BLUJEPA Film-coated tablet Ref.[115538] Active ingredients: Gepotidacin

The 24-hour free‑drug AUC to minimum inhibitory concentration (MIC) ratio has been shown in animal infection and in vitro pharmacokinetic‑pharmacodynamic (PK‑PD) models to be the PK‑PD index predictive of gepotidacin antibacterial efficacy.

Cardiac Electrophysiology

The effect of gepotidacin on the QTc interval was evaluated in a randomized, active (moxifloxacin 400 mg) and placebo‑controlled, double‑blind cross‑over trial in healthy subjects who received single intravenous (IV) infusions of gepotidacin over 2 hours. A dose- and concentration‑dependent QTc prolongation effect of gepotidacin was observed. The mean placebo‑corrected change from baseline heart rate values around T_max were approximately 6 bpm at 1,000 mg IV (not an approved dosing regimen and route of administration) and approximately 10 bpm at 1,800 mg IV (not an approved dosing regimen and route of administration). The mean placebo‑corrected change from baseline QTcF values around T_max were 12 msec at 1,000 mg IV and 22 msec at 1,800 mg IV [see Warnings and Precautions (5.1)]. The C_max of gepotidacin following a single 1,000 mg IV dose (not an approved dosing regimen and route of administration) is approximately 1.7 times that of the C_max at steady state for the 1,500 mg oral dose twice daily.

Pharmacokinetic Parameters

The pharmacokinetic properties of gepotidacin are summarized in Table 2 as mean (standard deviation [SD]) unless otherwise specified.

Table 2. Pharmacokinetic Parameters of Gepotidacin:

^a Pharmacokinetic parameters are presented at steady state in patients with uUTI and eGFR greater than or equal to 90 mL/min after oral administration of BLUJEPA 1500 mg every 12 hours over 5 days.
^b Studies evaluating the effect on food were performed with standard and moderate fat meal. Clinical studies were not performed with a high fat meal (1000 calories, 50% fat).

Specific Populations

Modelling and simulation analyses of gepotidacin showed no clinically relevant effect of age (12 to <18 years of age or 65 to 89 years of age), sex, race, or body weight (range: 40 kg to 140 kg) on gepotidacin exposure [see Use in Specific Populations (8.4), (8.5)].

Patients with Renal Impairment

The pharmacokinetics of gepotidacin were evaluated in subjects with moderate renal impairment (eGFR 30 to 59 mL/min) and in subjects with severe renal impairment/end stage renal disease (ESRD) on intermittent hemodialysis and not on intermittent hemodialysis (eGFR <30 mL/min). Gepotidacin plasma C_max and AUC in subjects with moderate renal impairment were 1.2‑fold and 1.5‑fold higher than matched healthy controls, respectively. Gepotidacin plasma C_max and AUC in severe renal impairment/ESRD not on intermittent hemodialysis were 1.7-fold and 2.1‑fold higher than matched healthy controls, respectively. Gepotidacin plasma C_max and AUC in ESRD subjects requiring intermittent hemodialysis were 2.3‑fold and 2.5‑fold higher before intermittent hemodialysis than healthy matching subjects, respectively, and were 6.2‑fold and 4.2‑fold higher after intermittent hemodialysis than matched healthy controls, respectively [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Moderate hepatic impairment did not have a clinically relevant effect on gepotidacin pharmacokinetics. In subjects with severe hepatic impairment compared with subjects with normal hepatic function, gepotidacin plasma exposure parameters (C_max and AUC) were increased by approximately 1.9‑fold and 1.7‑fold, respectively [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Clinical Drug Interaction Studies

Effect of CYP3A4 Inhibitors on the Pharmacokinetics of Gepotidacin: Concomitant administration of a strong inhibitor of CYP3A4 (itraconazole; 200 mg per day for 3 days), and a single 1,500 mg dose of BLUJEPA resulted in an increase in the maximum concentration (C_max) of gepotidacin of approximately 1.4‑fold and area under the curve (AUC) of approximately 1.5‑fold [see Drug Interactions (7.1)].

Effect of CYP3A4 Inducers on the Pharmacokinetics of Gepotidacin: Concomitant administration of BLUJEPA (single 1,500 mg dose) with a strong CYP3A4 inducer (rifampin; 600 mg once daily for 7 days) resulted in a decrease of 52% in gepotidacin plasma AUC_(0-∞) [see Drug Interactions (7.2)].

Effect of BLUJEPA on Pharmacokinetics of Other Drugs: Concomitant administration of a single 0.5 mg dose of digoxin with two 3,000 mg doses of BLUJEPA (an in vitro P‑glycoprotein inhibitor), given 12 hours apart (not an approved dosage of BLUJEPA), resulted in a 1.5‑fold increase in the digoxin C_max (at 3 hours post dose), a 1.1‑fold increase in the digoxin AUC_(0-∞), and a delayed digoxin T_max [see Drug Interactions (7.2)].

Concomitant administration of midazolam (2 mg single dose) with BLUJEPA (2 doses of 3,000 mg, given 12 hours apart; not an approved dosage of BLUJEPA) resulted in a 1.9‑fold increase in midazolam AUC_(0-∞) [see Drug Interactions (7.2)].

In-Vitro Drug Interaction Studies

In vitro, gepotidacin was not an inducer of CYP1A2, 2B6 or 3A4. In vitro, gepotidacin is not a substrate of any of the hepatic organic anion transporting polypeptides (OATPs) 1B1, 1B3, and 2B1, organic anion transporters (OATs) OAT1, OAT2 and OAT3, organic cation transporters (OCTs) OCT2 and OCT3.

In-Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

In vitro, gepotidacin inhibited multidrug and toxin extrusion (MATEs) MATE1 (IC₅₀=16.6 µM), and MATE2‑K (IC₅₀=6.9 μM). In vitro, gepotidacin is a substrate of breast cancer resistance protein (max flux rate ratio of 11.0).

Mechanism of Action

BLUJEPA is a triazaacenaphthylene antibacterial that inhibits Type II topoisomerases including bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, thereby inhibiting DNA replication.

Gepotidacin has bactericidal activity against pathogens as determined by time‑kill studies. In vitro studies demonstrated a gepotidacin post‑antibiotic effect ranging from 1.8 to 2.2 hours for E. coli, 1 to >6.6 hours for K. pneumoniae, 1.4 to 3 hours for P. mirabilis, 1 to 2.6 hours for C. freundii, 2.7 to 4.3 hours for S. saprophyticus, and 1.2 to 2.7 hours for E. faecalis at 5 times the MIC.

Resistance

Although no clear mechanisms of resistance have been identified for gepotidacin, potential mechanisms that may impact gepotidacin activity are gepotidacin‑specific alterations of DNA gyrase (gyrA, gyrB) and/or topoisomerase IV (parC, parE) gene targets, plasmid‑mediated quinolone resistance genes (especially qnr), and efflux. The following amino acids may be important for gepotidacin activity GyrA P35, V44, D82, A175, GyrB D426, P445 and ParC D79 as shown through studies with isogenic mutants in E. coli and K. pneumoniae. A single target‑specific mutation may not significantly impact gepotidacin activity. The relationship between gepotidacin and fluoroquinolone susceptibility does not appear to include amino acid substitutions in GyrA and ParC that are known to reduce fluoroquinolone susceptibility in E. coli. Gepotidacin activity against E. coli and K. pneumoniae is unrelated to beta-lactam resistance mechanisms.

The frequency of resistance development to gepotidacin due to spontaneous mutations in the gram‑negative and gram‑positive uropathogens tested in vitro at 10 times MIC ranged from 10^-9 to 10^-10.

Target‑specific cross‑resistance with other classes of antibacterial drugs has not been identified; therefore, isolates resistant to other drugs may be susceptible to gepotidacin. However, isolates of Enterobacterales with ≥4-fold increases in gepotidacin MIC have been identified in vitro and in clinical studies.

During clinical studies, gepotidacin demonstrated activity against some isolates of the following multilocus sequence typing (MLST) for E. coli: ST10, ST131, ST1193, ST69, ST95 and ST73.

Interaction with Other Antimicrobials

In in vitro studies, no antagonism against Enterobacterales or gram‑positive isolates was observed for gepotidacin in combination with multiple antibacterial drugs, including fluoroquinolones, sulfonamides, cephalosporins, macrolides, tetracyclines, aminoglycosides, glycopeptides, carbapenems, nitrofurans, monobactams, and oxazolidinones.

Antimicrobial Activity

Gepotidacin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]:

Aerobic bacteria:

Gram-positive bacteria

Enterococcus faecalis
Staphylococcus saprophyticus

Gram-negative bacteria

Citrobacter freundii complex
Escherichia coli
Klebsiella pneumoniae

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for gepotidacin against isolates of similar genus or organism group. However, the efficacy of gepotidacin in treating clinical infections caused by these bacteria has not been established in adequate and well‑controlled clinical trials.

Aerobic bacteria:

Gram-negative bacteria

Citrobacter koseri
Klebsiella aerogenes
Klebsiella oxytoca/Raoltella ornithinolytica
Morganella morganii
Proteus mirabilis
Providencia rettgeri

Susceptibility Test Methods

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Carcinogenesis

Long term carcinogenicity studies have not been conducted with gepotidacin.

Mutagenesis

Gepotidacin was positive in an in vitro micronucleus test in human peripheral blood lymphocytes and in an L5178Y mouse lymphoma assay, consistent with the known in vitro clastogenic effects of topoisomerase inhibitors in in vitro mammalian cell assays. Gepotidacin was negative in an in vivo micronucleus test or Comet assay in rat. Based on an overall weight of evidence, gepotidacin is unlikely to be genotoxic.

Impairment of Fertility

In animal studies with gepotidacin, there were no adverse effects on fertility in male and female rats treated for approximately 3 weeks at 4-times the exposure at the MRHD (AUC extrapolated from rats orally administered the same dose for up to 4 weeks). There were no effects on spermatogenesis in rats and dogs at 4 and 5 times the exposure at MRHD, respectively, when treated for up to 13 weeks.

14.1 Uncomplicated Urinary Tract Infections

A total of 3,136 female patients with uUTI were randomized in 2 multicenter, parallel‑group, double‑blind, double‑dummy, non‑inferiority (NI) trials (Trial 1 [NCT04020341] and Trial 2 [NCT04187144]). Both trials compared BLUJEPA 1,500 mg (administered orally twice daily with food for 5 days) to nitrofurantoin 100 mg (administered orally twice daily for 5 days).

Patients entered the trials with at least 2 symptoms consistent with uUTI (dysuria, frequency, urgency, or lower abdominal pain) and with evidence of urinary nitrite or pyuria. Patients with any medical condition or presentation suggestive of a complicated UTI, or an upper UTI (e.g., pyelonephritis, urosepsis) were excluded.

Efficacy was assessed as a composite of clinical cure and microbiological response at the Test‑of‑Cure (TOC) Visit (Study Day 10 to 13) in the microbiological ITT nitrofurantoin‑susceptible (micro-ITTS) population, which included all patients who received at least 1 dose of study medication, had at least 1 baseline qualifying uropathogen (≥105 colony‑forming units [CFU]/mL), and excluded patients with organisms not susceptible to nitrofurantoin. Clinical cure was defined as resolution of all signs and symptoms of acute cystitis present at baseline and no new signs and symptoms without the patient receiving other systemic antimicrobials.

Microbiological response was defined as having all qualifying uropathogens found at baseline at ≥10⁵ CFU/mL reduced to <10³ CFU/mL without the patient receiving other systemic antimicrobials.

Both trials demonstrated non‑inferiority of BLUJEPA to nitrofurantoin for composite response (Table 3).

In Trial 1, the micro-ITTS population consisted of 634 female patients with uUTI (n=336 BLUJEPA; n=298 nitrofurantoin). The median age of patients was 54 years, 57% were >50 years of age, 84% were White, 40% had a history of recurrent infection. The U.S. enrolled the greatest percentage of patients (39%). Patient demographic and baseline characteristics were generally balanced between treatment groups [see Adverse Reactions (6.1)].

In Trial 2, the micro-ITTS population consisted of 567 female patients with uUTI (n=292 BLUJEPA; n=275 nitrofurantoin). The median age of patients was 51 years, 52% were >50 years of age, 85% were White, 41% had history of recurrent infection. The majority of patients (67%) were enrolled from the U.S. Patient demographic and baseline characteristics were generally balanced between treatment groups [see Adverse Reactions (6.1)].

Table 3 summarizes the composite response, clinical cure, and microbiological response rates at the TOC visit for Trials 1 and 2 in the micro-ITTS population.

Table 3. Composite Response, Clinical Cure, and Microbiological Response Rates at the Test-of-Cure Visit (Micro-ITTS Population):

Micro-ITTS = Microbiological Intent to Treat nitrofurantoin-susceptible; CI = confidence interval.
^a BLUJEPA was non-inferior to nitrofurantoin in both studies. The determination of Trial 1 non‑inferiority was based on a planned interim analysis of 607 subjects in Micro-ITTS population. The determination of Trial 2 non‑inferiority was based on a planned interim analysis of 541 subjects in Micro-ITTS population.
^b Treatment difference (BLUJEPA – nitrofurantoin) calculated using Miettinen and Nurminen Summary Score method adjusting for age group and recurrent/non-recurrent infection status combinations.

Table 4 summarizes the composite response rates at the TOC Visit for the most common baseline uropathogens across both trials in the micro-ITTS population.

Table 4. Composite Response Rates at the Test-of-Cure Visit by Baseline Uropathogen (Trial 1 and Trial 2 Pooled; Micro-ITTS Population)^a:

Micro-ITTS = Microbiological Intent to Treat nitrofurantoin-susceptible;
^a A patient is counted once under a uropathogen category if multiple qualifying uropathogens within that category are isolated at baseline for the patient. |
^b Patients may have been infected with 1 to 2 uropathogens at baseline.