1115. Evaluation of Gepotidacin (GSK2140944) Pharmacokinetics and Food Effect in Japanese Subjects

Abstract Background Gepotidacin, a novel, first-in-class triazaacenaphthylene antibiotic, inhibits bacterial replication and has in vitro and in vivo activity against key pathogens, including drug-resistant strains, associated with a range of infections. Gepotidacin is currently in Phase 3 clinical studies for the treatment of uncomplicated urinary tract infections and gonorrhea. This study (NCT02853435) was designed to assess gepotidacin pharmacokinetics (PK) in Japanese subjects (fasted and fed). Methods A tablet formulation of 750 mg gepotidacin free base was used in the study, which was conducted in two parts: Part 1, gepotidacin PK was assessed following 1500 and 3000 mg single oral doses in the fasted state; and Part 2, gepotidacin PK was assessed following 1500, 2250, and 3000 mg single oral doses in the fed state. Serial blood and urine samples were collected in both study parts. Results Part 1: The area under the plasma drug concentration-time curve from time 0 to infinity (AUC[0–∞]) and maximum observed concentration (Cmax) were slightly higher in Japanese subjects than in Caucasian subjects at the same dose levels and with the same formulation. Following gepotidacin dosing in the fasted state, the 1500 mg dose was tolerated, while the 3000 mg dose was poorly tolerated with mild or moderate gastro-intestinal adverse effects (GI AEs) reported by most subjects shortly after being dosed. Part 2: PK was linear with doses in the range of 1500–3000 mg. Administration of gepotidacin 3000 mg tablets in the fed state slightly reduced Cmax and slightly increased AUC at the 3000 mg dose level. The 1500 and 2250 mg doses were tolerated while the 3000 mg dose was better tolerated compared to the fasted state with fewer and short-lived GI AEs, mostly mild in intensity. After oral administration of 1500–3000 mg, high urine drug concentrations were achieved, remaining above the minimum inhibitory concentration of 4 μg/mL for up to 24 hours. Conclusion The PK of gepotidacin following administration of a single oral dose to Japanese subjects was linear from 1500–3000 mg and food decreased Cmax without impact on exposure (AUC). Administration of gepotidacin with food resulted in an improved GI tolerability profile at the higher dose tested in Japanese subjects. Disclosures Mohammad Hossain, PhD, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Courtney Tiffany, BSc, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Aline Barth, MSC;PHD, GlaxoSmithKline plc. (Employee, Shareholder, Employee of and shareholder in GlaxoSmithKline plc.) Aparna Raychaudhuri, Ph.D., GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and past/current shareholder in GlaxoSmithKline plc.) Etienne F. Dumont, MD, GlaxoSmithKline plc. (Employee, Shareholder, Former employee of and shareholder in GlaxoSmithKline plc.)


Conclusion.
While there was no difference in the primary composite outcome of presumed clinical cure, future studies can use these data to assess TDM patient selection and whether a bundled care approach of BLA regimens with known clinical benefit, early TDM-guided dose optimization, and continued clinical assessment improves outcomes in patients with PSAR PNA or BSI compared to use of each modality individually.

Evaluation of Gepotidacin (GSK2140944) Pharmacokinetics and Food Effect in Japanese Subjects
Mohammad Hossain, PhD 1 ; Courtney Tiffany, BSc 1 ; Aline Barth, MSC;PHD 2 ; Aparna Raychaudhuri, Ph.D. 2 ; Etienne F. Dumont, MD 1 ; 1 GlaxoSmithKline plc., Collegeville, PA, USA, Collegeville, Pennsylvania; 2 GSK Session: P-62. PK/PD Studies Background. Gepotidacin, a novel, first-in-class triazaacenaphthylene antibiotic, inhibits bacterial replication and has in vitro and in vivo activity against key pathogens, including drug-resistant strains, associated with a range of infections. Gepotidacin is currently in Phase 3 clinical studies for the treatment of uncomplicated urinary tract infections and gonorrhea. This study (NCT02853435) was designed to assess gepotidacin pharmacokinetics (PK) in Japanese subjects (fasted and fed).
Methods. A tablet formulation of 750 mg gepotidacin free base was used in the study, which was conducted in two parts: Part 1, gepotidacin PK was assessed following 1500 and 3000 mg single oral doses in the fasted state; and Part 2, gepotidacin PK was assessed following 1500, 2250, and 3000 mg single oral doses in the fed state. Serial blood and urine samples were collected in both study parts.
Results. Part 1: The area under the plasma drug concentration-time curve from time 0 to infinity (AUC [0-∞] ) and maximum observed concentration (C max ) were slightly higher in Japanese subjects than in Caucasian subjects at the same dose levels and with the same formulation. Following gepotidacin dosing in the fasted state, the 1500 mg dose was tolerated, while the 3000 mg dose was poorly tolerated with mild or moderate gastro-intestinal adverse effects (GI AEs) reported by most subjects shortly after being dosed. Part 2: PK was linear with doses in the range of 1500-3000 mg. Administration of gepotidacin 3000 mg tablets in the fed state slightly reduced C max and slightly increased AUC at the 3000 mg dose level. The 1500 and 2250 mg doses were tolerated while the 3000 mg dose was better tolerated compared to the fasted state with fewer and short-lived GI AEs, mostly mild in intensity. After oral administration of 1500-3000 mg, high urine drug concentrations were achieved, remaining above the minimum inhibitory concentration of 4 μg/mL for up to 24 hours.
Conclusion. The PK of gepotidacin following administration of a single oral dose to Japanese subjects was linear from 1500-3000 mg and food decreased C max without impact on exposure (AUC). Administration of gepotidacin with food resulted in an improved GI tolerability profile at the higher dose tested in Japanese subjects.
Disclosures Background. Pharmacokinetic/pharmacodynamic (PK/PD) targets and attainment are well described for beta-lactams; however, are rarely considered for beta-lactamase inhibitors. Recent evidence suggests that tazobactam (TAZ) target exposures to restore piperacillin bacteriostatic and 1 log 10 bactericidal activity against Enterobacterales are fT> the piperacillin/tazobactam (TZP) MIC of 64% and 77%, respectively. The aim of this study was to evaluate TAZ probability of target attainment (PTA) of a 500 mg every 6-hour dose of tazobactam using population PK data in both healthy volunteers and hospitalized patients.
Methods. PK exposures in 1,000 patients with varying degrees of renal function were simulated using a previously described TAZ PK model developed with data from critically ill infected patients. An identical one-compartment structural model describing TAZ PK using mean population parameters observed in phase 1 PK studies was also used to simulate exposures in healthy volunteers. All simulated patients received 500 mg of TAZ as an intravenous infusion over 30 minutes or as a 3-hour extended-infusion.
Results. The table displays PTA results for patients with an estimated creatinine clearance of 60 mL/min. Based on healthy volunteer data, the highest TZP MIC where ~90% PTA was achieved for bacteriostasis was 1 mg/L and was 0.25 mg/L for bactericidal activity. These were only achieved with extended infusion administration of TAZ. In the cohort of hospitalized patients, >90% PTA of TAZ exposures associated with both bacteriostasis and 1 log kill were achieved up to a MIC of 2 for intermittent infusion and up to 4 mg/L for extended infusion, due to decreased TAZ clearance in hospitalized patients. These values are significantly lower than the CLSI TZP susceptibility breakpoint of 16 mg/L, and PTA rates were lower at increased creatinine clearances.