A Study to Compare the Pharmacokinetics (PK) of GSK2982772 Following Administration of Different Modified Release (MR) Formulations in Capsule and MR Tablet Formulations Relative to an Immediate Release (IR) Tablet Formulation and to Check the PK of MR Formulation in Capsule Following Repeat Doses
Condition: Autoimmune Diseases
MeSH terms: Autoimmune Diseases
Intervention: GSK2982772 Modified Release; GSK2982772 Immediate Release
Intervention description: GSK2982772 MR will be available as prototype MR minitablet in capsules with unit dose strength of 60 mg in Part A. In Part B, GSK2982772 MR minitablet in capsules with unit dose strength of 15, 30 or 60 mg will be administered by subjects for Days 1 to 3. In Part C, GSK2982772 MR tablet with unit dose strength of 240, 360 or 480 mg will be administered by subjects. GSK2982772 MR will be administered orally with 240 mL of water.; In part A, GSK2982772 IR tablet will be available with unit dose strength of 30 mg and the total dose administered by subjects will be 120 mg (4 tablets of dose strength 30 mg) orally with 240 mL of water. In part C, GSK2982772 IR tablet will be available with unit dose strength of 30 mg and the total dose administered by subjects will be 240 mg (8 tablets of dose strength 30 mg) orally with 240 mL of water.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Part A of the study will be a non-randomized 6 period, sequential, 6-way fixed sequence design. Part B of the study will be a repeat dose study. Part C of the study will be a non-randomized 6 period, sequential, fixed sequence crossover design.
Masking: None (Open Label)
Enrollment: 45.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: immediate release tablet; GSK2982772; Modified release; minitablet

Summary:

      GSK2982772 is a first-in-class, highly selective, receptor-interacting protein-1 (RIP1)
      kinase inhibitor being developed for the treatment of inflammatory bowel disease, plaque
      psoriasis (PsO), rheumatoid arthritis (RA) and other disease conditions. PK data from the
      first time in human (FTIH) study for GSK2982772 showed that the half life of GSK2982772 was
      short (approximately 2 to 3 hours). A once daily (QD) formulation would be more convenient
      from a subject perspective and could offer the advantage of providing a flatter GSK2982772
      concentration time profile. Following completion of Parts A and B, it was determined that the
      slowest minitab formulation provided a PK profile suitable for QD dosing but this formulation
      was susceptible to a food effect. This study will evaluate the pharmacokinetics of GSK2982772
      following administration of different minitab MR formulations in a capsule relative to an IR
      reference tablet formulation, the pharmacokinetics of selected MR formulation in capsule
      following repeat doses for 3 days and to compare the pharmacokinetics of GSK2982772 following
      administration of MR tablet formulations in the fed and fasted state relative to an IR tablet
      formulation. The study is divided into three parts: Part A will be a non-randomized 6
      periods, sequential, 6-way fixed sequence design in which up to 4 MR minitab formulations in
      a capsule will be evaluated. Periods 1, 2, and 3 will evaluate a slow MR release duration
      (nominally 24 hours), a fast MR release duration (nominally 10 hours), and IR tablet
      respectively. Periods 4, 5 and 6 will have flexible dose regimen and it will depend on the
      outcomes of Period 1 to 3. Subjects will be admitted to the clinic the previous day before
      dosing. Each in-patient period will consist of 3 days and 2 nights followed by a minimum
      washout period of 7 days between doses, for both Part A and C. In Part A and C, 16 healthy
      subjects will be enrolled such that at least 12 evaluable subjects complete the study. Part B
      will be an open-label, repeat dose study in which the selected MR minitab formulation in
      capsule will be evaluated. Each in-patient period will consist of 5 days and 4 nights. There
      will be a minimum of 7 days washout period between the last morning dose of one period and
      the first dose of the next period. In Part B, 10 healthy subjects will be enrolled such that
      at least 6 evaluable subjects complete the study. Part C of the study will be a
      non-randomised 6 period, sequential, fixed sequence crossover design in which MR tablet
      formulations will be evaluated. Periods 1 and 2 will evaluate single dose administration of a
      240 milligram (mg) MR tablet and the 240 mg IR tablet (reference), respectively. Periods 3,
      4, 5 and 6 will be flexible and the dosing regimen will be dependent on the outcome of
      Periods 1 and 2.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject must be 18 to 65 years of age inclusive, at the time of signing the informed
             consent.

          -  Subjects who are overtly healthy as determined by medical evaluation including medical
             history, physical examination, laboratory tests, and cardiac monitoring.

          -  Body weight greater than and equal to 50 kilogram (kg) and body mass index within the
             range 19.0 to 32.0 kilogram per meter square (kg/m^2) (inclusive).

          -  A male subject must agree to use a highly effective contraception during the treatment
             period and for at least 90 days after the last dose of study treatment and refrain
             from donating sperm during this period.

          -  A female subject is eligible to participate if she is not pregnant, not breastfeeding,
             not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the
             contraceptive during the treatment period and for at least 30 days before and 30 days
             after the last dose of study treatment.

          -  Capable of giving signed informed consent.

        Exclusion Criteria:

          -  History of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal
             (GI), endocrine, hematological, or neurological disorders capable of significantly
             altering the absorption, metabolism, or elimination of drugs; constituting a risk when
             taking the study treatment; or interfering with the interpretation of data.

          -  Parts A and C only: Any history of suicidal behavior within the past 6 months or any
             history of attempted suicide in a subject's lifetime.

          -  Part B only: Subjects with current history of suicidal ideation behavior as measured
             using the columbia-suicide severity rating scale (C-SSRS) or a history of attempted
             suicide.

          -  History of clinically significant psychiatric disorders as judged by the investigator.
             Depression requiring treatment in the last 2 years.

          -  History of herpes zoster (shingles) reactivation.

          -  History or diagnosis of obstructive sleep apnea.

          -  History of a significant respiratory disorder. Childhood asthma that has fully
             resolved is permitted.

          -  History or current evidence of febrile seizures, epilepsy, convulsions, significant
             head injury, or other significant neurologic conditions.

          -  A positive diagnostic tuberculosis (TB) test at screening defined as a positive
             QuantiFERON-TB Gold test or T-spot test. In cases where the QuantiFERON or T spot test
             is indeterminate, the subject may have the test repeated once, but they will not be
             eligible for the study unless the second test is negative.

          -  History of GI surgery (with exception of appendectomy).

          -  History of cholecystectomy or gall stones.

          -  Presence or history of clinically significant allergy requiring treatment, as judged
             by the investigator. Hay fever is allowed unless it is active.

          -  ALT greater than 1.5 times upper limit of normal (ULN).

          -  Bilirubin greater than 1.5 times ULN (isolated bilirubin greater than 1.5 times ULN is
             acceptable if bilirubin is fractionated and direct bilirubin less than 35 percentage
             of total).

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome).

          -  Corrected QT interval (QTc) greater than 450 millisecond (msec).

          -  Past or intended use of over-the-counter or prescription medication including herbal
             medications within 7 days prior to dosing (paracetamol/acetaminophen [up to 2 gram (g)
             per day], hormone replacement therapy and hormonal contraception are permitted).

          -  Live or attenuated vaccine(s) within 30 days of enrolment, or plans to receive such
             vaccines during the study or plans to receive a vaccine within 30 days + 5 half-lives
             of the last dose of study medication.

          -  Subject in the study would result in loss of blood or blood products in excess of 500
             milliliter (mL) within a 56 day period; therefore donation or loss of greater than 400
             mL of blood within the previous 3 months.

          -  Exposure to more than 4 new chemical entities within 12 months prior to the first
             dosing day.

          -  Current enrolment or past participation within the last 3 months before signing of
             consent in this or any other clinical study involving an investigational study
             treatment or any other type of medical research.

          -  Subjects who have previously been enrolled in this study. Subjects in Part A of this
             study are not permitted to participate in Part B. Subjects in Parts A or B of this
             study are not permitted to participate in Part C.

          -  Current or history of renal disease or estimated glomerular filtration rate (GFR) by
             Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation calculation less
             than 60 mL/minutes(min)/1.73m^2 at screening.

          -  Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C
             antibody test result at screening or within 3 months prior to first dose. As potential
             for and magnitude of immunosuppression with this compound is unknown, subjects with
             presence of hepatitis B core antibody (HBcAb) should be excluded. Subjects positive
             for HBsAg and/or positive for anti-HBc antibody (regardless of anti-HBs antibody
             status) are excluded.

          -  An elevated C-reactive protein (CRP) outside the normal reference range.

          -  Part B only: A positive anti-nuclear antibody (ANA) outside the normal reference
             range.

          -  Confirmed positive pre-study drug/alcohol screen.

          -  Positive human immunodeficiency virus (HIV) antibody test.

          -  Regular use of known drugs of abuse, or history of drug or alcohol abuse in the past 5
             years.

          -  Regular alcohol consumption within 6 months prior to the study defined as an average
             weekly intake of greater than 21 units for males or greater than 14 units for females.
             One unit is equivalent to 8 g of alcohol: a half-pint (approximately 240 mL) of beer,
             1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

          -  Current use or history of regular use of tobacco- or nicotine-containing products
             within 6 months prior to screening. A carbon monoxide breath test reading of greater
             than 10 parts per million (ppm).

          -  Sensitivity to any of the study treatments, or components thereof, or drug or other
             allergy that, in the opinion of the investigator or medical monitor, contraindicates
             participation in the study.

          -  Unwilling or unable to swallow multiple size 0-00 capsules as part of study
             participation.

          -  Subjects who do not have suitable veins for multiple venipunctures/cannulation as
             assessed by the investigator at screening.

          -  Total cholesterol greater than or equal to 300 milligram/deciliter (mg/dL) (greater
             than or equal to 7.77 millimoles per liter [mmol]/L]) or triglycerides greater than or
             equal to 250 mg/dL (greater than or equal to 2.82 mmol/L).

          -  Subjects who are study site employees, or immediate family members of a study site or
             sponsor employee.