohorts 1 to 4, and apparent total body clearance (CL/F) correlated (R2 = 0.585) with creatinine clearance (CLCR). TBP urinary excretion ranged from 38% to 64% of the administered dose for cohorts 1 to 4. Subjects in cohort 5 had an approximately 7-fold increase in TBP AUC and elimination half-life (t1/2) versus cohort 1. After 4 h of HD, mean TBP plasma exposure decreased by approximately 40%. Overall, TBP plasma exposure increased with increasing RI, highlighting the renal route importance in TBP elimination. A dose reduction of TBP-PI-HBr may be needed in patients with RI (CLCR of ≤50 mL/min) and those with ESRD on HD. TBP-PI-HBr was well tolerated across all cohorts. (This study has been registered at ClinicalTrials.gov under registration no. NCT04178577.).

Keywords: pharmacokinetics; renal impairment; tebipenem.

Conflict of interest statement

The authors declare a conflict of interest. Gina Patel is a principal in Patel Kwan Consultancy, LLC, and provided consulting services to Spero Therapeutics. Keith A. Rodvold is an employee of University of Illinois, Chicago, and provided consulting services to Spero Therapeutics. Leanne Gasink is a consultant to Spero Therapeutics. All other authors were paid employees of Spero Therapeutics, Cambridge, Massachusetts, USA.

Figures

FIG 1
FIG 1
Plasma concentrations over time for TBP for cohorts 1 to 4 (A) and cohort 5 (B).
FIG 2
FIG 2
(Top) Apparent total body clearance versus estimated creatinine clearance, (middle) total body clearance versus renal clearance, and (bottom) renal clearance versus creatinine clearance of TBP for cohorts 1 to 4.
FIG 3
FIG 3
Mean (±SD) cumulative amount of TBP excreted unchanged in urine for cohorts 1 to 4.
FIG 4
FIG 4
Study schematic.

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