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Evaluation of Pharmacokinetic Interaction Between GSK3640254 and Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, Midazolam, Digoxin, and Pravastatin in Healthy Adults

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ClinicalTrials.gov Identifier: NCT04425902
Recruitment Status : Completed
First Posted : June 11, 2020
Results First Posted : May 23, 2022
Last Update Posted : May 23, 2022
Sponsor:
Information provided by (Responsible Party):
ViiV Healthcare

Brief Summary:
This is an open-label, single sequence study that is being conducted to investigate the potential drug-drug interaction (DDI) when GSK3640254 is co-administered with a cocktail of cytochrome P450 (CYP) enzymes and transporter probe substrates in healthy participants. This study will aid in understanding these interactions and resulting changes in exposure (if any) when drugs that are metabolized via these pathways are given in combination with GSK3640254. The study will consist of a Screening period and 3 sequential treatment regimens. Participants will be administered a single dose of probe substrate drugs (caffeine 200 milligram (mg), metoprolol 100 mg, montelukast 10 mg, flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg and pravastatin 40 mg) on Day 1. Participants will then receive GSK3640254 200 mg once daily on Days 11 to 20 followed by co-administration of probe substrate drugs with GSK3640254 on Day 21.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: GSK3640254 200 mg Drug: Caffeine 200 mg Drug: Metoprolol 100 mg Drug: Montelukast 10 mg Drug: Flurbiprofen 100 mg Drug: Omeprazole 40 mg Drug: Midazolam 5 mg (2.5 mL) Drug: Digoxin 0.25 mg Drug: Pravastatin 40 mg Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This is a single-sequence, one-way drug interaction study.
Masking: None (Open Label)
Masking Description: This is a single-group, single-arm study that has no masking.
Primary Purpose: Treatment
Official Title: Effects of GSK3640254 on the Single-Dose Pharmacokinetics of Probe Substrates (Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, Midazolam, Digoxin, and Pravastatin) in Healthy Subjects
Actual Study Start Date : December 16, 2020
Actual Primary Completion Date : March 10, 2021
Actual Study Completion Date : March 10, 2021


Arm Intervention/treatment
Experimental: Probe Substrates/GSK3640254 200 mg/Probe Substrates+GSK3640254
All participants will receive a single dose of treatment A: Probe substrates (caffeine 200 milligram [mg], metoprolol 100 mg, montelukast 10 mg, flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg) on Day 1; followed by treatment B- GSK3640254 200 mg on Days 11 to 20; further followed by treatment C: Probe substrates (Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg) co-administered with GSK3640254 200 mg on Day 21.
Drug: GSK3640254 200 mg
GSK3640254 will be available as oral tablets at unit dose strength of 100 mg.

Drug: Caffeine 200 mg
Caffeine will be available as oral tablets at unit dose strength of 200 mg.

Drug: Metoprolol 100 mg
Metoprolol will be available as oral tablets at unit dose strength of 100 mg.

Drug: Montelukast 10 mg
Montelukast will be available as oral tablets at unit dose strength of 10 mg.

Drug: Flurbiprofen 100 mg
Flurbiprofen will be available as oral tablets at unit dose strength of 100 mg.

Drug: Omeprazole 40 mg
Omeprazole will be available as oral capsules at unit dose strength of 40 mg.

Drug: Midazolam 5 mg (2.5 mL)
Midazolam will be available as syrup for oral administration at unit dose strength of 2 milligram per milliliter (mg/mL).

Drug: Digoxin 0.25 mg
Digoxin will be available as oral tablet at unit dose strength of 0.25 mg.

Drug: Pravastatin 40 mg
Pravastatin will be available as oral tablet at unit dose strength of 40 mg.




Primary Outcome Measures :
  1. Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Time t (AUC[0-t]) for Caffeine [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of caffeine. Area under the plasma concentration-time curve from time zero to time t, to be calculated using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  2. AUC From Time Zero Extrapolated to Infinity (AUC[0-infinity]) for Caffeine [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of caffeine. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  3. Maximum Observed Plasma Concentration (Cmax) for Caffeine [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of caffeine.

  4. Time to Cmax (Tmax) for Caffeine [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of caffeine.

  5. Apparent Terminal Phase Half-life (t1/2) for Caffeine [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of caffeine.

  6. AUC(0-t) for Metoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of metoprolol. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  7. AUC(0-infinity) for Metoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of metoprolol. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  8. Cmax for Metoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of metoprolol.

  9. Tmax for Metoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of metoprolol.

  10. t1/2 for Metoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of metoprolol.

  11. AUC(0-t) for Montelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of montelukast. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  12. AUC(0-infinity) for Montelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of montelukast. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  13. Cmax for Montelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of montelukast.

  14. Tmax for Montelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of montelukast.

  15. t1/2 for Montelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of montelukast.

  16. AUC(0-t) for Flurbiprofen [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of flurbiprofen. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  17. AUC(0-infinity) for Flurbiprofen [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of flurbiprofen. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  18. Cmax for Flurbiprofen [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of flurbiprofen.

  19. Tmax for Flurbiprofen [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of flurbiprofen.

  20. t1/2 for Flurbiprofen [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of flurbiprofen.

  21. AUC(0-t) for Omeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of omeprazole. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  22. AUC(0-infinity) for Omeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of omeprazole. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  23. Cmax for Omeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of omeprazole.

  24. Tmax for Omeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of omeprazole.

  25. t1/2 for Omeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of omeprazole.

  26. AUC(0-t) for Midazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of midazolam. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  27. AUC(0-infinity) for Midazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of midazolam. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  28. Cmax for Midazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of midazolam.

  29. Tmax for Midazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of midazolam.

  30. t1/2 for Midazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of midazolam.

  31. AUC(0-t) for Digoxin [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of digoxin. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  32. AUC(0-infinity) for Digoxin [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of digoxin. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  33. Cmax for Digoxin [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of digoxin.

  34. Tmax for Digoxin [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of digoxin.

  35. t1/2 for Digoxin [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of digoxin.

  36. AUC(0-t) for Pravastatin [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of pravastatin. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  37. AUC(0-infinity) for Pravastatin [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of pravastatin. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  38. Cmax for Pravastatin [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of pravastatin.

  39. Tmax for Pravastatin [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of pravastatin.

  40. t1/2 for Pravastatin [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of pravastatin.


Secondary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Day 26 ]
    An 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. SAE was defined as any untoward medical occurrence that, at any dose, results in death, was life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect and other situations according to medical or scientific judgement.

  2. Treatment A: Absolute Values of Platelet Count, Leukocyte Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameters: platelet count, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  3. Treatment B: Absolute Values of Platelet Count, Leukocyte Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameters: platelet count, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  4. Treatment C: Absolute Values of Platelet Count, Leukocyte Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameters: platelet count, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  5. Treatment A: Absolute Values of Hematocrit [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  6. Treatment B: Absolute Values of Hematocrit [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  7. Treatment C: Absolute Values of Hematocrit [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  8. Treatment A: Absolute Values of Hemoglobin [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  9. Treatment B: Absolute Values of Hemoglobin [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  10. Treatment C: Absolute Values of Hemoglobin [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  11. Treatment A: Absolute Values of Erythrocytes [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  12. Treatment B: Absolute Values of Erythrocytes [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  13. Treatment C: Absolute Values of Erythrocytes [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  14. Treatment A: Absolute Values of Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  15. Treatment B: Absolute Values of Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  16. Treatment C: Absolute Values of Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  17. Treatment A: Absolute Values of Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  18. Treatment B: Absolute Values of Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  19. Treatment C: Absolute Values of Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  20. Treatment A: Absolute Values of Glucose, Carbon Dioxide, Cholesterol, Triglycerides, Anion Gap, Calcium, Chloride, Phosphate, Potassium, Sodium, Urea [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, carbon dioxide, cholesterol, triglycerides, anion gap, calcium, chloride, phosphate, potassium, sodium, urea. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  21. Treatment B: Absolute Values of Glucose, Carbon Dioxide, Cholesterol, Triglycerides, Anion Gap, Calcium, Chloride, Phosphate, Potassium, Sodium, Urea [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, carbon dioxide, cholesterol, triglycerides, anion gap, calcium, chloride, phosphate, potassium, sodium, and urea. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  22. Treatment C: Absolute Values of Glucose, Carbon Dioxide, Cholesterol, Triglycerides, Anion Gap, Calcium, Chloride, Phosphate, Potassium, Sodium, Urea [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, carbon dioxide, cholesterol, triglycerides, anion gap, calcium, chloride, phosphate, potassium, sodium and urea. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  23. Treatment A: Absolute Values of Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  24. Treatment B: Absolute Values of Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  25. Treatment C: Absolute Values of Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  26. Treatment A: Absolute Values of Albumin, Globulin, Protein [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  27. Treatment B: Absolute Values of Albumin, Globulin, Protein [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  28. Treatment C: Absolute Values of Albumin, Globulin, Protein [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  29. Treatment A: Absolute Values of Creatine Kinase, Lactate Dehydrogenase, Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Gamma-glutamyl Transferase [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  30. Treatment B: Absolute Values of Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST, and gamma-glutamyl transferase. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  31. Treatment C: Absolute Values of Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST, gamma-glutamyl transferase. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  32. Treatment A: Absolute Values of Amylase, Lipase [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A.

  33. Treatment B: Absolute Values of Amylase, Lipase [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B.

  34. Treatment C: Absolute Values of Amylase, Lipase [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C.

  35. Treatment A: Change From Baseline in Platelet Count, Leukocyte Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameters: platelet count, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  36. Treatment B: Change From Baseline in Platelet Count, Leukocyte Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameters: platelet count, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  37. Treatment C: Change From Baseline in Platelet Count, Leukocyte Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameters: platelet count, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  38. Treatment A: Change From Baseline in Hematocrit [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  39. Treatment B: Change From Baseline in Hematocrit [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  40. Treatment C: Change From Baseline in Hematocrit [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  41. Treatment A: Change From Baseline in Hemoglobin [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  42. Treatment B: Change From Baseline in Hemoglobin [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  43. Treatment C: Change From Baseline in Hemoglobin [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameter: hemoglobin. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  44. Treatment A: Change From Baseline in Erythrocytes [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  45. Treatment B: Change From Baseline in Erythrocytes [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  46. Treatment C: Change From Baseline in Erythrocytes [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  47. Treatment A: Change From Baseline in Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  48. Treatment B: Change From Baseline in Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  49. Treatment C: Change From Baseline in Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular volume. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  50. Treatment A: Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  51. Treatment B: Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  52. Treatment C: Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  53. Treatment A: Change From Baseline in Glucose, Carbon Dioxide, Cholesterol, Triglycerides, Anion Gap, Calcium, Chloride, Phosphate, Potassium, Sodium, Urea [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, carbon dioxide, cholesterol, triglycerides, anion gap, calcium, chloride, phosphate, potassium, sodium, and urea. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  54. Treatment B: Change From Baseline in Glucose, Carbon Dioxide, Cholesterol, Triglycerides, Anion Gap, Calcium, Chloride, Phosphate, Potassium, Sodium, Urea [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, carbon dioxide, cholesterol, triglycerides, anion gap, calcium, chloride, phosphate, potassium, sodium, and urea. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  55. Treatment C: Change From Baseline in Glucose, Carbon Dioxide, Cholesterol, Triglycerides, Anion Gap, Calcium, Chloride, Phosphate, Potassium, Sodium, Urea [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the chemistry parameters: glucose, carbon dioxide, cholesterol, triglycerides, anion gap, calcium, chloride, phosphate, potassium, sodium and urea. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  56. Treatment A: Change From Baseline in Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  57. Treatment B: Change From Baseline in Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  58. Treatment C: Change From Baseline in Urate, Creatinine, Bilirubin, Direct Bilirubin [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the chemistry parameters: urate, creatinine, bilirubin and direct bilirubin. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  59. Treatment A: Change From Baseline in Albumin, Globulin, Protein [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  60. Treatment B: Change From Baseline in Albumin, Globulin, Protein [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  61. Treatment C: Change From Baseline in Albumin, Globulin, Protein [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the chemistry parameters: albumin, globulin and protein. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  62. Treatment A: Change From Baseline in Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST and gamma-glutamyl transferase. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  63. Treatment B: Change From Baseline in Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST, and gamma-glutamyl transferase. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  64. Treatment C: Change From Baseline in Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST, Gamma-glutamyl Transferase [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the chemistry parameters: creatine kinase, lactate dehydrogenase, ALT, ALP, AST, gamma-glutamyl transferase. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  65. Treatment A: Change From Baseline in Amylase, Lipase [ Time Frame: Baseline (Day -1) and Day 10 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day -1), before the dose of Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  66. Treatment B: Change From Baseline in Amylase, Lipase [ Time Frame: Baseline (Day 10) and Day 20 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 10), before the first dose of Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  67. Treatment C: Change From Baseline in Amylase, Lipase [ Time Frame: Baseline (Day 20), Days 22 and 25 ]
    Blood samples were collected to analyze the chemistry parameters: amylase and lipase. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 20), before the dose of Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  68. Treatment A: Absolute Values for Electrocardiogram (ECG) Parameters: PR Interval, QRS Duration, QT Interval, Corrected QT Interval Using Fridericia's Formula (QTcF) [ Time Frame: Baseline (Day 1, Pre-Dose) and Day 10 ]
    Twelve-lead ECGs were obtained to measure PR Interval, QRS Duration, QT Interval and QTcF Interval. Twelve-lead ECGs were performed with the participant in a supine position after a rest of at least 10 minutes. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 1, Pre-Dose), before the dose in Treatment A.

  69. Treatment B: Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF Interval [ Time Frame: Baseline (Day 11, Pre-Dose) and Day 20 ]
    Twelve-lead ECGs were obtained to measure PR Interval, QRS Duration, QT Interval and QTcF Interval. Twelve-lead ECGs were performed with the participant in a supine position after a rest of at least 10 minutes. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 11, Pre-Dose), before the first dose in Treatment B.

  70. Treatment C: Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF Interval [ Time Frame: Baseline (Day 21, Pre-Dose), Days 22 and 25 ]
    Twelve-lead ECGs were obtained to measure PR Interval, QRS Duration, QT Interval and QTcF Interval. Twelve-lead ECGs were performed with the participant in a supine position after a rest of at least 10 minutes. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 21, Pre-Dose), before the first dose in Treatment C.

  71. Treatment A: Change From Baseline in ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF [ Time Frame: Baseline (Day 1, Pre-dose) and Day 10 ]
    Twelve-lead ECGs were obtained to measure PR Interval, QRS Duration, QT Interval and QTcF Interval. Twelve-lead ECGs were performed with the participant in a supine position after a rest of at least 10 minutes. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 1, Pre-Dose), before the dose in Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  72. Treatment B: Change From Baseline in ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF [ Time Frame: Baseline (Day 11, Pre-Dose) and Day 20 ]
    Twelve-lead ECGs were obtained to measure PR Interval, QRS Duration, QT Interval and QTcF Interval. Twelve-lead ECGs were performed with the participant in a supine position after a rest of at least 10 minutes. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 11, Pre-Dose), before the first dose in Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  73. Treatment C: Change From Baseline in ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF [ Time Frame: Baseline (Day 21, Pre-Dose), Days 22 and 25 ]
    Twelve-lead ECGs were obtained to measure PR Interval, QRS Duration, QT Interval and QTcF Interval. Twelve-lead ECGs were performed with the participant in a supine position after a rest of at least 10 minutes. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 21, Pre-Dose), before the first dose in Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  74. Treatment A: Absolute Values of Oral Temperature [ Time Frame: Baseline (Day 1, Pre-dose) and Day 10 ]
    Oral temperature was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 1, Pre-Dose), before the dose in Treatment A.

  75. Treatment B: Absolute Values of Oral Temperature [ Time Frame: Baseline (Day 11, Pre-Dose) and Day 20 ]
    Oral temperature was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 11, Pre-Dose), before the first dose in Treatment B.

  76. Treatment C: Absolute Values of Oral Temperature [ Time Frame: Baseline (Day 21, Pre-Dose), Days 22 and 25 ]
    Oral temperature was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 21, Pre-Dose), before the first dose in Treatment C.

  77. Treatment A: Absolute Values of Pulse Rate [ Time Frame: Baseline (Day 1, Pre-dose) and Day 10 ]
    Pulse rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 1, Pre-Dose), before the dose in Treatment A.

  78. Treatment B: Absolute Values of Pulse Rate [ Time Frame: Baseline (Day 11, Pre-Dose) and Day 20 ]
    Pulse rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 11, Pre-Dose), before the first dose in Treatment B.

  79. Treatment C: Absolute Values of Pulse Rate [ Time Frame: Baseline (Day 21, Pre-Dose), Days 22 and 25 ]
    Pulse rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 21, Pre-Dose), before the first dose in Treatment C.

  80. Treatment A: Absolute Values of Respiratory Rate [ Time Frame: Baseline (Day 1, Pre-dose) and Day 2 ]
    Respiratory rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 1, Pre-Dose), before the dose in Treatment A.

  81. Treatment B: Absolute Values of Respiratory Rate [ Time Frame: Baseline (Day 11, Pre-Dose) and Day 20 ]
    Respiratory rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 11, Pre-Dose), before the first dose in Treatment B.

  82. Treatment C: Absolute Values of Respiratory Rate [ Time Frame: Baseline (Day 21, Pre-Dose), Days 22 and 25 ]
    Respiratory rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 21, Pre-Dose), before the first dose in Treatment C.

  83. Treatment A: Absolute Values of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Baseline (Day 1, Pre-dose) and Day 10 ]
    SBP and DBP were measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 1, Pre-Dose), before the dose in Treatment A.

  84. Treatment B: Absolute Values of SBP and DBP [ Time Frame: Baseline (Day 11, Pre-Dose) and Day 20 ]
    SBP and DBP were measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 11, Pre-Dose), before the first dose in Treatment B.

  85. Treatment C: Absolute Values of SBP and DBP [ Time Frame: Baseline (Day 21, Pre-Dose), Days 22 and 25 ]
    SBP and DBP were measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 21, Pre-Dose), before the first dose in Treatment C.

  86. Treatment A: Change From Baseline in Oral Temperature [ Time Frame: Baseline (Day 1, Pre-dose) and Day 10 ]
    Oral temperature was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 1, Pre-Dose), before the dose in Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  87. Treatment B: Change From Baseline in Oral Temperature [ Time Frame: Baseline (Day 11, Pre-Dose) and Day 20 ]
    Oral temperature was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 11, Pre-Dose), before the first dose in Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  88. Treatment C: Change From Baseline in Oral Temperature [ Time Frame: Baseline (Day 21, Pre-Dose), Days 22 and 25 ]
    Oral temperature was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 21, Pre-Dose), before the first dose in Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  89. Treatment A: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 1, Pre-dose) and Day 10 ]
    Pulse rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 1, Pre-Dose), before the dose in Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  90. Treatment B: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 11, Pre-Dose) and Day 20 ]
    Pulse rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 11, Pre-Dose), before the first dose in Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  91. Treatment C: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 21, Pre-Dose), Days 22 and 25 ]
    Pulse rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 21, Pre-Dose), before the first dose in Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  92. Treatment A: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 1, Pre-dose) and Day 2 ]
    Respiratory rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 1, Pre-Dose), before the dose in Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  93. Treatment B: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 11, Pre-Dose) and Day 20 ]
    Respiratory rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 11, Pre-Dose), before the first dose in Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  94. Treatment C: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 21, Pre-Dose), Days 22 and 25 ]
    Respiratory rate was measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 21, Pre-Dose), before the first dose in Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  95. Treatment A: Change From Baseline in SBP and DBP [ Time Frame: Baseline (Day 1, Pre-dose) and Day 10 ]
    SBP and DBP were measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment A was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 1, Pre-Dose), before the dose in Treatment A. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  96. Treatment B: Change From Baseline in SBP and DBP [ Time Frame: Baseline (Day 11, Pre-Dose) and Day 20 ]
    SBP and DBP were measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment B was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 11, Pre-Dose), before the first dose in Treatment B. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  97. Treatment C: Change From Baseline in SBP and DBP [ Time Frame: Baseline (Day 21, Pre-Dose), Days 22 and 25 ]
    SBP and DBP were measured in the supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline for treatment C was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits (Day 21, Pre-Dose), before the first dose in Treatment C. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

  98. Treatment C: AUC(0-t) for GSK3640254 [ Time Frame: Pre-dose and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose in treatment period 3 ]
    Blood samples were collected at the indicated time points for steady-state pharmacokinetic analysis of GSK3640254. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  99. Treatment C: AUC From Time Zero to the End of the Dosing Interval at Steady State (AUC[0-tau]) for GSK3640254 [ Time Frame: Pre-dose and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose in treatment period 3 ]
    Blood samples were collected at the indicated time points for steady-state pharmacokinetic analysis of GSK3640254.

  100. Treatment C: Cmax for GSK3640254 [ Time Frame: Pre-dose and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose in treatment period 3 ]
    Blood samples were collected at the indicated time points for steady-state pharmacokinetic analysis of GSK3640254.

  101. Treatment C: Plasma Concentration at the End of the Dosing Interval (Ctau) for GSK3640254 [ Time Frame: Pre-dose and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose in treatment period 3 ]
    Blood samples were collected at the indicated time points for steady-state pharmacokinetic analysis of GSK3640254.

  102. Treatment C: Tmax for GSK3640254 [ Time Frame: Pre-dose and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose in treatment period 3 ]
    Blood samples were collected at the indicated time points for steady-state pharmacokinetic analysis of GSK3640254.

  103. Treatment C: t1/2 for GSK3640254 [ Time Frame: Pre-dose and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, 48, 72, 96, and 120 hours post-dose in treatment period 3 ]
    Blood samples were collected at the indicated time points for steady-state pharmacokinetic analysis of GSK3640254.

  104. AUC(0-t) for Alpha-hydroxymetoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of alpha-hydroxymetoprolol. Alpha-hydroxymetoprolol is a metabolite of metoprolol. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  105. AUC(0-infinity) for Alpha-hydroxymetoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of alpha-hydroxymetoprolol. Alpha-hydroxymetoprolol is a metabolite of metoprolol. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  106. Cmax for Alpha-hydroxymetoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of alpha-hydroxymetoprolol. Alpha-hydroxymetoprolol is a metabolite of metoprolol.

  107. Tmax for Alpha-hydroxymetoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of alpha-hydroxymetoprolol. Alpha-hydroxymetoprolol is a metabolite of metoprolol.

  108. t1/2 for Alpha-hydroxymetoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of alpha-hydroxymetoprolol. Alpha-hydroxymetoprolol is a metabolite of metoprolol.

  109. AUC(0-t) for 36-hydroxymontelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 36-hydroxymontelukas. 36-hydroxymontelukast is a metabolite of montelukast. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  110. AUC(0-infinity) for 36-hydroxymontelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 36-hydroxymontelukast. 36-hydroxymontelukast is a metabolite of montelukast. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  111. Cmax for 36-hydroxymontelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 36-hydroxymontelukast. 36-hydroxymontelukast is a metabolite of montelukast.

  112. Tmax for 36-hydroxymontelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 36-hydroxymontelukast. 36-hydroxymontelukast is a metabolite of montelukast.

  113. t1/2 for 36-hydroxymontelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 36-hydroxymontelukast. 36-hydroxymontelukast is a metabolite of montelukast.

  114. AUC(0-t) for 5-hydroxyomeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 5-hydroxyomeprazole. 5-hydroxyomeprazole is a metabolite of omeprazole. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  115. AUC(0-infinity) for 5-hydroxyomeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 5-hydroxyomeprazole. 5-hydroxyomeprazole is a metabolite of omeprazole. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  116. Cmax for 5-hydroxyomeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 5-hydroxyomeprazole. 5-hydroxyomeprazole is a metabolite of omeprazole.

  117. Tmax for 5-hydroxyomeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 5-hydroxyomeprazole. 5-hydroxyomeprazole is a metabolite of omeprazole.

  118. t1/2 for 5-hydroxyomeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 5-hydroxyomeprazole. 5-hydroxyomeprazole is a metabolite of omeprazole.

  119. AUC(0-t) for 1-hydroxymidazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 1-hydroxymidazolam. 1-hydroxymidazolam is a metabolite of midazolam. The AUC(0-t) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  120. AUC(0-infinity) for 1-hydroxymidazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 1-hydroxymidazolam. 1-hydroxymidazolam is a metabolite of midazolam. The AUC(0-infinity) was determined using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

  121. Cmax for 1-hydroxymidazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 1-hydroxymidazolam. 1-hydroxymidazolam is a metabolite of midazolam.

  122. Tmax for 1-hydroxymidazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 1-hydroxymidazolam. 1-hydroxymidazolam is a metabolite of midazolam.

  123. t1/2 for 1-hydroxymidazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of 1-hydroxymidazolam. 1-hydroxymidazolam is a metabolite of midazolam.

  124. Ratio of Cmax of Alpha-hydroxymetoprolol to Metoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of parent drug (metoprolol) and its metabolite (alpha-hydroxymetoprolol). Ratio of Cmax of metabolite to parent drug has been presented.

  125. Ratio of AUC(0-infinity) of Alpha-hydroxymetoprolol to Metoprolol [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of parent drug (metoprolol) and its metabolite (alpha-hydroxymetoprolol). Ratio of AUC(0-infinity) of metabolite to parent drug has been presented.

  126. Ratio of Cmax of 36-hydroxymontelukast to Montelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of parent drug (montelukast) and its metabolite (36-hydroxymontelukast). Ratio of Cmax of metabolite to parent drug has been presented.

  127. Ratio of AUC(0-infinity) of 36-hydroxymontelukast to Montelukast [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of parent drug (montelukast) and its metabolite (36-hydroxymontelukast). Ratio of AUC(0-infinity) of metabolite to parent drug has been presented.

  128. Ratio of Cmax of 5-hydroxyomeprazole to Omeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of parent drug (omeprazole) and its metabolite (5-hydroxyomeprazole). Ratio of Cmax of metabolite to parent drug has been presented.

  129. Ratio of AUC(0-infinity) of 5-hydroxyomeprazole to Omeprazole [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of parent drug (omeprazole) and its metabolite (5-hydroxyomeprazole). Ratio of AUC(0-infinity) of metabolite to parent drug has been presented.

  130. Ratio of Cmax of 1-hydroxymidazolam to Midazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of parent drug (midazolam) and its metabolite (1-hydroxymidazolam). Ratio of Cmax of metabolite to parent drug has been presented.

  131. Ratio of AUC(0-infinity) of 1-hydroxymidazolam to Midazolam [ Time Frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, and 120 hours post-dose in treatment period 1 and 3 ]
    Blood samples were collected at the indicated time points for pharmacokinetic analysis of parent drug (midazolam) and its metabolite (1-hydroxymidazolam). Ratio of AUC(0-infinity) of metabolite to parent drug has been presented.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent.
  • Participants who are overtly healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination (including cardiopulmonary examination), laboratory tests, and cardiac monitoring (history and ECG).
  • Body weight more than or equal to (>=) 50.0 kilograms (kg) (110 pounds [lbs]) for men and >=45.0 kg (99 lbs) for women and body mass index within the range 18.5 to 31.0 kilogram per square meter (kg/m^2) (inclusive).
  • Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • Male participants should not engage in intercourse while confined in the clinic. There is no need for an extended period of double barrier use or prolonged abstinence after study discharge.
  • A female participant is eligible to participate if she is not pregnant or breastfeeding and at least one of the following conditions applies:
  • Is not a woman of childbearing potential (WOCBP) or
  • Is a WOCBP and using a non-hormonal contraceptive method that is highly effective, with a failure rate of less than (<) 1 percent (%) for 28 days before intervention, during the intervention period, and for at least 28 days after the last dose of study intervention.
  • A WOCBP must have a negative highly sensitive serum pregnancy test at Screening and check-in (Day-1).
  • 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.

Exclusion Criteria:

  • Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • A pre-existing condition interfering with normal gastrointestinal (GI) anatomy or motility (e.g., gastro-esophageal reflux disease, gastric ulcers, gastritis) or hepatic and/or renal function that could interfere with the absorption, metabolism, and/or excretion of the study intervention or render the participant unable to take oral study intervention.
  • Prior cholecystectomy surgery.
  • Any history of significant underlying psychiatric disorder, including, but not limited to, schizophrenia, bipolar disorder with or without psychotic symptoms, other psychotic disorders, or schizotypal (personality) disorder.
  • Any history of major depressive disorder with or without suicidal features, or anxiety disorders that required medical intervention (pharmacologic or not) such as hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient treatment.

Participants with other conditions such as adjustment disorder or dysthymia that have required shorter term medical therapy (<6 months) without inpatient treatment and are currently well-controlled clinically or resolved may be considered for entry after discussion and agreement with the ViiV Healthcare (VH)/GlaxoSmithKline (GSK) Medical Monitor.

  • Any pre-existing physical or other psychiatric condition (including alcohol or drug abuse), which, in the opinion of the investigator (with or without psychiatric evaluation), could interfere with the participant's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the participant.
  • Medical history of cardiac arrhythmias, prior myocardial infarction in the past 3 months, or cardiac disease or a family or personal history of long QT syndrome.
  • History of asthma, bronchospasm, or sleep apnea.
  • History of chronic musculoskeletal pain (myalgias).
  • History of rhabdomyolysis.
  • History of a bleeding disorder.
  • History of Raynaud's disease.
  • History indicative of an increased risk of a cardiac arrhythmia or cardiac disease, including the following:
  • History of cardiac arrhythmias or palpitations associated with presyncope or syncope, or history of unexplained syncope.
  • History of clinically relevant cardiac disease including symptomatic or asymptomatic arrhythmias (including but not limited to ventricular fibrillation, ventricular tachycardia, any degree of atrioventricular block, Brugada syndrome, Wolff-Parkinson-White syndrome, and sinus bradycardia, defined as heart rate less than 50 beats per minute (bpm) based on vital signs or ECG), presyncope or syncopal episodes, or additional risk factors for torsades de pointes (e.g., heart failure).
  • History of clinically relevant structural cardiac disease including hypertrophic obstructive cardiomyopathy.
  • History of hypokalemia.
  • History of heart disease (e.g., coronary heart disease).
  • Presence of hepatitis B surface antigen at Screening or within 3 months prior to starting study intervention.
  • Positive hepatitis C antibody test result at Screening or within 3 months prior to starting study intervention and positive on reflex to hepatitis C Ribonucleic Acid (RNA).
  • Positive HIV-1 and 2 antigen/antibody immunoassay at Screening.
  • ALT>=1.5 × upper limit of normal (ULN). A single repeat of ALT is allowed within a single screening period to determine eligibility.
  • Bilirubin >=5 × ULN (isolated bilirubin >=5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). A single repeat of any laboratory abnormality is allowed within a single screening period to determine eligibility.
  • Any acute laboratory abnormality at Screening which, in the opinion of the investigator, should preclude participation in the study of an investigational compound.
  • Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of lipid abnormalities (e.g., total cholesterol, triglycerides), and ALT, will exclude a participant from the study unless the investigator can provide a compelling explanation for the laboratory result(s) and has the assent of the sponsor.
  • A positive test result for drugs of abuse (including marijuana), alcohol, or cotinine (indicating active current smoking) at Screening or before the first dose of study intervention.
  • Unable to refrain from the use of prescription or nonprescription drugs including vitamins, herbal and dietary supplements (including St John's wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study intervention and for the duration of the study.
  • Treatment with any vaccine within 30 days prior to receiving study intervention.
  • Unwillingness to abstain from excessive consumption of any food or drink containing grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos or their fruit juices within 7 days prior to the first dose of study intervention(s) until the end of the study.
  • Participation in another concurrent clinical study or prior clinical study (with the exception of imaging trials) prior to the first dosing day in the current study: 30 days, 5 half-lives, or twice the duration of the biological effect of the study intervention (whichever is longer).
  • Prior exposure to GSK3640254 in another clinical study.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
  • Any positive (abnormal) response confirmed by the investigator on a screening clinician- or qualified designee-administered Columbia-Suicide Severity Rating Scale (C-SSRS).
  • SBP <100 mm Hg. Up to 2 repeats are allowed for confirmation.
  • Any significant arrhythmia or ECG finding (e.g., prior myocardial infarction in the past 3 months, symptomatic bradycardia, non-sustained or sustained atrial arrhythmias, non-sustained or sustained ventricular tachycardia, any degree of atrioventricular block, or conduction abnormality) which will interfere with the safety for the individual participant.
  • Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): Heart rate- <50 or >100 bpm, PR interval- >200 milliseconds and QTcF- >450 milliseconds.
  • History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 units. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 1 (25 mL) measure of spirits.
  • Unable to refrain from tobacco or nicotine-containing products within 3 months prior to 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.
  • History of aspirin allergy.
  • A participant with known or suspected active coronavirus disease of 2019 (COVID-19) infection OR contact with an individual with known COVID-19, within 14 days of study enrollment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04425902


Locations
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United States, Nevada
GSK Investigational Site
Las Vegas, Nevada, United States, 89113
Sponsors and Collaborators
ViiV Healthcare
Investigators
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Study Director: GSK Clinical Trials ViiV Healthcare
  Study Documents (Full-Text)

Documents provided by ViiV Healthcare:
Study Protocol  [PDF] April 12, 2021
Statistical Analysis Plan  [PDF] July 19, 2021

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Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT04425902    
Other Study ID Numbers: 213052
First Posted: June 11, 2020    Key Record Dates
Results First Posted: May 23, 2022
Last Update Posted: May 23, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (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.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by ViiV Healthcare:
GSK3640254
Human immunodeficiency virus (HIV) infections
Drug interaction
Pharmacokinetics
Probe substrate
Additional relevant MeSH terms:
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HIV Infections
Infections
Blood-Borne Infections
Communicable Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Flurbiprofen
Metoprolol
Digoxin
Midazolam
Caffeine
Omeprazole
Pravastatin
Montelukast
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics