Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants with Uncomplicated Urinary Tract Infection (Acute Uncomplicated Cystitis)

Abstract

Gepotidacin, a triazaacenaphthylene bacterial type II topoisomerase inhibitor, is in development for treatment of uncomplicated urinary tract infection (uUTI). This phase 2a study in female participants with uUTI evaluated the pharmacokinetics (primary objective), safety, and exploratory efficacy of gepotidacin. Eligible participants (n = 22) were confined to the clinic at baseline, received oral gepotidacin at 1,500 mg twice daily for 5 days (on-therapy period; days 1 to 5), and returned to the clinic for test-of-cure (days 10 to 13) and follow-up (day 28 ± 3) visits. Pharmacokinetic, safety, clinical, and microbiological assessments were performed. Maximum plasma concentrations were observed approximately 1.5 to 2 h postdose. Steady state was attained by day 3. Urinary exposure over the dosing interval increased from 3,742 μg·h/ml (day 1) to 5,973 μg·h/ml (day 4), with trough concentrations of 322 to 352 μg/ml from day 3 onward. Gepotidacin had an acceptable safety-risk profile with no treatment-limiting adverse events and no clinically relevant safety trends. Clinical success was achieved in 19 (86%) and 18 (82%) of 22 participants at test-of-cure and follow-up visits, respectively. Eight participants had a qualifying baseline uropathogen (growth; ≥105 CFU/ml). A therapeutic (combined clinical and microbiological [no growth; <103 CFU/ml]) successful response was achieved in 6 (75%) and 5 (63%) of 8 participants at test-of-cure and follow-up visits, respectively. Plasma area under the free-drug concentration-time curve over 24 h at steady state divided by the MIC (fAUC0–24/MIC) and urine AUC0–24/MIC ranged from 6.99 to 90.5 and 1,292 to 121,698, respectively. Further evaluation of gepotidacin in uUTI is warranted. (This study has been registered in ClinicalTrials.gov under identifier NCT03568942.)

Pharmacokinetics of Gepotidacin in Subjects With Normal Hepatic Function and Hepatic Impairment

“…Efficacy of gepotidacin was demonstrated in a phase 2 study in participants with uncomplicated urinary tract infection, in which the minimum gepotidacin urine concentrations remained above the clinically relevant gepotidacin minimum inhibitory concentration value of 4 μg/mL throughout the dosing interval. 8 Saliva concentrations displayed a linear relationship with plasma (both bound and unbound) gepotidacin concentrations (R 2 = 0.76). The ratio of saliva AUC to unbound plasma AUC was consistently close to unity (ratio of the AUC 0-t and AUC 0-∞ ranged from 0.746 to 0.839).…”

“…In clinical trials, gepotidacin has demonstrated efficacy in acute bacterial skin and skin structure infections, uncomplicated urogenital gonorrhea, and uncomplicated urinary tract infection. [5][6][7][8] Gepotidacin is currently in phase 3 clinical studies for the treatment of uncomplicated urinary tract infection (1500 mg twice daily for 5 days) (ClinicalTrials.gov identification numbers NCT04020341 and NCT04187144) and uncomplicated urogenital gonorrhea (2 doses of 3000 mg separated by 10-12 hours) (ClinicalTrials.gov identification number NCT04010539).…”

Pharmacokinetics of Oral Formulations of Gepotidacin (GSK2140944), a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor, in Healthy Adult and Adolescent Participants

“…Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action ( 1 , 2 ), which confers activity against most strains of Escherichia coli , Staphylococcus saprophyticus , and Neisseria gonorrhoeae , including those resistant to current antibiotics ( 3 – 7 ). Phase 2 clinical trials indicated that gepotidacin may be a viable treatment for urogenital gonorrhea, uncomplicated urinary tract infection (UTI), and acute bacterial skin and skin structure infections ( 8 – 10 ). Phase 3 confirmatory studies are currently in progress to support urogenital gonorrhea (ClinicalTrials.gov identifier NCT04010539) and uncomplicated UTI (ClinicalTrials.gov identifiers NCT04020341 and NCT04187144) indications.…”

“…Throughout phase 1 and 2 clinical development, the pharmacokinetics (PK) of gepotidacin have been well defined in healthy adult participants ( 8 – 15 ) and in participants with renal or hepatic impairment ( 16 , 17 ). Gepotidacin formulations used in the PK evaluations included mesylate salt for an intravenous solution, capsules, tablets, and the free base for capsules and tablets.…”

Pharmaceutical Approaches on Antimicrobial Resistance: Prospects and Challenges

“…Zoliflodacin is currently in a phase 3 clinical trial for uncomplicated gonorrhea [ 89 ]. Meanwhile, gepotidacin is being developed for uncomplicated UTI and uncomplicated gonorrhea [ 90 ].…”