Drug-drug Interaction Study of Gepotidacin

NCT04493931 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 213678
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a drug-drug interaction (DDI), pharmacokinetics (PK), safety and tolerability study in adult healthy participants, including Japanese cohort. This study is designed to assess co-administration of probe substrates with gepotidacin in study cohorts 1 to 3 and establishing PK and safety in Japanese participants in cohort 4. Food effect will also be evaluated in cohort 4.

Conditions

Infections, Bacterial

Keywords

Gepotidacin; Drug Interaction; Pharmacokinetic; Safety; Bacterial Infection; Japanese Healthy Adults

Outcome Measures

Primary Outcomes (48)

• Cohort 1: Maximum Observed Concentration (Cmax) of Gepotidacin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric least square (LS) mean and 90 percent (%) confidence interval (CI) of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 1: Time to Reach Maximum Observed Concentration (Tmax) of Gepotidacin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 1: Terminal Phase Half-life (t1/2) of Gepotidacin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90% CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

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

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90% CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 1: AUC From Time 0 (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) of Gepotidacin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90% CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 2: Cmax of Gepotidacin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90% CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 2: Lag Time Before Observation of Drug Concentrations (Tlag) of Gepotidacin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 2: Tmax of Gepotidacin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 2: AUC(0-t) of Gepotidacin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90% CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 2: AUC(0-infinity) of Gepotidacin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90 % CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 3: Cmax of Digoxin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of digoxin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90 % CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 24 Hours, 36 Hours, 48 Hours, 72 Hours, 96 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 3: Tlag of Digoxin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of digoxin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 24 Hours, 36 Hours, 48 Hours, 72 Hours, 96 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 3: Tmax of Digoxin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of digoxin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 24 Hours, 36 Hours, 48 Hours, 72 Hours, 96 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 3: AUC(0-t) of Digoxin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of digoxin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90 % CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 24 Hours, 36 Hours, 48 Hours, 72 Hours, 96 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 3: AUC(0-infinity) of Digoxin in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of digoxin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90 % CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 24 Hours, 36 Hours, 48 Hours, 72 Hours, 96 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 3: Cmax of Midazolam in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of midazolam was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90 % CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 3: Tlag of Midazolam in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of midazolam was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 3: Tmax of Midazolam in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of midazolam was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 3: AUC(0-t) of Midazolam in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of midazolam was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90 % CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 3: AUC(0-infinity) of Midazolam in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of midazolam was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90 % CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 4: Cmax of Gepotidacin Following Single Dose of 1500 mg in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours post-dose in each Treatment Periods 1 and 2

• Cohort 4: Tmax of Gepotidacin Following Single Dose of 1500 mg in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours post-dose in each Treatment Periods 1 and 2

• Cohort 4: Area Under the Concentration-time Curve From Time 0 (Pre-dose) to the Concentration at 24 Hours Post-dose (AUC[0-24]) of Gepotidacin Following Single Dose of 1500 mg in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours post-dose in each Treatment Periods 1 and 2

• Cohort 4: Area Under the Concentration-time Curve From Time 0 (Pre-dose) to the Concentration at 48 Hours Post-dose (AUC[0-48]) of Gepotidacin Following Single Dose of 1500 mg in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours post-dose in each Treatment Periods 1 and 2

• Cohort 4: AUC(0-t) of Gepotidacin Following Single Dose of 1500 mg in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours post-dose in each Treatment Periods 1 and 2

• Cohort 4: AUC(0-infinity) of Gepotidacin Following Single Dose of 1500 mg in Plasma

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours post-dose in each Treatment Periods 1 and 2

• Cohort 4: Cmax of Gepotidacin in Plasma After the First Dose of 3000 mg -Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24, 36, 48, 60 Hours post-dose in Treatment Period 3

• Cohort 4: Tmax of Gepotidacin in Plasma After the First Dose of 3000 mg -Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24, 36, 48, 60 Hours post-dose in Treatment Period 3

• Cohort 4: AUC From Time 0 (Predose) to Time Tau (AUC[0-tau]) of Gepotidacin in Plasma After the First Dose of 3000 Mg-Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24, 36, 48, 60 Hours post-dose in Treatment Period 3

• Cohort 4: Cmax of Gepotidacin in Plasma After the Second Dose of 3000 mg (Second Dose)-Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24, 36, 48, 60 Hours post-dose in Treatment Period 3

• Cohort 4: Tmax of Gepotidacin in Plasma After the Second Dose of 3000 mg (Second Dose)-Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24, 36, 48, 60 Hours post-dose in Treatment Period 3

• Cohort 4: AUC(0-tau) of Gepotidacin in Plasma After the Second Dose of 3000 mg (Evening Dose)-Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24, 36, 48, 60 Hours post-dose in Treatment Period 3

• Cohort 4: Accumulation Ratio Based on Cmax (RoCmax) of Gepotidacin in Plasma After the Second Dose of 3000 mg (Second Dose)-Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Accumulation ratio was calculated as Cmax after the second dose divided by Cmax after the first dose.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24, 36, 48, 60 Hours post-dose in Treatment Period 3

• Cohort 4: Accumulation Ratio Based on AUC(0-tau) (RoAUC) of Gepotidacin in Plasma After the Second Dose of 3000 mg (Second Dose)-Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Accumulation ratio was calculated as AUC(0-tau) after the second dose, where 0 is the timepoint prior to second dose, divided by AUC(0-tau) after the first dose, where 0 is the predose timepoint prior to the first dose.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24, 36, 48, 60 Hours post-dose in Treatment Period 3

• Cohort 4: AUC(0-24) of Gepotidacin in Plasma Following Two 3000 mg Doses (First Dose + Second Dose)-Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24 Hours post-dose in Treatment Period 3

• Cohort 4: AUC(0-48) of Gepotidacin in Plasma Following Two 3000 mg Doses (First Dose + Second Dose)-Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24, 36, 48 Hours post-dose in Treatment Period 3

• Cohort 4: AUC(0-t) of Gepotidacin in Plasma Following Two 3000 mg Doses (First Dose + Second Dose)-Fed State

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hours, 2 Hours 30 minutes, 3, 4, 6, 8, 12 Hours, 12 Hours 30 minutes, 13 Hours, 13 Hours 30 minutes, 14 Hours, 14 Hours 30 minutes, 15, 16, 18, 20, 24, 36, 48, 60 Hours post-dose in Treatment Period 3

• Cohort 4: Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events (Non-SAE)

  An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any serious adverse event that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or any other situations as per Medical or scientific judgment.

  Up to 22 days

• Cohort 4: Number of Participants With Worst Case Hematology Results Relative to Normal Range Post-Baseline Relative to Baseline

  Blood samples were collected at indicated time points for analysis of hematology parameters including Basophils, Eosinophils, Erythrocyte Mean Corpuscular Hemoglobin (MCH), Erythrocyte Mean Corpuscular Volume (MCV), Erythrocytes, Hematocrit, Hemoglobin, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets. Participants were counted in the worst case category that their value changes to (low, normal or high), unless there was no change in their category. Participants whose laboratory (lab) value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the 'To Normal or No Change' category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100 (%). High and low indicated that participants had values flagged as high and low respectively for the particular parameter any time on-treatment.

  Up to 22 days

• Cohort 4: Number of Participants With Worst Case Clinical Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline

  Blood samples were collected at indicated time points for analysis of clinical chemistry parameters including Alanine Aminotransferase (ALT), Albumin, Alkaline Phosphatase (Alk Phos), Aspartate Aminotransferase (AST), Bilirubin, Calcium, Carbon Dioxide, Chloride, Creatine Kinase, Creatinine, Direct Bilirubin, Glucose, Magnesium, Potassium, Protein, Sodium, Blood Urea Nitrogen (BUN). Participants were counted in the worst case category that their value changes to (low, normal or high), unless there was no change in their category. Participants whose lab value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the 'To Normal or No Change' category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%. High and low indicated that participants had values flagged as high and low respectively for the particular parameter any time on-treatment.

  Up to 22 days

• Cohort 4: Number of Participants With Worst Case Urinalysis Results Relative to Normal Range Post-Baseline Relative to Baseline

  Urine samples were collected at indicated time points for the analysis of urinalysis parameters including potential of hydrogen (pH) of urine, presence of glucose, protein, blood, ketones, bilirubin, nitrite, leukocyte esterase in urine by dipstick. Specific gravity of urine was measured by microscopic examination. Participants were counted in the worst case category that their value changes to (low, normal, high, or abnormal), unless there is no change in their category. Participants whose lab value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the 'To Normal or No Change' category. Participants were counted twice if the participant has values that changed 'To Low' and 'To High', so the percentages may not add to 100%. High and low indicated that participants had values flagged as high and low respectively for the particular parameter any time on-treatment.

  Up to 22 days

• Cohort 4: Number of Participants With Worst Case Vital Sign Results Relative to Normal Range Post-Baseline Relative to Baseline

  Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate were measured in a semi-supine position after 5 minutes rest. Participants were counted in the worst case category that their value changes to (low, normal or high), unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, were recorded in the 'To Normal or No Change' category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%. High and low indicated that participants had values flagged as high and low respectively for the particular parameter any time on-treatment.

  Up to 22 days

• Cohort 4: Number of Participants With Any Increase in Maximum Post-Baseline Electrocardiogram (ECG) Parameter Corrected QT (QTc) Interval

  A 12-lead ECG was recorded with the participant in a semi-supine position after a rest of at least 10 minutes using an ECG machine that automatically calculated the QTc interval. Number of participants with any increase of \>450 milliseconds in corrected QT interval using the Bazett formula (QTcB) Interval and corrected QT interval using the Fridericia formula (QTcF) Interval has been reported.

  Up to 22 days

• Cohort 4: Cmax of Gepotidacin Following Single Dose of 1500 mg in Plasma - Food Effect in Japanese Participants

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90 % CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours post-dose in each Treatment Periods 1 and 2

• Cohort 4: Tlag of Gepotidacin Following Single Dose of 1500 mg in Plasma - Food Effect in Japanese Participants

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours post-dose in each Treatment Periods 1 and 2

• Cohort 4: Tmax of Gepotidacin Following Single Dose of 1500 mg in Plasma - Food Effect in Japanese Participants

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours post-dose in each Treatment Periods 1 and 2

• Cohort 4: AUC(0-t) of Gepotidacin Following Single Dose of 1500 mg in Plasma - Food Effect in Japanese Participants

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90 % CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours post-dose in each Treatment Periods 1 and 2

• Cohort 4: AUC(0-infinity) of Gepotidacin Following Single Dose of 1500 mg in Plasma - Food Effect in Japanese Participants

  Blood samples were collected at indicated time points. Pharmacokinetic analysis of gepotidacin was conducted using standard non-compartmental analysis. Analysis was performed using a linear mixed-effect model with treatment as a fixed effect and participant as a random effect. Geometric LS mean and 90 % CI of the geometric LS means have been presented.

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours post-dose in each Treatment Periods 1 and 2

Secondary Outcomes (90)

• Cohort 1: AUC (0-24) of Gepotidacin in Plasma

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 1: AUC(0-48) of Gepotidacin in Plasma

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 1: Tlag of Gepotidacin in Plasma

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 1: Apparent Volume of Distribution (Vz/F) of Gepotidacin in Plasma

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

• Cohort 1: Apparent Oral Clearance (CL/F) of Gepotidacin in Plasma

  Pre-dose, 30 minutes, 1 Hour, 1 Hour 30 minutes, 2 Hour, 2 Hours 30 minutes, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours, 36 Hours, 48 Hours Post-dose in each Treatment Periods 1 and 2

Other Outcomes (1)

• Cohort 4: AUC(0-tau) of Gepotidacin Following Single Dose of 1500 mg Under Fed Condition in Urine

  Pre-dose, 0-2 Hours, 2-4 Hours, 4-6 Hours, 6-8 Hours, 8-12 Hours, 12-24 Hours, 24-36 Hours, 36-48 Hours post-dose in each Treatment Periods 1 and 2

Study Arms (7)

Cohort 1: Gepotidacin 1500 mg + Cimetidine 400 mg

EXPERIMENTAL

This is a fixed sequence (Sequence AB) cohort. Participants will receive gepotidacin 1500 milligrams (mg) single dose (SD) on Day 1 of Period 1 (Treatment A); and Cimetidine 400 mg 4 times daily on Days 1 through 4 of Period 2 and gepotidacin 1500 mg single dose (Treatment B). Gepotidacin will be administered 1 hour after the first dose of cimetidine on Day 2 of Period 2. There will be a washout of at least 3 days between Treatment A and Treatment B, and a follow-up visit 5 to 7 days after the last dose of cimetidine.

Drug: Gepotidacin; Drug: Cimetidine

Cohort 2: Gepotidacin 1500 mg + Rifampicin 600 mg

EXPERIMENTAL

This is a fixed sequence (Sequence CDE) cohort. Participants will receive gepotidacin 1500 mg single dose on Day 1 of Period 1 (Treatment C), rifampicin 600 mg (administered in the evenings) once daily for 7 days (Days 1 through 7 of Period 2, to elicit maximal enzyme induction) (Treatment D); and gepotidacin 1500 mg single dose administered in the morning on Day 8 and rifampicin 600 mg administered in the evening on Days 8 and 9 of Period 2 (Treatment E). There will be a washout of at least 3 days between Treatment C and Treatment D, and a follow-up visit 7 to 10 days after the last dose of rifampicin.

Drug: Gepotidacin; Drug: Rifampicin

Cohort 3: Digoxin 0.5mg+Midazolam 2mg then Gepotidacin 3000mg

EXPERIMENTAL

Participants will receive digoxin 0.5 mg and midazolam 2 mg (Treatment F) in Period 1 on Day 1 then gepotidacin two 3000 mg doses (given 12 hours apart) co-administered with digoxin 0.5 mg and midazolam 2 mg in Period 2 on Day 1, with the 2 probe drugs administered with the second daily dose of gepotidacin only (Treatment G). There will be a washout of at least 10 days between treatments. In Sequence 2, these regimens are reversed. A follow-up visit will occur 7 to 10 days after the last dose of study intervention in Period 2.

Drug: Gepotidacin; Drug: Midazolam; Drug: Digoxin

Cohort 3: Gepotidacin 3000mg then Digoxin 0.5mg+Midazolam 2mg

EXPERIMENTAL

Participants will receive gepotidacin two 3000 mg doses (given 12 hours apart) co-administered with digoxin 0.5 mg and midazolam 2 mg in Period 1 on Day 1, with the 2 probe drugs administered with the second daily dose of gepotidacin only (Treatment G) followed by digoxin 0.5 mg and midazolam 2 mg (Treatment F) in Period 2 on Day 1. A follow-up visit will occur 7 to 10 days after the last dose of study intervention in Period 2.

Drug: Gepotidacin; Drug: Midazolam; Drug: Digoxin

Cohort 4: Gepotidacin 1500 mg fed then fasted then 3000 mg fed

EXPERIMENTAL

Cohort 4 will include Japanese participants. Participants will receive a single dose of gepotidacin 1500 mg under fed conditions in Period 1 (Treatment H), then a single dose of gepotidacin 1500 mg under fasted conditions in Period 2 (Treatment I), followed by two doses of gepotidacin up to 3000 mg (given 12 hours apart) under fed conditions in Period 3 (Treatment J). There will be a washout of at least 3 days between each treatment, and a follow-up visit 5 to 7 days after the last dose of gepotidacin.

Drug: Gepotidacin

Cohort 4: Gepotidacin 1500 mg fasted then fed then 3000 mg fed

EXPERIMENTAL

Cohort 4 will include Japanese participants. Participants will receive a single dose of gepotidacin 1500 mg under fasted conditions in Period 1 (Treatment I), then a single dose of gepotidacin 1500 mg under fed conditions in Period 2 (Treatment H), followed by two doses of gepotidacin up to 3000 mg (given 12 hours apart) under fed conditions in Period 3 (Treatment J). There will be a washout of at least 3 days between each treatment, and a follow-up visit 5 to 7 days after the last dose of gepotidacin.

Drug: Gepotidacin

Cohort 4: Placebo fed then fasted then fed

PLACEBO COMPARATOR

Cohort 4 will include Japanese participants. Participants will receive a single dose of placebo under fed conditions in Period 1, then a single dose of placebo under fasted conditions in Period 2, followed by two doses of placebo (given 12 hours apart) under fed conditions in Period 3. There will be a washout of at least 3 days between each period, and a follow-up visit 5 to 7 days after the last dose of placebo.

Other: Placebo matching to gepotidacin

Interventions

Gepotidacin DRUG

Gepotidacin tablets will be available as unit dose strength 750 mg and will be administered orally.

Also known as: GSK2140944

Cohort 1: Gepotidacin 1500 mg + Cimetidine 400 mg; Cohort 2: Gepotidacin 1500 mg + Rifampicin 600 mg; Cohort 3: Digoxin 0.5mg+Midazolam 2mg then Gepotidacin 3000mg; Cohort 3: Gepotidacin 3000mg then Digoxin 0.5mg+Midazolam 2mg; Cohort 4: Gepotidacin 1500 mg fasted then fed then 3000 mg fed; Cohort 4: Gepotidacin 1500 mg fed then fasted then 3000 mg fed

Cimetidine DRUG

Cimetidine tablets will be available as unit dose strength 400 mg and will be administered orally.

Cohort 1: Gepotidacin 1500 mg + Cimetidine 400 mg

Rifampicin DRUG

Rifampicin Capsules will be available as unit dose strength 300 mg and will be administered orally.

Cohort 2: Gepotidacin 1500 mg + Rifampicin 600 mg

Midazolam DRUG

Midazolam oral syrup 2 milligrams per milliliter (mg/mL) will be available to be administered orally.

Cohort 3: Digoxin 0.5mg+Midazolam 2mg then Gepotidacin 3000mg; Cohort 3: Gepotidacin 3000mg then Digoxin 0.5mg+Midazolam 2mg

Digoxin DRUG

Digoxin tablets will be available as unit dose strength 0.25 mg and will be administered orally.

Cohort 3: Digoxin 0.5mg+Midazolam 2mg then Gepotidacin 3000mg; Cohort 3: Gepotidacin 3000mg then Digoxin 0.5mg+Midazolam 2mg

Placebo matching to gepotidacin OTHER

Placebo matching to gepotidacin tablets will be administered orally.

Cohort 4: Placebo fed then fasted then fed

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participant must be greater than or equal to (\>=) 18 to less than or equal to (=\<) 50 years of age inclusive, at the time of signing the informed consent.
• Participants who are healthy as determined by the investigator or medically qualified designee based on medical evaluation including medical history, physical examination, clinical laboratory tests, vital sign measurements, and 12-lead ECG results. A participant with 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.
• The participant has/had 2 Japanese parents and 4 Japanese grandparents who are/were all non-naturalized Japanese citizens, as confirmed by interview.
• The participant has been living outside of Japan for up to 10 years as confirmed by interview.
• Participants have a body weight \>=40 kilograms (kg) and body mass index within the range 18.5 to 32.0 kilograms per square meter (kg/m\^2) (inclusive).
• Male and/or female: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Female participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: Is a woman of non-childbearing potential or Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective, with a failure rate of \<1 percent (%), for at least 30 days prior to dosing until completion of the follow-up Visit. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) before the first dose of study intervention and for women not on effective contraception at least 14 days prior to baseline visit.
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.

You may not qualify if:

• Clinically significant abnormality in the past medical history or at the screening physical examination that in the investigator's opinion may place the participant at risk or interfere with the outcome variables of the study. This includes, but is not limited to, history or current cardiac, hepatic, renal, neurologic, gastro-intestinal (GI), respiratory, hematologic, or immunologic disease.
• Any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study intervention, or any other condition that may place the participant at risk, in the opinion of the investigator.
• Female participant has a positive pregnancy test result or is lactating at Screening or upon admission to the clinic.
• Positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Note: Testing will be performed according to site procedures.
• Within 2 months before Screening, either a confirmed history of Clostridium difficile (C. difficile) diarrhea infection or a past positive of C. 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 drug and/or alcohol abuse within 6 months before Screening, as determined by the investigator, or has a positive drug screen at Screening or upon admission to the clinic.
• History of sensitivity/hypersensitivity to any of the study drugs, components thereof, or a history of drug or other allergy that, in the opinion of the Investigator or GlaxoSmithKline (GSK) Medical Monitor contraindicates their participation.
• Cohort 2 Only: Participant is a contact lens wearer who is unable or unwilling to wear glasses for the duration of the study and for 5 half-lives after the last dose of rifampicin.
• Use of any systemic antibiotic within 30 days of screening.
• Participants must abstain from taking prescription or non-prescription drugs (except for hormonal contraceptives and/or acetaminophen at doses of \<=2 grams/day), vitamins, and dietary or herbal supplements, within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to study intervention until completion of the follow-up Visit, unless, in the opinion of the investigator and Sponsor, the medication will not interfere with the study. Any exceptions will be discussed with the Sponsor or Medical Monitor on a case-by-case basis and the reasons will be documented.
• Previous exposure to gepotidacin.
• Participant has participated in a clinical trial and has received an investigational product (IP) prior to gepotidacin administration within 30 days, 5 half-lives, or twice the duration of the biological effect of IP (whichever is longer).
• Past participation in this clinical study.
• Baseline corrected QT interval using the Fridericia formula (QTcF) of \>450 milliseconds (msec) at Screening or Check-in.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Las Vegas, Nevada, 89113, United States

Location

MeSH Terms

Conditions

Bacterial Infections

Interventions

gepotidacin; Cimetidine; Rifampin; Midazolam; Digoxin

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Guanidines; Amidines; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Glycosides; Carbohydrates

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: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Cohort 1 to 3 are open-label cohorts. Cohort 4 is a double-blind cohort which contains blinded treatment of gepotidacin and placebo.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Cohort 1 and 2 are open-label, fixed sequence DDI cohorts. Cohort 3 is an open-label, 2-sequence, 2-period crossover randomized DDI cohort. Cohort 4 is a double-blind, placebo-controlled, randomized sequence study to investigate the safety and PK of gepotidacin.

Study Record Dates

• First Submitted: July 28, 2020
• First Posted: July 30, 2020
• Study Start: August 14, 2020
• Primary Completion: December 21, 2020
• Study Completion: December 21, 2020
• Last Updated: March 4, 2022
• Results First Posted: March 4, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (1)