A First Time in Human Study to Evaluate the Safety and Tolerability of GSK4381406 in Healthy Participants

This is a 3-part First Time in Human (FTIH) study to evaluate the safety, tolerability, and pharmacokinetics (PK) profile of GSK4381406 following administration of single ascending doses (Part 1), repeat ascending doses (Part 2), and repeat doses with an indomethacin challenge (Part 3) in healthy adult participants. Part 1 consists of 4 planned cohorts with up to 2 treatment periods in each and is expected to have 6 doses (but can accommodate up to 7 doses). The impact of food on PK of GSK4381406 will also be assessed. Part 2 will investigate 14 days of repeat dosing in 3 cohorts with 3 dose levels. Part 3 will evaluate the impact of repeat doses of GSK4381406 versus placebo on indomethacin induced changes in small intestinal permeability in healthy participants.


Eligibility Criteria:
Inclusion Criteria:

* Body weight greater than (\>)50 kg and body mass index (BMI) within the range 18-29.9 kilogram per meter square (kg/m\^2) (inclusive)
* Male and female participants
* A female participant is eligible to participate if she is of non-childbearing potential
* Capable of giving signed informed consent

Exclusion Criteria:

* Medical history of cardiovascular, cerebrovascular (including transient ischemic attack (TIA), ischemic and hemorrhagic stroke), respiratory, hepatic, renal (including chronic kidney disease), gastrointestinal (including IBD and IBS), endocrine, hematologic (including anemia and coagulopathies), or neurological disorders
* Abnormal blood pressure (BP) (defined as systolic BP greater than or equal to \[≥\]130 millimetres of mercury (mmHg) or diastolic BP ≥85 mmHg) measured (based on the average of triplicate BP readings)
* Medical history of antihypertensive drugs
* Presence, or history within the past 14 days, of irregularities in bowel movements, including diarrhea (the passage of 3 or more loose or liquid stools per day) and constipation (3 or fewer bowel movements per week or requiring the use of laxatives).
* Symptomatic herpes zoster within 3 months prior to screening.
* Clinically significant multiple or severe drug allergies, intolerance to corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A \[IgA\] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
* Any history or presence of malignancy except for basal cell or squamous epithelial carcinomas of the skin.
* Alanine transaminase (ALT) \>1.5x Upper limit of normal (ULN)
* Total bilirubin \>1.5x ULN (isolated total bilirubin \>1.5xULN is acceptable if total bilirubin is fractionated and direct bilirubin lesser than \[\<\]35 percentage \[%\]).
* Current or chronic history of liver disease or known hepatic or biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones).
* QT interval corrected for heart rate according to Fridericia's formula (QTcF) \>450 millisecond (msec)
* Unable to refrain from the use of over-the-counter or prescription medication, including herbal medications and vitamins within 7 days or 5 half-lives (whichever is longer) prior to dosing until after follow-up visit, unless in the opinion of the Investigator and the GSK medical monitor, the medication will not interfere with the study procedures or compromise participant safety
* Use of a systemic antimicrobial within 30 days of screening
* The use of NSAIDs, including aspirin, are not permitted throughout the study (except on Part 3 Indomethacin challenge) and should not have been taken within 14 days immediately preceding the first dose of study intervention. For analgesia, paracetamol (acetaminophen) at doses of less than or equal to (≤)4 gram per day (g/day) is permitted
* Unable to refrain from consumption of red wine, Seville oranges, grapefruit, or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to first dose of study intervention until completion of the follow up period
* Live vaccine(s) within 1 month prior to screening or plans to receive such vaccines during the study
* Participation in the study would result in loss of blood or blood products in excess of 450 millilitre (mL) within the last 3 months prior to the Screening Visit. Blood donation during the study is not permitted
* Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day
* Current enrolment or past participation in another investigational study in which an investigational intervention (e.g., drug, vaccine, invasive device) was administered within the last 40 days or 5 half-lives, whichever is longer, before the first day of dosing (Day 1)
* Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention
* Positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention
* Positive hepatitis C ribo nucleic acid (RNA) test result at screening or within 3 months prior to first dose of study intervention.
* Positive pre-study drug/alcohol screen
* Regular use of known drugs of abuse, including tetrahydrocannabinol.
* Positive human immunodeficiency virus (HIV) antibody test.
* Evidence of active or latent tuberculosis (TB) as documented by medical history and examination, and TB testing: a positive (not indeterminate) TB test such as QuantiFERON-TB Gold Plus test
* Positive smoke breathalyzer levels 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 (e.g., nicotine patches or vaporizing devices) within 6 months prior to screening.
* Estimated glomerular filtration rate (eGFR) of \<90 millilitre per minute per 1.73 meter square (mL/min/1.73 m\^2) and / or UACR of \>30 milligram per gram (mg/g) (\>3 milligram per millimoles \[mg/mmol\]) at screening.
* Electrocardiogram (ECG) evidence of ischemic heart disease as determined by the Investigator.
* Positive test for Coronavirus disease 2019 (COVID-19) infection or signs and symptoms suggestive of COVID-19
* Regular excess alcohol consumption within 6 months prior to the study defined as an average weekly intake of \>14 units for males and females
* 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 Additional exclusions for part 3 cohort only -
* Medical history of NSAIDs hypersensitivities, bronchial asthma, psychiatric and neurologic disorders, gastrointestinal disorders (including gastroesophageal reflux disease \[GORD\], gastritis, peptic ulcer disease and previous GI bleeding), cardiac or renal disease, coagulation defects and who are not on concomitant medication that may potentiate the potential harmful effects of indomethacin.
* Medical history of diabetes, defined as an HbA1c \>5.6%, \>39 mmol/mol.
* History of severe lactose intolerance or galactosaemia