Evaluation of Pharmacokinetic Interaction Between GSK3640254 and Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, Midazolam, Digoxin, and Pravastatin in Healthy Adults
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: GSK3640254 200 mg; Caffeine 200 mg; Metoprolol 100 mg; Montelukast 10 mg; Flurbiprofen 100 mg; Omeprazole 40 mg; Midazolam 5 mg (2.5 mL); Digoxin 0.25 mg; Pravastatin 40 mg
Intervention description: GSK3640254 will be available as oral tablets at unit dose strength of 100 mg.; Caffeine will be available as oral tablets at unit dose strength of 200 mg.; Metoprolol will be available as oral tablets at unit dose strength of 100 mg.; Montelukast will be available as oral tablets at unit dose strength of 10 mg.; Flurbiprofen will be available as oral tablets at unit dose strength of 100 mg.; Omeprazole will be available as oral capsules at unit dose strength of 40 mg.; Midazolam will be available as syrup for oral administration at unit dose strength of 2 milligram per milliliter (mg/mL).; Digoxin will be available as oral tablet at unit dose strength of 0.25 mg.; Pravastatin will be available as oral tablet at unit dose strength of 40 mg.
Intervention MeSH terms: Flurbiprofen; Metoprolol; Digoxin; Midazolam; Caffeine; Omeprazole; Pravastatin; Montelukast
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
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.
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: GSK3640254; Human immunodeficiency virus (HIV) infections; Drug interaction; Pharmacokinetics; Probe substrate

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.
    

Eligibility 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.