Drug Interaction Assessment of GSK3882347 in Healthy Participants Aged 18 to 65 Years
- Registration Number
- NCT05760261
- Lead Sponsor
- GlaxoSmithKline
- Brief Summary
The objective of this study is to determine the magnitude and clinical relevance of a potential drug-drug interaction of GSK3882347 with midazolam (MDZ) in healthy participants. This study assesses the effect of GSK3882347 as an inducer of Cytochrome P450 3A4 (CYP3A4) using MDZ, a sensitive substrate of hepatic and intestinal CYP3A4. The study will investigate MDZ pharmacokinetic (PK) effect in two dosing periods:
Period 1: A single dose of MDZ Period 2: 14-days of once daily repeat dosing of GSK3882347 followed by single dose of MDZ co-administered with GSK3882347 on Day 15 (14-days has been selected as this duration is required in order to maximize any potential CYP3A4 enzyme induction).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 27
Not provided
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History or presence of significant cardiovascular, respiratory, hepatic, renal, urological, gastrointestinal, metabolic, endocrinological, hematological, immunologic, dermatologic, neurological or psychiatric disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data or in the opinion of the investigator places the participants at unacceptable risk or would make adhering to study procedures for the duration of the study difficult. Participants who have had a gastric bypass or a cholecystectomy are excluded from the study.
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Abnormal blood pressure, as determined by the investigator.
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Alanine transferase (ALT) value greater than (>)1.5 × upper limit of normal (ULN).
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Bilirubin value >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
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The participant has a current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
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The participant has congenital long QT syndrome or known prolongation of the corrected QT (QTc) interval.
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The participant has any history of heart failure.
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The participant has a family history of QT prolongation or sudden death.
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The participant has any current or previous a history of episodes of symptomatic bradycardia or bradyarrhythmia.
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The participant has a QTc >450 millisecond (msec). Note: The QTc is the QT interval corrected for heart rate according to Fridericia formula, machine, or manual overread.
- The participant has anuria, oliguria, or impairment of renal function (GFR by Modification of diet in renal disease [MDRD] <90 milliliter per minute per 1.73 meter square [mL/min/1.73m^2] or serum creatinine > ULN or urine albumin-creatinine ratio [ACR] of ≥300 milligram per gram [mg/g] at screening).
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The participant must agree to and adhere to the concomitant therapy (including nondrug therapies) restrictions from the Screening Visit through to the end of the end of the study (including telephone visit).
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Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 56 days.
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Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
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Current enrolment or past participation within the last 30 days or 5 half-lives, whichever is longer, before signing of consent in any other clinical study involving an investigational study intervention or any other type of medical research.
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Current enrolment or past participation in this clinical study.
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Positive human immunodeficiency virus (HIV) antibody test.
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Presence of Hepatitis B surface antigen (HbsAg) at screening or within 3 months prior to first dose of study intervention.
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Hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.
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A positive confirmation of Coronavirus disease 2019 (COVID-19) infection, or high clinical index of suspicion for COVID-19.
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The participant, in the judgment of the investigator, would not be able or willing to comply with the protocol or complete the study.
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Regular alcohol consumption within 6 months prior to the study. An average weekly intake of >14 units for males or females. One unit is equivalent to approximately to 8 g of alcohol: a half-pint (approximately [~]240 mL) of beer, one glass (125 mL) of wine or one (25 mL) measure of spirits.
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Positive smoke breathalyzer indicative of smoking history at screening and each in-house admission to the clinical research unit or regular use of tobacco or nicotine-containing products (i.e., nicotine patches or vaporizing devices) within 3 months prior to screening.
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Regular use of combustible tobacco products, and non-combustible nicotine delivery systems, inclusive of cigarettes, cigars, pipes, and materials used to "vape".
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Any history of substance abuse or a positive urine test for drugs of abuse/ alcohol breath screen at screening or admission.
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Known hypersensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
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Contraindication for MDZ (i.e., Hypersensitivity to the active substance, benzodiazepines or to any of the excipients, myasthenia gravis, respiratory insufficiency, sleep apnea syndrome, severe hepatic impairment).
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Use of any products intended to treat medical conditions that are not approved by the governing health authority in a given country or region (for example, herbal medicine, health supplements, traditional medicine, homeopathic remedies, etc.).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description GSK3882347 and MDZ Midazolam Period 1: Participants will receive MDZ on Day 1. Period 2: Participants will receive 14-days of repeat dosing of GSK3882347 Followed by one dose of MDZ co-administered with GSK3882347 on Day 15. GSK3882347 and MDZ GSK3882347 Period 1: Participants will receive MDZ on Day 1. Period 2: Participants will receive 14-days of repeat dosing of GSK3882347 Followed by one dose of MDZ co-administered with GSK3882347 on Day 15.
- Primary Outcome Measures
Name Time Method Period 1: Cmax of 1-hydroxy-MDZ Up to Day 2 Period 2: Cmax of MDZ Up to Day 15 Period 2: Cmax of 1-hydroxy-MDZ Up to Day 15 Period 1: Area under the curve from time zero to 24 hours (AUC [0-24]) for plasma concentration of MDZ Up to 24 hours Period 1: AUC (0-24) for plasma concentration of 1-hydroxy-MDZ Up to 24 hours Period 1: Time to Cmax (Tmax) of MDZ Up to Day 2 Period 2: AUC (0-24) for plasma concentration of MDZ Up to 24 hours Period 2: AUC (0-24) for plasma concentration of 1-hydroxy-MDZ Up to 24 hours Period 1: Tmax of 1-hydroxy-MDZ Up to Day 2 Period 2: Tmax of MDZ Up to Day 15 Period 2: Tmax of 1-hydroxy-MDZ Up to Day 15 Period 1: AUC from time zero to last time of quantifiable concentration (AUC [0-tau]) for plasma concentration of MDZ Up to Day 2 Period 1: Time lag before observation of measurable concentrations (Tlag) of MDZ Up to Day 2 Period 1: Tlag of 1-hydroxy-MDZ Up to Day 2 Period 1: AUC (0-tau) for plasma concentration of 1-hydroxy-MDZ Up to Day 2 Period 2: AUC (0-tau) for plasma concentration of MDZ Up to Day 15 Period 2: AUC (0-tau) for plasma concentration of 1-hydroxy-MDZ Up to Day 15 Period 1: AUC from time zero extrapolated to infinite time (AUC [0-inf]) for plasma concentration of MDZ Up to Day 2 Period 2: AUC (0-inf) for plasma concentration of MDZ Up to Day 15 Period 2: AUC (0-inf) for plasma concentration of 1-hydroxy-MDZ Up to Day 15 Period 2: Tlag of MDZ Up to Day 15 Period 2: Tlag of 1-hydroxy-MDZ Up to Day 15 Period 1: Time to half-life (T1/2) of MDZ Up to Day 2 Period 1: T1/2 of 1-hydroxy-MDZ Up to Day 2 Period 2: T1/2 of MDZ Up to Day 15 Period 1: Maximum plasma concentration (Cmax) of MDZ Up to Day 2 Period 2: T1/2 of 1-hydroxy-MDZ Up to Day 15 Period 1: AUC (0-inf) for plasma concentration of 1-hydroxy-MDZ Up to Day 2
- Secondary Outcome Measures
Name Time Method Cmax for repeat dose of GSK3882347 Up to Day 15 Time invariance using AUC(0-tau) (repeat dose) of GSK3882347 Up to Day 15 Number of participants with clinically significant changes in vital sign values Up to Day 15 AUC (0-24) for plasma concentration of GSK3882347 Up to 24 hours Plasma concentrations over the dosing interval tau (Ctau) of GSK3882347 Up to Day 15 Oral clearance (CL/F) of GSK3882347 Up to Day 15 Number of participants with adverse events (AEs) and serious adverse events (SAEs) Up to Day 15 Number of participants with clinically significant changes in hematology laboratory values Up to Day 15 Number of participants with clinically significant changes in chemistry laboratory values Up to Day 15 Volume of distribution/ Bioavailability (Vd/F) of GSK3882347 Up to Day 15 AUC(0-tau) for repeat dose of GSK3882347 Up to Day 15 Number of participants with clinically significant changes in 12-lead electrocardiogram (ECG) readings Up to Day 15 Number of participants with clinically significant changes in urinalysis laboratory values Up to Day 15 Mean residence time (MRT) of GSK3882347 Up to Day 15 AUC(0-inf) for single dose of GSK3882347 Up to Day 2 Cmax for single dose of GSK3882347 Up to Day 2 Accumulation ratio (Ro) using AUC (0-tau) for repeat dose of GSK3882347 Up to Day 15 Time invariance using AUC(0-inf) (single dose) of GSK3882347 Up to Day 2 Achievement of steady state of GSK3882347 Up to Day 15
Trial Locations
- Locations (1)
GSK Investigational Site
🇬🇧Cambridge, United Kingdom