To Assess Bioavailability, Food Effect and Pharmacokinetics of Gepotidacin Tablets: A Phase I, Single-Dose, 2 Part Study in Healthy Subjects.

NCT02853435 | Completed Phase 1 Results

• 1 other identifier: 117351
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 2

Brief Summary

This study is divided in 2 parts. Part 1a is being conducted to evaluate the safety, tolerability, and relative bioavailability of the 2 free base tablet formulations (roller compacted \[RC\] and high shear wet granulation \[HSWG\]) compared to the reference capsule formulation under fasted conditions. This is a 3-period; cross-over study that will guide which gepotidacin formulation will be used for future studies. Following review of pharmacokinetic (PK) and safety data in Part 1a, a decision will be made whether to proceed with Parts 1b and 2. Part 1b is a 2-period, cross-over study and will assess the effect of food on the PK of the selected gepotidacin tablet formulation from Part 1a. In Part 2, the PK of the selected gepotidacin tablet formulation from Part 1a in Japanese (2a) and Chinese (2b) subjects will be evaluated under fasted conditions. The duration of the study (from Screening to the Follow-up visit) will be approximately 44 days (Part 1a), 41 days (Part 1b) and 38 days (Part 2a and 2b each), respectively. The approximate number of subjects enrolled in Part 1a will be 27 (9 subjects in each of the 3 treatment sequences), 16 in Part 1b (8 subjects in each of the 2 treatment sequences) and 12 Japanese and 12 Chinese subjects in Part 2a and 2b, respectively.

Conditions

Infections, Bacterial

Keywords

Cross-over; Gepotidacin; Pharmacokinetics; Relative Bioavailability; non-compartmental PK analysis; High shear wet granulation

Outcome Measures

Primary Outcomes (46)

• Area Under the Concentration-time Curve From Time 0 (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) of Plasma Gepotidacin for Part 1a

  Blood samples for pharmacokinetic (PK) analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1a. For each sample, 3 milliliters (mL) of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher. The PK Parameter Population consisted of all participants in the PK Population, for whom valid and evaluable PK parameters were derived. Statistics has been presented on geometric least square (LS) means.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Area Under the Concentration-time Curve (AUC) From Time 0 (Pre-dose) to Time of the Last Quantifiable Concentration (AUC [0-t]) of Plasma Gepotidacin for Part 1a

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1a. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher. Statistics has been presented on geometric LS means.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Relative Bioavailability of Drug (Frel) of Plasma Gepotidacin for Part 1a

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1a. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher. NA indicates data was not available as this was the reference capsule the Frel of each tablet type was being compared to.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Maximum Observed Concentration (Cmax) Determined Directly From the Concentration Time Data of Plasma Gepotidacin for Part 1a

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1a. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher. Statistics has been presented on geometric LS means.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Time to First Occurrence of Cmax (Tmax) of Plasma Gepotidacin for Part 1a

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1a. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Plasma Gepotidacin for Part 1a

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1a. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Terminal Phase Half-life (t1/2) of Plasma Gepotidacin for Part 1a

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1a. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Total Unchanged Drug (Total Amount of Drug Excreted in Urine [Ae Total]) for Part 1a

  PK urine samples were collected at 0 (predose), 0 to 2, 2 ot 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours

• Percentage of the Given Dose of Drug Excreted in Urine (fe%) of Plasma Gepotidacin for Part 1a

  PK urine samples were collected at 0 (pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours

• Renal Clearance of Drug in Urine (CLr) for Part 1a

  PK urine samples were collected at 0 (pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours

• Amount of Drug Excreted in Urine in a Time Intervals for Pre-dose, 0 to 2 Hours, 2 to 4 Hours, 4 to 6 Hours, 6 to 8 Hours, 8 to 12 Hours, 12 to 24 Hours, 24 to 36 Hours, and 36 to 48 Hours (Ae [t1-t2]) for Part 1a

  PK urine samples were collected at 0 (pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher. Only those participants available at the specific time points were analyzed (represented by n = X in the category titles).

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours

• Area Under the Urine Concentration-time Curve Over Time 0 (Pre-dose) to 12 Hours (AUC [0-12]) for Part 1a

  PK urine samples were collected at 0 (pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• Area Under the Urine Concentration-time Curve Over Time 0 (Pre-dose) to 24 Hours (AUC [0-24]) After Dosing for Part 1a

  PK urine samples were collected at 0 (pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours

• Area Under the Urine Concentration-time Curve Over Time 0 (Pre-dose) to 48 Hours (AUC [0-48]) After Dosing for Part 1a

  PK urine samples were collected at 0 (pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher. Only those participants with data available at the indicated time point were analyzed.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours

• AUC (0-infinity) of Plasma Gepotidacin for Part 1b

  Blood samples for PK analysis of gepotidacin was planned to be collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1b. Since the relative bio-availability of the RC tablet formulation under fasted and fed conditions had been previously evaluated in Study BTZ117349 (NCT02045849), Part 1b was not conducted.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• AUC (0-t) of Plasma Gepotidacin for Part 1b

  Blood samples for PK analysis of gepotidacin was planned to be collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1b. Since the relative bio-availability of the RC tablet formulation under fasted and fed conditions had been previously evaluated in Study BTZ117349 (NCT02045849), Part 1b was not conducted.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Cmax of Plasma Gepotidacin for Part 1b

  Blood samples for PK analysis of gepotidacin was planned to be collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1b. Since the relative bio-availability of the RC tablet formulation under fasted and fed conditions had been previously evaluated in Study BTZ117349 (NCT02045849), Part 1b was not conducted.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Tmax of Plasma Gepotidacin for Part 1b

  Blood samples for PK analysis of gepotidacin was planned to be collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1b. Since the relative bio-availability of the RC tablet formulation under fasted and fed conditions had been previously evaluated in Study BTZ117349 (NCT02045849), Part 1b was not conducted.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Tlag of Plasma Gepotidacin for Part 1b

  Blood samples for PK analysis of gepotidacin was planned to be collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1b. Since the relative bio-availability of the RC tablet formulation under fasted and fed conditions had been previously evaluated in Study BTZ117349 (NCT02045849), Part 1b was not conducted.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• t1/2 of Plasma Gepotidacin for Part 1b

  Blood samples for PK analysis of gepotidacin was planned to be collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 1b. Since the relative bio-availability of the RC tablet formulation under fasted and fed conditions had been previously evaluated in Study BTZ117349 (NCT02045849), Part 1b was not conducted.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• AUC (0-infinity) of Plasma Gepotidacin for Part 2

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 2. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• AUC (0-t) of Plasma Gepotidacin for Part 2

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 2. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Cmax of Plasma Gepotidacin for Part 2

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 2. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Tlag of Plasma Gepotidacin for Part 2

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 2. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Tmax of Plasma Gepotidacin for Part 2

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 2. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• t1/2 of Plasma Gepotidacin for Part 2

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 2. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Total Unchanged Drug (Ae Total) for Part 2

  PK urine samples were collected at 0 (pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• Ae (t1-t2) for Part 2

  PK urine samples were collected at 0 (pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• AUC (0-12) for Part 2

  PK urine samples were collected at 0 (pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• AUC (0-24) for Part 2

  PK urine samples were collected at 0 (pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• AUC (0-48) for Part 2

  PK urine samples were collected at pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• fe% for Part 2

  PK urine samples were collected at pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• CLr for Part 2

  PK urine samples were collected at pre-dose), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• AUC (0-infinity) of Plasma Gepotidacin for Part 3

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 3. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• AUC (0-t) of Plasma Gepotidacin for Part 3

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 3. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Cmax of Plasma Gepotidacin for Part 3

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 3. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Tmax of Plasma Gepotidacin for Part 3

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 3. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Tlag of Plasma Gepotidacin for Part 3

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 3. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• t1/2 of Plasma Gepotidacin for Part 3

  Blood samples for PK analysis of gepotidacin were collected at Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in Part 3. For each sample, 3 mL of blood was drawn via an indwelling catheter and/or direct venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. PK parameters were determined from the plasma concentration-time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours (Day 1), 24, 36 hours (Day 2) and 48 hours (Day 3) in each treatment period

• Total Unchanged Drug (Ae Total) for Part 3

  PK urine samples were collected at pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours

• Urine Ae (t1-t2) for Part 3

  PK urine samples were collected at pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher. Only those participants available at the specific time points were analyzed (represented by n = X in the category titles).

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• Urine AUC (0-12) for Part 3

  PK urine samples were collected at pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• Urine AUC (0-24) for Part 3

  PK urine samples were collected at pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• Urine AUC (0-48) for Part 3

  PK urine samples were collected at pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• fe% for Part 3

  PK urine samples were collected at pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher.

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

• CLr for Part 3

  PK urine samples were collected at pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours. PK parameters were determined from the urine concentration- time data and were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin Version 6.2.1 or higher

  Pre-dose, 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, 24 to 36, and 36 to 48 hours.

Secondary Outcomes (65)

• Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) for Part 1a

  Up to 14 days

• Change From Baseline in Clinical Chemistry Parameters Serum Glucose, Serum Calcium, Serum Carbon Dioxide, Serum Chloride, Serum Potassium, Serum Sodium and Serum Urea Nitrogen for Part 1a

  Baseline and up to 14 days

• Change From Baseline in Clinical Chemistry Parameters Serum Alanine Aminotransferase (ALT), Serum Alkaline Phosphatase (AP), Serum Aspartate Aminotransferase (AST) and Serum Creatinine Kinase (CK) for Part 1a

  Baseline and up to 14 days

• Change From Baseline in Clinical Chemistry Parameters Serum Albumin and Serum Protein for Part 1a

  Baseline and up to 14 days

• Change From Baseline in Clinical Chemistry Parameters Serum Bilirubin, Serum Creatinine and Serum Direct Bilirubin for Part 1a

  Baseline and up to 14 days

Study Arms (7)

Part1a: Gepotidacin 1500 mg-Sequence A-capsules, B-RC, C-HSWG

EXPERIMENTAL

Subjects will be receive treatment sequence (ABC) which is a single dose of gepotidacin 1500 mg (three tablets of 500 mg) reference capsule (Treatment A) in Period 1, 1500 mg (two tablets of 750 mg) RC tablet (Treatment B) in Period 2 or 1500 mg (two tablets of 750 mg) HSWG tablet (Treatment C) in Period 3, according to randomization. There will be a washout period of at least 3 days between doses.

Drug: Gepotidacin RC Tablet; Drug: Gepotidacin HSWG Tablet; Drug: Gepotidacin Capsule

Part1a: Gepotidacin 1500 mg-Sequence C-HSWG, A-capsules, B-RC)

EXPERIMENTAL

Subjects will receive treatment sequence (CAB) to receive a single dose of gepotidacin 1500 mg (two tablets of 750 mg) HSWG tablet (Treatment C) in Period 1, 1500 mg (three tablets of 500 mg) reference capsule (Treatment A) in Period 2 or 1500 mg (two tablets of 750 mg) RC tablet (Treatment B) in Period 3 according to randomization. There will be a washout period of at least 3 days between doses.

Drug: Gepotidacin RC Tablet; Drug: Gepotidacin HSWG Tablet; Drug: Gepotidacin Capsule

Part1a: Gepotidacin 1500 mg-Sequence B-RC, C-HSWG, A-capsules)

EXPERIMENTAL

Subjects will receive treatment sequence (BCA) to receive a single dose of gepotidacin 1500 mg (two tablets of 750 mg) RC tablet (Treatment B) in period 1, 1500 mg (two tablets of 750 mg) HSWG tablet (Treatment C) in Period 2, or 1500 mg (three tablets of 500 mg) (Treatment A) in Period 3 reference capsule according to randomization.. There will be a washout period of at least 3 days between doses.

Drug: Gepotidacin RC Tablet; Drug: Gepotidacin HSWG Tablet; Drug: Gepotidacin Capsule

Part1b: Gepotidacin 1500 mg-Sequence DE-fasted followed by fed

EXPERIMENTAL

Subjects will receive treatment sequence (DE) according to randomization which is a single 1500 mg (two tablets of 750 mg) dose of gepotidacin tablet (RC or HSWG) selected from Part 1a under fasted condition (Treatment D) in Period 1 followed by fed conditions (Treatment E) in period 2. There will be a washout period of at least 3 days between doses.

Drug: Gepotidacin RC Tablet; Drug: Gepotidacin HSWG Tablet

Part1b: Gepotidacin 1500 mg-Sequence ED-fed followed by fasted

EXPERIMENTAL

Subjects will be receive treatment sequence (ED) according to randomization which is single 1500 mg (two tablets of 750 mg) dose of gepotidacin tablet (RC or HSWG) selected from Part 1a under fed condition (Treatment E) in period 1 followed by fasted conditions (Treatment D) in Period 2. There will be a washout period of at least 3 days between doses.

Drug: Gepotidacin RC Tablet; Drug: Gepotidacin HSWG Tablet

Part 2a: Gepotidacin 1500 mg (RC or HSWG)- Japanese subjects

EXPERIMENTAL

Japanese subjects will receive a single 1500 mg (two tablets of 750 mg) dose of gepotidacin tablet (RC or HSWG) selected from Part 1a.

Drug: Gepotidacin RC Tablet; Drug: Gepotidacin HSWG Tablet

Part 2b: Gepotidacin 1500 mg (RC or HSWG)- Chinese subjects

EXPERIMENTAL

Chinese subjects will receive a single 1500 mg (two tablets of 750 mg) dose of gepotidacin tablet (RC or HSWG) selected from Part 1a.

Drug: Gepotidacin RC Tablet; Drug: Gepotidacin HSWG Tablet

Interventions

Gepotidacin RC Tablet DRUG

The tablet is a capsule shape white film coated tablet with no identifying markings. This is an immediate release tablet containing gepotidacin 750 mg (free base) and inactive formulation excipients administered orally with 240 mL of water. Up to an additional 100 mL of water may be given to assist in swallowing tablets.

Part 2a: Gepotidacin 1500 mg (RC or HSWG)- Japanese subjects; Part 2b: Gepotidacin 1500 mg (RC or HSWG)- Chinese subjects; Part1a: Gepotidacin 1500 mg-Sequence A-capsules, B-RC, C-HSWG; Part1a: Gepotidacin 1500 mg-Sequence B-RC, C-HSWG, A-capsules); Part1a: Gepotidacin 1500 mg-Sequence C-HSWG, A-capsules, B-RC); Part1b: Gepotidacin 1500 mg-Sequence DE-fasted followed by fed; Part1b: Gepotidacin 1500 mg-Sequence ED-fed followed by fasted

Gepotidacin HSWG Tablet DRUG

The tablet is an oval shape white film coated tablet with no identifying markings. This is an immediate release tablets containing gepotidacin 750 mg (free base) and inactive formulation excipients administered orally with 240 mL of water. Up to an additional 100 mL of water may be given to assist in swallowing tablets.

Part 2a: Gepotidacin 1500 mg (RC or HSWG)- Japanese subjects; Part 2b: Gepotidacin 1500 mg (RC or HSWG)- Chinese subjects; Part1a: Gepotidacin 1500 mg-Sequence A-capsules, B-RC, C-HSWG; Part1a: Gepotidacin 1500 mg-Sequence B-RC, C-HSWG, A-capsules); Part1a: Gepotidacin 1500 mg-Sequence C-HSWG, A-capsules, B-RC); Part1b: Gepotidacin 1500 mg-Sequence DE-fasted followed by fed; Part1b: Gepotidacin 1500 mg-Sequence ED-fed followed by fasted

Gepotidacin Capsule DRUG

It is a pink gelatin size 00 capsule with no identifying markings containing slightly agglomerated pale yellow to grayish yellow to yellowish gray powder. This is an immediate release capsules containing gepotidacin 500 mg (mesylate salt) and inactive formulation excipients administered orally with 240 mL of water. Up to an additional 100 mL of water may be given to assist in swallowing capsules.

Part1a: Gepotidacin 1500 mg-Sequence A-capsules, B-RC, C-HSWG; Part1a: Gepotidacin 1500 mg-Sequence B-RC, C-HSWG, A-capsules); Part1a: Gepotidacin 1500 mg-Sequence C-HSWG, A-capsules, B-RC)

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female subjects between 18 and 64 years of age inclusive, at the time of signing the informed consent.
• Healthy as determined by the investigator based on medical history, clinical laboratory results (serum chemistry, hematology, urinalysis, and serology), vital sign measurements, 12-lead ECG results, and physical examination findings. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the investigator feels and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Body weight for subjects in Part 1a and 1b: more than equal to (\>=) 50 kilogram (kg) and body mass index (BMI) within the range 19 and 32 kilogram per meter square (kg/m\^2), inclusive and for Japanese and Chinese subjects (Part 2a and 2b): \>=50 kg and BMI within the range 18 and 32 kg/m\^2, inclusive.
• Male or female: a female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin test, not lactating, and at least one of the following conditions applies. Non-reproductive potential defined as: pre-menopausal females with one of the following: documented tubal ligation, documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, hysterectomy, documented bilateral oophorectomy and postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle-stimulating hormone and estradiol levels consistent with menopause). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential from 30 days prior to the first dose of study medication and until completion of the Follow-up visit.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

You may not qualify if:

• Subject has a clinically significant abnormality in past medical history or at the Screening physical examination that in the investigator's opinion may place the subject at risk or interfere with outcome variables of the study. This includes, but is not limited to, history or current cardiac, hepatic, renal, neurologic, gastrointestinal, respiratory, hematologic, or immunologic disease.
• Subject has any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study drug, or any other condition that may place the subject at risk, in the opinion of the investigator.
• QTc more than (\>) 450 millisecond (msec).
• Use of a systemic antibiotic within 30 days of Screening.
• Within 2 months before Screening, either a confirmed history of Clostridium difficile diarrhea infection or a past positive Clostridium difficile toxin test.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic uses heparin to maintain intravenous cannula patency).
• Subjects cannot use any over-the-counter, or prescription medication (except for hormonal contraceptives and/or acetaminophen), vitamin supplement, or herbal medication within 7 days (or 5 half-lives, whichever is longer) before dosing and during the study.
• History of regular alcohol consumption within 6 months of screening defined as an average weekly intake of \>21 units (or an average daily intake of \>3 units) for males or an average weekly intake of \>14 units (or an average daily intake \>2 units) for females. One unit is equivalent to 270 milliliter (mL) of full strength beer, 470 mL of light beer, 30 mL of spirits, or 100 mL of wine.
• Urinary cotinine level indicative of smoking or history or regular use of tobacco- or nicotine containing products within 3 months before screening.
• History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.
• Presence of hepatitis B surface antigen, positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
• Female subject has a positive pregnancy test result or is lactating at Screening or upon admission to the clinic.
• ALT \>1.5×upper limit of normal (ULN)
• Bilirubin \>1.5×ULN (isolated bilirubin \>1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin less than \[\<\] 35 percent \[%\]).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Anaheim, California, 92801, United States

Location

GSK Investigational Site

Austin, Texas, 78744, United States

Location

Related Publications (1)

• Barth A, Hossain M, Brimhall DB, Perry CR, Tiffany CA, Xu S, Dumont EF. Pharmacokinetics of Oral Formulations of Gepotidacin (GSK2140944), a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor, in Healthy Adult and Adolescent Participants. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0126321. doi: 10.1128/AAC.01263-21. Epub 2021 Oct 11.

  PMID: 34633853 DERIVED

MeSH Terms

Conditions

Bacterial Infections

Interventions

gepotidacin

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2016
• First Posted: August 3, 2016
• Study Start: August 4, 2016
• Primary Completion: October 17, 2017
• Study Completion: October 17, 2017
• Last Updated: October 8, 2020
• Results First Posted: November 14, 2018

Record last verified: 2020-09

Locations

US (2)