This study aims to evaluate whether GSK3772701 alters the pharmacokinetics (PK) of midazolam (MDZ), a standard probe substrate for the CYP3A4 enzyme. The findings are planned to be used to determine whether GSK3772701 acts as an inducer and/or inhibitor of CYP3A4 and will help guide recommendations for safe co-administration with CYP3A4 substrates.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
20
Participants receive MDZ orally.
Participants receive GSK3772701 orally.
GSK Investigational Site
Miami, Florida, United States
RECRUITINGMaximum observed concentration (Cmax) of MDZ
Time frame: At 0 hours (h) (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
Area under the concentration-time curve. from time 0 to the last measurable concentration [AUC(0-t)] of MDZ
Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
Area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUC(0-inf)] of MDZ
Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
Cmax of 1-hydroxymidazolam (OH-MDZ)
Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
AUC(0-t) of 1-OH-MDZ
Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
AUC(0-inf) of 1-OH-MDZ
Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
Metabolite-to-parent ratios (1-OH-MDZ/MDZ) based on Cmax
Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
Metabolite-to-parent ratios (1-OH-MDZ/MDZ) based on AUC(0-t)
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Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
Metabolite-to-parent ratios (1-OH-MDZ/MDZ) based on AUC(0-inf)
Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
Time to maximum observed concentration (Tmax) of MDZ and 1-OH-MDZ
Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
Terminal half-life (t1/2) of MDZ and 1-OH-MDZ
Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
Apparent oral plasma clearance (CL/F) of MDZ
Time frame: At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10
Cmax of GSK3772701
Time frame: At 0h (pre-dose) and at 0.5, 1, 2, 3, 4, 6, 12, 20 and 24 hours post-dose on days 3 and 5
AUC(0-t) of GSK3772701
Time frame: At 0h (pre-dose) and at 0.5, 1, 2, 3, 4, 6, 12, 20 and 24 hours post-dose on days 3 and 5
Area under the plasma concentration-time curve from time zero to 24 hours [AUC(0-24)] of GSK3772701
Time frame: At 0h (pre-dose) and at 0.5, 1, 2, 3, 4, 6, 12, 20 and 24 hours post-dose on days 3 and 5
Tmax of GSK3772701
Time frame: At 0h (pre-dose) and at 0.5, 1, 2, 3, 4, 6, 12, 20 and 24 hours post-dose on days 3 and 5
Concentration at 24 hours post dose (C24h) of GSK3772701
Time frame: At Day 4 pre-dose (24 hours post Day 3 dose), Day 5 pre-dose (24 hours post Day 4 dose) and Day 6 (24 hours post Day 5 dose)
Incidence of adverse events (AEs) overall, by severity and relationship to GSK3772701
An AE is defined as 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. The severity of AEs is determined by the investigator using the Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading of Severity of Adult and Pediatric Adverse Events, corrected version 2.1. Grades are defined based on numeric criteria as follows Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: potentially life-threatening; Grade 5: death. Higher grades indicate greater severity. The incidence rate describes the rate at which an event occurs.
Time frame: From Day 1 to Day 12
Incidence of serious adverse events (SAEs) overall, by severity and relationship to GSK3772701
An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or extends existing hospitalization, causes persistent or significant disability/incapacity, involves a congenital anomaly/birth defect in a participants offspring, includes an abnormal pregnancy outcome, or occurs in any other situation per the investigators judgement. The severity of SAEs is determined by the investigator using the DAIDs Table for Grading of Severity of Adult and Pediatric Adverse Events, corrected version 2.1. Grades are defined based on numeric criteria as follows Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: potentially life-threatening; Grade 5: death. Higher grades indicate greater severity. The incidence rate describes the rate at which an event occurs.
Time frame: From Day -30 to Day 12