On January 3, 2022, Spero Therapeutics, Inc., the manufacturer of tebipenem HBr oral tablets, announced that the U.S. Food and Drug Administration (FDA) has granted Priority Review designation for tebipenem HBr oral tablets for treatment in adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of June 27, 2022. The manufacturer anticipates the launch of tebipenem HBr oral tablets by the second half of 2022. [1]
Tebipenem pivoxil hydrobromide (TBPM-PI-HBr) is an orally available prodrug of tebipenem with activity against multi-drug resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacteriaceae. A 2021 review described tebipenem pivoxil (TBPM-PI) was first marketed in Japan as a fine granule formulation (Orapenem®) for the treatment of otitis media, sinusitis, and pneumonia in pediatric patients. Tebipenem pivoxil hydrobromide, has been recently designed to improve several drug properties, such as stability and oral bioavailability, and to be used in the treatment of complicated urinary tract infections (cUTI) and acute pyelonephritis (AP) in adults. A study on the safety, pharmacokinetics, and food effects of TBPM-PI-HBr revealed a dose of 600 mg q8h provides bioavailability in the range of 50-60%. Despite the high protein binding (98.7%), about 55-60% of the total tebipenem dose is recovered in the urine as an intact drug, making this agent a suitable alternative to manage UTI. A phase 3 trial for the treatment of cUTI (ADAPT-PO trial; see Table 2) indicated oral administration of TBPM-PI-HBr (600mg, Q8H; 1.8 g/day) was non-inferior to intravenous (IV) ertapenem (1 g Q24H) for a treatment period of 7-10 days with similar safety profile (mild, transient diarrhea as the most commonly reported adverse event). While tebipenem can be possibly approved as the first- or second-line agent in patients who failed other oral antibiotics and potentially reduce the need for IV antibiotic therapy, oral administration of tebipenem may lead to increased risk of selecting carbapenem resistance with an additional impact on intestinal flora. [2], [3], [4]
A 2018 expert review states oral formulation of tebipenem can address the need for an oral treatment for severe UTI infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae and fluoroquinolone resistance. Use of oral agent may also reduce hospitalizations and subsequently decrease both cost and the potential complications. Stability studies have found tebipenem retained potent antibacterial activity against methicillin-susceptible S. aureus, E. coli, and K. pneumoniae strains with MICs ≤0.05 mcg/mL expressing either penicillinases or ESBLs. One animal study found TBPIM-PI superior to amoxicillin in treating acute otitis media caused by penicillin-resistant S. pneumoniae, >80% vs. 30% animal survival, with a greater reduction of bacterial burden. [4]
A double-blind comparative phase 3 study in 204 children with acute otitis media found TBPM-PI BID at 4 mg/kg was non-inferior to high-dose cefditoren pivoxil TID (≧4.2 mg/kg to <6.0 mg/kg) with the efficacy of 98.2% vs. 92.6%, respectively and similar incidence of drug-related reactions (15.3% vs. 13.9%). Other pharmacokinetic studies investigated the clinical efficacy and safety of TBPM-PI in pediatric patients with bacterial pneumonia caused by H. influenzae, S. pneumoniae, M. catarrhalis, and S. pyogenes. A phase 2 study observed a 100% cure rate with 4 mg/kg TBPM-PI BID for 7 days while 6mg/kg BID dosing resulted in 87.5% clinical efficacy. Another phase 3 study found the cure rates were 95.7% and 92.3% in the 4 and 6 mg/kg groups treated over 7 days. One phase 2 clinical study included adult patients (N= 51) with cUTI indicated clinical efficacy after 7 days was 92.9%, 94.1%, and 100% for the 100 mg TID, 150 mg BID, and 150 mg TID groups, respectively. Another phase 2 study (N= 37) showed 93.8% for both the 250 mg BID and 300 mg TID groups in patients affected with complicated pyelonephritis (n= 5) and complicated cystitis (n= 27). Post-marketing surveillance of TBPM-PI has also been performed in Japan showing this drug proved to be safe and adequately efficacious in patients with pneumonia, otitis media, or sinusitis. [4]
A 2010 study observes improved oral bioavailability of tebipenem pivoxil compared to the other similar β-lactam prodrugs. Tebipenem pivoxil is considered to exhibit higher intestinal absorption based on the cumulative amount of urinary excretion of active form (tebipenem pivoxil 54-73%, cefditoren pivoxil 20%, cefcapene pivoxil 33-41%, cefetamet pivoxil 41-51%, cefuroxime axetil 32-45%, cefpodoxime proxetil 36-45%, cefteram pivoxil 27%). The study suggests its remarkably high absorption compared to other prodrugs is due to high intestinal apical membrane permeability of tebipenem pivoxil using plural intestinal transport routes (e.g., uptake transporters such as OATP1A2 and OATP2B1) along with simple diffusion. The authors emphasized this study is considered the first report to demonstrate the contribution of OATP family to the intestinal absorption of β-lactam antibiotics. [5]