What is tebipenem pivoxil used for and what are the potential benefits/drawbacks over other carbapenems?

Comment by InpharmD Researcher

Tebipenem pivoxil hydrobromide (HBr), an orally available prodrug of tebipenem with activity against multi-drug resistant gram-negative pathogens, was first marketed in Japan as a fine granule formulation (Orapenem®) for the treatment of otitis media, sinusitis, and pneumonia in pediatric patients. Based on the results of a pivotal phase 3 trial (see Table 2) indicating non-inferiority of oral tebipenem pivoxil HBr to intravenous ertapenem, the manufacturer announced that the U.S. FDA has granted Priority Review designation for tebipenem HBr oral tablets for the treatment of complicated urinary tract infection in adults with an anticipated launch by the second half of 2022. The use of oral tebipenem as an alternative for resistant pathogens may reduce hospitalizations, costs, and further complications.

Background

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]

References:

[1] Spero Therapeutics. Spero Therapeutics announces FDA acceptance and priority review of New Drug Application for tebipenem HBr for the treatment of complicated urinary tract infections including pyelonephritis. Published January 3, 2022. Accessed April 13, 2022.
[2] Veeraraghavan B, Bakthavatchalam YD, Sahni RD. Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections. Infect Dis Ther. 2021;10(4):1815-1835. doi:10.1007/s40121-021-00509-4
[3] ​​Eckburg PB, Jain A, Walpole S, et al. Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects. Antimicrob Agents Chemother. 2019;63(9):e00618-19. Published 2019 Aug 23. doi:10.1128/AAC.00618-19
[4] ​​Jain A, Utley L, Parr TR, Zabawa T, Pucci MJ. Tebipenem, the first oral carbapenem antibiotic. Expert Rev Anti Infect Ther. 2018;16(7):513-522. doi:10.1080/14787210.2018.1496821
[5] Kato K, Shirasaka Y, Kuraoka E, et al. Intestinal absorption mechanism of tebipenem pivoxil, a novel oral carbapenem: involvement of human OATP family in apical membrane transport. Mol Pharm. 2010;7(5):1747-1756. doi:10.1021/mp100130b

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

what is tebipenem pivoxil used for, and what is the potential benefits/drawbacks over other carbapenems?

Please see Tables 1-2 for your response.


 

Oral tebipenem pivoxil hydrobromide studies

Clinical phase of development

Patient population

Doses and duration

Comparator 

Findings

Clinical cure 

Phase I (NCT03395249)

N= 124

Healthy subjects 

Single ascending dose (SAD):
100–900 mg q8h for 14 days

Multiple ascending doses (MAD): 300 or 600 mg q8h for 14 days

None

Evaluation of SAD and MAD revealed that AUC was more than twofold greater on day 1 (2.7-fold) and day 14 (2.5-fold) for 600 mg q8h than for 300 mg q8h N/A

Phase I (NCT04178577)

N= 39

Patients with renal impairment 

600 mg single dose None Completed, awaiting for results  N/A

Phase III ADAPT-PO trial

(NCT03788967)

N= 1,372

Patients with complicated urinary tract infection or acute pyelonephritis

600 mg q8h for 7–10 days

Ertapenem IV: 1 g q24h for 7–10 days  Tebipenem was non-inferior to ertapenem IV

 

Tebipenem 58.8% vs. Ertapenem 61.6%

References:

Adapted from:
Veeraraghavan B, Bakthavatchalam YD, Sahni RD. Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections. Infect Dis Ther. 2021;10(4):1815-1835. doi:10.1007/s40121-021-00509-4

 

Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection

Design

Phase 3, international, double-blind, double-dummy trial (ADAPT-PO)

N= 868 (micro-biologic intention-to-treat population)

Objective

To evaluate oral tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in hospitalized patients with complicated urinary tract infection or acute pyelonephritis

Study Groups

Tebipenem pivoxil hydrobromide (n= 449)

Ertapenem (n= 419)

Inclusion Criteria

Hospitalized male and female patients aged ≥ 18 years who had been diagnosed with complicated urinary tract infection or acute pyelonephritis

Exclusion Criteria

Confirmed or suspected infection with a carbapenem-resistant pathogen, creatinine clearance of ≤ 30 mL/min, receipt of more than one dose of a short-acting antibiotic within 72 hours before randomization, septic shock, severe hepatic impairment, pregnancy, immunocompromised, and hypersensitivity to any beta-lactam antibiotic

Methods

Eligible patients were randomized (1:1) to receive either 600 mg (two 300-mg tablets; one 300-mg tablet in renal impairment) tebipenem pivoxil hydrobromide PO Q8H plus a dummy ertapenem infusion Q24H or 1 g ertapenem administered intravenously over 30 min Q24H plus dummy tebipenem pivoxil hydrobromide tablets PO Q8H. Patients received treatment for 7 to 10 days (or up to 14 days in patients with bacteremia). 

The micro-biologic intention-to-treat population included all the patients with a confirmed diagnosis of complicated urinary tract infection or acute pyelonephritis and positive urine culture at baseline. A noninferiority margin of 12.5% was used to compare tebipenem with ertapenem. 

Duration

From June 2019 through May 2020

Follow-up: 25 ± 2 days

Outcome Measures

Primary: overall response (a composite of clinical cure and microbiologic response) in the micro-biologic intention-to-treat population at the test-of-cure visit (on day 19, within a ±2-day window) 

Secondary: overall response at the test-of-cure visit in the microbiologically evaluable population; overall response at the end-of-treatment visit and the late follow-up visit (day 25, within a ±2-day window) in the microbiologic intention-to-treat and microbiologically evaluable populations; clinical cure, time to reduction of symptoms, and per-patient and per-pathogen microbiologic responses at the end-of-treatment, test-of-cure, and late follow-up visits in the microbiologic intention-to-treat and microbiologically evaluable populations

Baseline Characteristics

 

Tebipenem pivoxil hydrobromide (n= 449)

Ertapenem (n= 419)

 

Age, years

57.6±18.7  58.7±17.9  

Female

252 (56.1%)  253 (60.4%)  

White

446 (99.3%) 417 (99.5%)  

Infection type

Complicated urinary tract infection

Acute pyelonephritis

 

223 (49.7%)

226 (50.3%)

 

218 (52.0%)

201 (48.0%)

 

Bacteremia 

47 (10.5%)

53 (12.6%)

 

Modified systemic inflammatory response syndrome (SIRS) criteria

98 (21.8%)

73 (17.4%)

 

Systemic antibiotic use within 30 days before randomization

19 (4.2%)

22 (5.3%)

 

Infection with resistant Enterobacterales pathogen, no. of patients with resistant pathogen/ total no. with Enterobacterales pathogen

ESBL-positive

Fluoroquinolone-nonsusceptible

TMP-SMX–resistant

 

105/396 (26.5%)

159/396 (40.2%)

168/396 (42.4%)

 

85/386 (22.0%)

146/386 (37.8%)

168/386 (43.5%)

 

Duration of therapy, days 

8.7±1.8

8.5±1.9

 

All the patients (100%) received at least 80% of the intended doses of the oral trial drug, and 99.6% of the patients received at least 80% of the intended doses of intravenous trial drug.

Results

Endpoint

Tebipenem pivoxil hydrobromide (n= 449)

Ertapenem (n= 419)

Treatment difference (95% confidence interval [CI])

Overall response at test-of-cure visit

264 (58.8%) 258 (61.6%) −3.3 (−9.7 to 3.2)

Overall response at end-of-treatment visit

437 (97.3%) 396 (94.5%) 2.8 (0.1 to 5.7)

Clinical response

Clinical improvement at day 5

Clinical cure at end-of-treatment visit

Clinical cure at test-of-cure visit

Sustained clinical cure at late follow-up

 

336 (74.8%)

446 (99.3%)

418 (93.1%)

398 (88.6%)

 

321 (76.6%)

410 (97.9%)

392 (93.6%)

377 (90.0%)

 

−1.9 (−7.6 to 3.8)

1.4 (−0.1 to 3.4)

−0.6 (−4.0 to 2.8)

−1.5 (−5.7 to 2.6)

Microbiological response

Response at day 5

Response at end-of-treatment visit

Response at test-of-cure visit

Sustained response at late follow-up

 

427 (95.1%)

439 (97.8%)

267 (59.5%)

257 (57.2%)

 

397 (94.7%)

403 (96.2%)

266 (63.5%)

244 (58.2%)

 

0.3 (−2.7 to 3.4)

1.5 (−0.8 to 4.1)

−4.5 (−10.8 to 1.9)

−1.5 (−7.9 to 5.0)

Across all the subgroups, pre-specified analysis of overall response at the test-of-cure visit according to baseline characteristics was consistent with the results of the primary analysis.

Adverse Events

Common Adverse Events: tebipenem (n= 685) vs ertapenem (n= 687) alanine aminotransferase level increase (1% vs 1%); aspartate aminotransferase level increase (1% vs 0.7%); diarrhea (5.7% vs 4.4%); edema peripheral (0.4% vs 1%); headache (3.8% vs 3.8%); hypertension (0.4% vs 1%); nausea (1.5% vs 0.9%); vulvovaginal candidiasis (0.7% vs 1%)

Three Clostridioides difficile–associated adverse events of diarrhea were reported during the trial; all occurred in the ertapenem group.

Serious Adverse Events: 1.3% vs 1.7%

Percentage that Discontinued due to Adverse Events: 0.1% vs 1.2%

Study Author Conclusions

Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis and had a similar safety profile. In the absence of other effective oral agents, tebipenem pivoxil hydrobromide may provide an option for the treatment of complicated urinary tract infection and acute pyelonephritis due to antibiotic-resistant uropathogens.

InpharmD Researcher Critique

The required inpatient 7-to-10-day course of antibiotic therapy (up to 14 days for patients with bacteremia) may not reflect the real-life scenario and current practice in the US. Local biogram and resistant patterns may differ from the study regions (United States, South Africa, and Europe), limiting the generalizability of study results. Regardless, noninferiority is achieved in this trial and tebipenem may be considered in selected patients.



References:

Eckburg PB, Muir L, Critchley IA, et al. Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection. N Engl J Med. 2022;386(14):1327-1338. doi:10.1056/NEJMoa2105462