This is a first time in human (FTIH), 2-period study, to assess the relative bioavailability of a mesylate salt capsule of GSK3640254, compared to a bis- hydrochloride salt capsule of GSK3640254, in healthy subjects, administered following a moderate calorie and fat meal. The subjects will be randomized to 2 sequences, Regimen AB or Regimen BA. For Regimen AB: The Regimen A, which will include oral administration of GSK3640254 bis-hydrochloride Capsule 200 milligram (mg) (reference), which will be administered, in Period 1 and Regimen B will include GSK3640254 Mesylate salt capsule (test), 200 mg, which will be administered in Period 2. For the regimen BA, the regimen B, will be administered, in Period 1 and regimen A, in Period 2. Each of the regimens will be given orally as 2 capsules in the morning, as per randomization sequence. There will be a minimum washout of 7 days between each dose of study treatment. A total, of 14 subjects, are planned to be enrolled in the study. The maximum duration of the study from screening to follow-up is approximately 7 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Administered orally (as single dose) on morning of Day 1, as 2 capsules of 100 mg following a moderate calorie and fat meal during Period 1 and Period 2, at the specified sequence, as per study.
Administered orally (as single dose) on morning of Day 1, as 2 capsules of , 100 mg following a moderate calorie and fat meal during Period 1 and Period 2, at the specified sequence, as per study.
GSK Investigational Site
Nottingham, United Kingdom
Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) of GSK3640254 Following Single Oral Dose in Healthy Participants
Blood samples were collected at designated timepoints. Pharmacokinetic (PK) parameters of GSK3640254 were calculated using non-compartmental methods. Geometric mean and percentage (%) geometric coefficient of variation have been presented.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hours post-dose in each treatment period
Area Under the Concentration-time Curve From Zero to Time of Last Sample Taken (AUC[0-t]) of GSK3640254 Following Single Oral Dose in Healthy Participants
Blood samples were collected at designated timepoints. PK parameters of GSK3640254 were calculated using non-compartmental methods. Geometric mean and % geometric coefficient of variation have been presented. Statistical analysis of PK parameters was done using mixed effect model for evaluation of relative bioavailability (Frel). Point estimate and 90% confidence interval (CI) for the ratio of geometric least square mean of the test mesylate salt capsule to the reference Hydrochloride capsule were calculated for AUC(0-t).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours post-dose in each treatment period
Maximum Observed Concentration (Cmax) of GSK3640254 Following Single Oral Dose in Healthy Participants
Blood samples were collected at designated timepoints. PK parameters of GSK3640254 were calculated using non-compartmental methods. Geometric mean and % geometric coefficient of variation have been presented. Statistical analysis of PK parameters was done using mixed effect model for evaluation of Frel. Point estimate and 90% CI for the ratio of geometric least square mean of the test mesylate salt capsule to the reference Hydrochloride capsule were calculated for Cmax.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours post-dose in each treatment period
Time to Reach Maximum Observed Concentration (Tmax) of GSK3640254 Following Single Oral Dose in Healthy Participants
Blood samples were collected at designated timepoints. PK parameters of GSK3640254 were calculated using non-compartmental methods. Median and full range of Tmax have been presented.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours post-dose in each treatment period
Concentration at 24 Hours Post-dose (C24h) of GSK3640254 Following Single Oral Dose in Healthy Participants
Blood samples were collected at designated timepoints. PK parameters of GSK3640254 were calculated using non-compartmental methods. Geometric mean and % geometric coefficient of variation have been presented.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post-dose in each treatment period
Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other situations according to medical or scientific judgement.
Time frame: Up to 25 days
Change From Baseline in Clinical Chemistry Parameters; Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Aspartate Aminotransferase (AST)
Blood samples were collected to analyze the clinical chemistry parameters; ALT, ALP and AST. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-Dose visit value. Mean and standard deviation have been presented.
Time frame: Baseline (Day -1) and Day 3
Change From Baseline in Clinical Chemistry Parameters; Bicarbonate, Calcium, Chloride, Glucose (Fasting), Potassium, Sodium and Urea
Blood samples were collected to analyze the clinical chemistry parameters; Bicarbonate, Calcium, Chloride, Glucose (fasting), Potassium, Sodium and Urea. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-Dose visit value. Mean and standard deviation have been presented.
Time frame: Baseline (Day -1) and Day 3
Change From Baseline in Clinical Chemistry Parameters; Bilirubin, Creatinine and Direct Bilirubin
Blood samples were collected to analyze the clinical chemistry parameters; Bilirubin, Creatinine and Direct Bilirubin. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-Dose visit value. Mean and standard deviation have been presented.
Time frame: Baseline (Day -1) and Day 3
Change From Baseline in Clinical Chemistry Parameter; Protein
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Blood samples were collected to analyze the clinical chemistry parameter; Protein. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-Dose visit value. Mean and standard deviation have been presented.
Time frame: Baseline (Day -1) and Day 3
Number of Participants With Worst Case Hematology Results by Potential Clinical Importance (PCI) Criteria
Blood samples were collected to analyze the hematology parameters; Hematocrit (Hct), Hemoglobin (Hb), Leukocytes, Lymphocytes, Neutrophils and Platelets. PCI ranges were Hct (Male and Female \[high: \>0.54 proportion of red blood cells in blood\]), Hb (Male and Female \[high: \>180 grams per liter\]), lymphocytes (low: \<0.8x10\^9 cells per liter), neutrophils (low: \<1.5x10\^9 cells per liter), platelets (low: \<100x10\^9 cells per liter and high: \>550x10\^9 cells per liter) and leukocytes (low: \<3x10\^9 cells per liter and high: \>12x10\^9 cells per liter). Participants were counted in the worst case category such that their value changed to (low, normal or high). If values were unchanged (example: High to High), or whose value became normal, were recorded in the 'To Normal or No Change' category.
Time frame: Up to 22 days
Number of Participants With Urinalysis Results by Dipstick Method by Visit
Urine samples were collected to assess urine bilirubin, urine glucose, urine ketones, urine leukocyte esterase (LE), urine nitrite, urine occult blood, urine protein, urobilinogen and monitor urine potential of hydrogen (pH). The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as negative, trace and positive, indicating proportional concentrations in the urine sample. All the numeric result values \>0 have been considered as "positive".
Time frame: Day -1 and Day 3
Number of Participants With Clinically Significant Abnormal Findings for Electrocardiogram (ECG) Parameters
A single 12-lead ECGs was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, QT corrected (QTc) and QT interval corrected for heart rate according to Fridericia's formula (QTcF) intervals. Clinically significant abnormal ranges were: PR: lower: \<120 milliseconds (msec) and upper: \>200 msec; QRS: lower: \<60 msec and upper: \>120 msec and QTcF: lower: \<320 msec and upper: \>450 msec. The number of participants with clinically significant abnormal findings for ECG parameters have been presented.
Time frame: Day -1, pre-dose, 2, 4, 6, 24 and 72 hours post-dose in each treatment period
Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) at Indicated Time-points
Vital signs including DBP and SBP were measured at the indicated time-points and summarized during the study to evaluate the safety of the participants. Mean and standard deviation have been presented.
Time frame: Day -1, pre-dose, 2, 4, 6, 24 and 72 hours post-dose in each treatment period
Pulse Rate (PR) at Indicated Time-points
Vital sign including PR was measured at the indicated time-points and summarized during the study to evaluate the safety of the participants. Mean and standard deviation have been presented.
Time frame: Day -1, pre-dose, 2, 4, 6, 24 and 72 hours post-dose in each treatment period
Respiratory Rate (RR) at Indicated Time-points
Vital sign including RR was measured at the indicated time-point and summarized during the study to evaluate the safety of the participants. Mean and standard deviation have been presented.
Time frame: Day -1, pre-dose, 2, 4, 6, 24 and 72 hours post-dose in each treatment period
Temperature at Indicated Time-points
Vital sign including temperature was measured at the indicated time-points and summarized during the study to evaluate the safety of the participants. Mean and standard deviation have been presented.
Time frame: Day -1, pre-dose, 2, 4, 6, 24 and 72 hours post-dose in each treatment period
Number of Participants With the Indicated Assessment Events of Suicidal Behavior (SB) and Suicidal Ideation (SI) Via the Columbia Suicide Severity Rating Scale (C-SSRS)
Assessment of suicidality was conducted using the C-SSRS, a brief questionaire designed to assess severity and change in suicidality by integrating both behavior and ideation using a semi-structured interview to probe participant responses.
Time frame: Day 3 in each treatment period