Drug-drug Interaction (DDI) Study of GSK3640254 With Darunavir/Ritonavir (DRV/RTV) and Etravirine (ETR)
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: GSK3640254; Darunavir/Ritonavir (DRV/RTV); Etravirine (ETR)
Intervention description: GSK3640254 will be available as oral tablets.; DRV/RTV will be available as oral tablets.; ETR will be available as oral tablets.
Intervention MeSH terms: Ritonavir; Darunavir; Etravirine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: This is an open-label, single-sequence, multiple-dose and 3-cohort study.
Masking: None (Open Label)
Masking description: This is an open-label study.
Enrollment: 54.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Darunavir; Ritonavir; Etravirine; GSK3640254; Pharmacokinetics

Summary:

      This is an open-label, single-sequence, multiple-dose, 3 cohort study to investigate the
      effects of DRV/RTV and/or ETR on the pharmacokinetics (PK) of GSK3640254 and the effects of
      GSK3640254 on the PK of DRV/RTV and/or ETR. This study will aid in understanding these
      interactions and resulting changes in exposure (if any) when given in combination with
      GSK3640254.
    

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 investigator or medically
             qualified designee based on a medical evaluation including medical history, physical
             examination, laboratory tests, and cardiac monitoring (history and screening 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
             kilograms per square meter (kg/m^2) (inclusive).

          -  Male or female participants:

               1. Male participants should not engage in intercourse while confined in the study
                  site. There is no need for an extended period of double barrier use or prolonged
                  abstinence after study discharge.

               2. Female participants:

             (i) 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. The investigator should evaluate the
             effectiveness of the contraceptive method in relationship to the first dose of study
             intervention.

        (ii) A WOCBP must have a negative highly sensitive serum or urine 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 this
             protocol.

        Exclusion criteria:

          -  Participants with 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 (for example [e.g.], gastroesophageal 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 (prior appendectomy is acceptable).

          -  Clinically significant illness, including viral syndromes within 3 weeks of dosing.

          -  A participant with known or suspected active Coronavirus Disease-2019 (COVID-19)
             infection or contact with an individual with known COVID-19, within 14 days of study
             enrollment (World Health Organization [WHO] definitions).

          -  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 (more than [>]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/GlaxoSmithKline (VH/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.

          -  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.

          -  Positive Human immunodeficiency virus (HIV)-1 and -2 antigen/antibody immunoassay at
             screening.

          -  Alanine aminotransferase (ALT) >1.5 times upper limit of normal (ULN). A single repeat
             of ALT is allowed within a single screening period to determine eligibility.

          -  Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times 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 creatine
             phosphokinase (CPK), lipid abnormalities (e.g., total cholesterol, triglycerides), and
             ALT (described above), 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 single repeat of any laboratory abnormality is allowed
             within a single screening period to determine eligibility.

          -  Urine drug screen positive (showing presence of): amphetamines, barbiturates,
             cannabinoids, cocaine, or phencyclidine, or non-prescribed opiates, oxycodone,
             benzodiazepines, methadone, Methylenedioxymethamphetamine (MDMA), methamphetamines, or
             tricyclic antidepressants 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 Saint [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 or prior intolerance to DRV/RTV or ETR in this or another
             clinical study.

          -  Prior intolerance to any other study medications: DRV/RTV or ETR.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 milliliters (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).

          -  Systolic blood pressure <100 millimeters of mercury (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, in the opinion of the investigator or VH/GSK
             medical monitor, will interfere with the safety for the individual participant.

          -  Exclusion criteria for screening ECG (a single repeat is allowed for eligibility
             determination):

               1. Heart rate: <50 or >100 beats per minute (bpm).

               2. PR interval >200 milliseconds (ms).

               3. Corrected QT interval (QTc) >450 ms.

          -  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.