Safety, Tolerability and Pharmacokinetics (PKs) Investigation of GSK3186899 in Healthy Subjects

Phase 1

Terminated

Conditions: Leishmaniasis

Interventions: Drug: GSK3186899
Drug: Placebo

Registration Number: NCT03874234

Lead Sponsor: GlaxoSmithKline

Brief Summary: The purpose of this study is to evaluate the safety, tolerability and PK profile of single and repeat ascending doses of GSK3186899 in healthy subjects. This is a Phase 1 first time in human study, to investigate the effect of food on PK of GSK3186899. This study will consists of two parts. Part A (dose escalation phase) will be a single ascending, sequential cross-over design in cohorts 1, 2 and 3 of subjects. Cohort 1 and 2 will be 4-way cross-over which includes 4 dosing regimens of GSK3186899 and placebo (3:1 ratio) under fasted conditions. Cohort 3 will be 2-way cross-over which includes 2 treatment periods, 2 dosing regimens in fasted and fed conditions. In Part B (repeat dose escalation phase) subjects will be randomized to receive repeat doses of either GSK3186899 or placebo (3:1 ratio) in either fed or fasted conditions. Part B will be conducted based on the review of all safety, tolerability and PK data from Part A. The study duration includes screening, treatment periods and follow-up.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 25

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part A: Subjects receiving GSK3186899 + placebo in Cohort 2	GSK3186899	Subjects will receive 3 SAD of GSK3186899 and 1 dose of placebo as spray dried powder, under fasted conditions on Day 1 of cohort 2 in each of the four treatment periods. In each treatment period GSK3186899 and placebo will be administered in a 3:1 ratio. A wash out period of at least 10 days will be maintained between each treatment period.
Part A: Subjects receiving GSK3186899 + placebo in Cohort 1	Placebo	Subjects will receive 3 single ascending oral doses (SAD) of GSK3186899 and 1 dose of placebo as spray dried powder, under fasted conditions on Day 1 of cohort 1 in each of the four treatment periods. In each treatment period GSK3186899 and placebo will be administered in a 3:1 ratio. A wash out period of at least 10 days will be maintained between each treatment period.
Part A: Subjects receiving GSK3186899 + placebo in Cohort 2	Placebo	Subjects will receive 3 SAD of GSK3186899 and 1 dose of placebo as spray dried powder, under fasted conditions on Day 1 of cohort 2 in each of the four treatment periods. In each treatment period GSK3186899 and placebo will be administered in a 3:1 ratio. A wash out period of at least 10 days will be maintained between each treatment period.
Part A: Subjects receiving GSK3186899 + placebo in Cohort 1	GSK3186899	Subjects will receive 3 single ascending oral doses (SAD) of GSK3186899 and 1 dose of placebo as spray dried powder, under fasted conditions on Day 1 of cohort 1 in each of the four treatment periods. In each treatment period GSK3186899 and placebo will be administered in a 3:1 ratio. A wash out period of at least 10 days will be maintained between each treatment period.
Part B: Subjects receiving GSK3186899	GSK3186899	Subjects will receive GSK3186899, orally, twice daily (BID) on Days 1 to 10. Subjects will receive each dose after either fed or fasted conditions. Part B will be initiated based on the review of all safety, tolerability and PK data from Part A.
Part B: Subjects receiving placebo	Placebo	Subjects will receive placebo, orally, BID on Days 1 to 10. Subjects will receive each dose after either fed or fasted conditions. Part B will be initiated based on the review of all safety, tolerability and PK data from Part A.
Part A: Subjects receiving GSK3186899 in Cohort 3	GSK3186899	Subjects will receive GSK3186899 orally, under fasted condition and fed conditions on Day 1 of cohort 3 in each of the two treatment periods. There will be a wash out period of at least 10 days between each treatment period. A dose level will be determined based on the effect of food on the safety, tolerability and PK of a single dose of GSK3186899, with dose level selected from Cohorts 1 and 2.

Primary Outcome Measures

Name	Time	Method
Part A- Cohorts 1 and 2: Number of Participants With Worst-Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method	Up to Week 12	Urine samples were collected for analysis of occult blood, ketones and protein by a dipstick method. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine occult blood and protein can be read as negative, trace, 1+, 2+, 3+ indicating proportional concentrations in the urine sample. Any increase means any increase to trace, 1+, 2+ or 3+ post-Baseline relative to Baseline. Number of participants with worst case any increase in urinalysis results post-Baseline relative to Baseline has been presented.
Part A- Cohort 3: Number of Participants With Worst-Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method	Up to Week 9	Urine samples were planned to be collected to analyze urine parameters.
Part A- Cohort 3: Number of Participants With Non-SAEs and SAEs	Up to Week 9	An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above.
Part B: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline	Up to Week 9	Blood samples were planned to be collected to analyze chemistry parameters.
Part A- Cohort 3: Number of Participants Abnormal Cardiac Telemetry Findings	Up to 24 hours post-dose	Continuous cardiac telemetry was planned to be performed in a supine position after at least 5 minutes of rest.
Part A- Cohorts 1 and 2: Number of Participants With Worst Case Hematology Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline	Up to Week 12	PCI ranges were \<0.0 or \>0.1\10\^9 cells per(/)liter(L)(basophils), \<37 or \>50 proportion of red blood cells(RBC) in blood(hematocrit),\<130 or \>170 grams/L(hemoglobin\[Hb\]), \<1.2 or \>3.65\10\^9cells(c)/L (lymphocytes),\<0.2 or \>1\10\^9c/L(monocytes), \<2 or \>7.5\10\^9c/L(neutrophils), \<150 or \>400\10\^9 c/L(platelets), \<3.0 or \>10\10\^9c/L(white blood cell\[WBC\]count), \<4.4 or \>5.8\10\^12 c/L(RBC count), \<80 or \>99 femtoliter(mean corpuscular\[MC\] volume), \<26.0 or \>33.5 picogram(MC Hb), \<0.0 or \>0.4\10\^9 c/L(eosinophils). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became within range, were recorded in To within Range or No Change category.Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100 percentage(%).
Part A- Cohort 3: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline	Up to Week 9	Blood samples were planned to be collected to analyze chemistry parameters.
Part A- Cohorts 1 and 2: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline	Up to Week 12	Vital signs included systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. PCI ranges were, SBP (millimeters of mercury \[mmHg\]): \<85 (low) or \>160 (high), DBP (mmHg): \<45 (low) or \>100 (high), pulse rate (beats per minute): \<40 (low) or \>110 (high), respiration rate (breaths per minute): \<10(low) or \>25(high) and body temperature (degrees Celsius) \<35 (low) or \>38 (high). Participants were counted in the worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose vital signs value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the "To within Range 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%.
Part A- Cohorts 1 and 2: Number of Participants With Non-serious Adverse Events (Non-SAEs) and SAEs	Up to Week 12	An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above. Safety Population consisted of all randomized participants who received at least one dose of study treatment.
Part A- Cohorts 1 and 2: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline	Up to Week 12	PCI ranges were \<34 or \>50 grams/L(albumin),\<40 or \>129 international units/L\[IU/L\](alkaline phosphatase),\<10 or \>50 IU/L(alanine aminotransferase),\<0 or \>37(aspartate aminotransferase), \<0 or \>20 micromoles(mcmol)/L (direct bilirubin),\<0 or \>20 mcmol/L(bilirubin), \<2.2 or \>2.6 millimoles/L(mmol/L)(calcium),\<66 or \>112 upper limit of normal mmol/L(creatinine), \<3.5 or \>5.1 mmol/L (potassium),\<0.6 or \>1 mmol/L (magnesium),\<0.87 or \>1.45mmol/L (phosphate),\<63 or \>83 g/L (protein),\<135 or \>145 mmol/L (sodium), \<0.0 or \>5.0 mg/L (C-reactive protein). Participants were counted in worst case category that their value changes to(low, within range \[WR\] or no change\[NC\] or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g. High to High) or whose value became WR, were recorded in To WR or NC category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.
Part A- Cohort 3: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings	Up to Week 9	Twelve lead ECGs were planned to be performed to measure PR interval, QRS duration, QT interval and corrected QT intervals.
Part B: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline	Up to Week 9	Vital signs were planned to be measured in a semi-supine position after 5 minutes of rest.
Part B: Number of Participants With Non-SAEs and SAEs	Up to Week 9	An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above.
Part A- Cohort 3: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline	Up to Week 9	Blood samples were planned to be collected to analyze hematology parameters.
Part B: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline	Up to Week 9	Blood samples were planned to be collected to analyze hematology parameters.
Part B: Number of Participants With Worst-Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method	Up to Week 9	Urine samples were planned to be collected to analyze urine parameters.
Part A- Cohorts 1 and 2: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings	Up to Week 12	Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT intervals. Abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.
Part A- Cohort 3: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline	Up to Week 9	Vital signs were planned to be measured in a semi-supine position after 5 minutes of rest.
Part A- Cohorts 1 and 2: Number of Participants With Abnormal Cardiac Telemetry Findings	Up to 24 hours post-dose	Continuous cardiac telemetry was performed in a supine position after at least 5 minutes of rest. Abnormal findings were categorized as CS and not NCS. Clinically significant abnormal findings were those which were not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
Part B: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings	Up to Week 9	Twelve lead ECGs were planned to be performed to measure PR interval, QRS duration, QT interval and corrected QT intervals.
Part B: Number of Participants Abnormal Cardiac Telemetry Findings	Up to 24 hours post-dose	Continuous cardiac telemetry was planned to be performed in a supine position after at least 5 minutes of rest.

Secondary Outcome Measures

Name	Time	Method
Part A- Cohort 3: AUC(0-infinity) After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohorts 1 and 2: Trough Plasma Concentration (Ctau) After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part B: AUC(0-t) After Repeat Dose Administration of GSK3186899	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part B: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval (AUC[0-tau]) After Repeat Dose Administration of GSK3186899	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part B: Dose-proportionality of GSK3186899 Administered as Repeat Dose Based on Ctau	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose	Blood samples were planned to be collected at indicated time points for PK analysis.
Part B: Time Invariance Ratio of GSK3186899 After Repeat Dose Administration Using AUC	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose	Blood samples were planned to be collected at indicated time points for PK analysis. Time-invariance ratio was planned to be calculated as AUC(0-12) on Day 10 to AUC(0-infinity) on Day 1.
Part A- Cohort 3: Plasma Concentration After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohorts 1 and 2: Time to Maximum Observed Plasma Drug Concentration (Tmax) After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohort 3: Predicted Accumulation Ratio After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part B: AUC(0-infinity) After Repeat Dose Administration of GSK3186899	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohort 3: AUC(0-t) After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohorts 1 and 2: Area Under the Plasma Concentration-time Curve From Time 0 to Extrapolated to Infinity (AUC[0-infinity]) After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohorts 1 and 2: Maximum Observed Plasma Drug Concentration (Cmax) After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohorts 1 and 2: Predicted Accumulation Ratio After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were collected at indicated time points for PK analysis of GSK3186899. Predicted accumulation ratio is calculated as 1/(1-e\^\[k\*tau\]) where k is elimination rate constant following the single dose and tau is the dosing interval for the intended repeat dosing.
Part B: Tmax After Repeat Dose Administration of GSK3186899	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohort 3: T1/2 After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohort 3: Dose-proportionality of GSK3186899 Administered as Single Dose Based on AUC(0-infinity)	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis.
Part B: Relative Accumulation Ratio of GSK3186899 After Repeat Dose Administration by Ctau	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose	Blood samples were planned to be collected at indicated time points for PK analysis. Accumulation ratio was planned to be calculated as ratio of Ctau at Day 10 to Ctau at Day 1.
Part A- Cohorts 1 and 2: Plasma Concentration After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK3186899. PK Population consisted of all participants in the Safety Population who received at least 1 non-missing PK assessment.
Part A- Cohorts 1 and 2: Area Under the Plasma Concentration-time Curve From Time 0 to Last Time of Quantifiable Concentration (AUC[0-t]) After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohort 3: Cmax After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohort 3: Tmax After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohort 3: Ctau After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohorts 1 and 2: Apparent Terminal Half-life (T1/2) After Single Dose Administration of GSK3186899	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were collected at indicated time points for PK analysis of GSK3186899.
Part B: Plasma Concentration After Repeat Dose Administration of GSK3186899	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohorts 1 and 2: Dose-proportionality of GSK3186899 Administered as Single Dose Based on AUC(0-infinity)	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were collected at indicated time points for PK analysis. Dose proportionality was assessed using Power model with fixed effects of logarithm of treatment and participant as random effect. Slope and 90% confidence interval for the slope are presented.
Part A- Cohorts 1 and 2: Dose-proportionality of GSK3186899 Administered as Single Dose Based on Cmax	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were collected at indicated time points for PK analysis. Dose proportionality was assessed using Power model with fixed effects of logarithm of treatment and participant as random effect. Slope and 90% confidence interval for the slope are presented.
Part B: Dose-proportionality of GSK3186899 Administered as Repeat Dose Based on AUC(0-tau)	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose	Blood samples were planned to be collected at indicated time points for PK analysis.
Part B: Cmax After Repeat Dose Administration of GSK3186899	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part B: T1/2 After Repeat Dose Administration of GSK3186899	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose	Blood samples were planned to be collected at indicated time points for PK analysis of GSK3186899.
Part A- Cohort 3: Dose-proportionality of GSK3186899 Administered as Single Dose Based on Cmax	Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period	Blood samples were planned to be collected at indicated time points for PK analysis.
Part B: Dose-proportionality of GSK3186899 Administered as Repeat Dose Based on Cmax	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose; Days 2 to 9: Pre-dose	Blood samples were planned to be collected at indicated time points for PK analysis.
Part B: Relative Accumulation Ratio of GSK3186899 After Repeat Dose Administration by AUC(0-tau)	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose	Blood samples were planned to be collected at indicated time points for PK analysis. Accumulation ratio was planned to be calculated as ratio of AUC(0-tau) at Day 10 to AUC(0-tau) at Day 1.
Part B: Relative Accumulation Ratio of GSK3186899 After Repeat Dose Administration by Cmax	Days 1 and 10: Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours post-dose	Blood samples were planned to be collected at indicated time points for PK analysis. Accumulation ratio was planned to be calculated as ratio of Cmax at Day 10 to Cmax at Day 1.