A Study to Investigate the Pharmacokinetics (PK) of Modified Release (MR) Prototype Coated Tablet Formulations of GSK2982772
Condition: Autoimmune Diseases
MeSH terms: Autoimmune Diseases
Intervention: GSK2982772 Modified Release; GSK2982772 Immediate Release
Intervention description: GSK2982772 MR will be available as MR prototype coated tablet with unit dose strength of 240 mg in Part A. In Part B, GSK2982772 MR prototype coated tablet with unit dose strength of 120 mg (may be changed following interim review of Part B) will be administered by subjects. GSK2982772 MR will be administered orally with 240 milliliter (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 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 will be a 6-period, 6-way fixed sequence design, in which up to 4 MR tablet prototype coated formulation will be evaluated, following single dose administration (240 mg) in fasted or fed state. There will be a minimum 7-day washout between doses. Part B of the study is optional. Following the final period of Part A, there will be an interim review to determine whether to proceed with optional Part B, and if so, the formulations and tablet strengths to be investigated in Part B. The Part B of the study will be a 7-period fixed sequence which will evaluate the selected MR prototype coated tablet formulation(s) at different tablet strengths or as multiple unit doses.
Masking: None (Open Label)
Masking description: There will be no masking as this is an open-label study.
Enrollment: 33.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Tablet formulation; Sequence; Immediate release; Pharmacokinetic

Summary:

      Previous clinical studies of immediate release (IR) formulations of GSK2982772 resulted in a
      high peak to trough ratio of GSK2982772. Additionally, the short half-life for GSK2982772
      (approximately 2 to 3 hours) necessitates twice a daily (BID) or thrice daily (TID) dosing of
      an IR formulation. As a result, MR formulations using a polymer matrix approach with
      minitablets in capsule and MR tablet formulations were investigated. The emerging PK data of
      the MR formulations investigated to date have demonstrated that a once daily (QD) PK profile
      can be achieved in the fasted state but the polymer matrix formulation is susceptible to food
      effects when administered with a high fat breakfast. The purpose of this study is to evaluate
      MR prototype coated tablet formulations. This study will evaluate the PK of MR prototype
      coated tablet formulations of GSK2982772. The study is divided into two parts; Part A and
      Part B. The MR tablet coating used in Part A and the initial periods of Part B will have an
      aperture drilled into the enteric coating of either side of the tablet. This allows some drug
      release to commence in the stomach whilst providing controlled release throughout the
      gastrointestinal (GI) tract. In Part B only, a new investigational medicinal product (IMP)
      will be manufactured to allow comparison of the tablet coating either with apertures (i.e.,
      drilled) or without apertures (i.e., full coat/non drilled). Part A will be a 6-period, 6-way
      fixed sequence design, up to 4 MR tablet prototype coated formulations will be evaluated in
      fasted state at 240 milligrams (mg). Periods 1, 2 and 3 will evaluate MR1, IR tablet and MR2
      respectively. Periods 4, 5 and 6 will be flexible and the dosing regimen will be dependent on
      the outcome of Periods 1 to 3. In addition, the impact of food (high fat meal, standard
      breakfast or administration 30 or 60 minutes before a standard breakfast) on selected MR
      prototype coated tablet formulations may also be evaluated in Period 4, 5 or 6 of Part A.
      Each inpatient period for MR regimens (Periods 1, 3, 4 to 6) will consist of 4 days and 3
      nights, and the inpatient period for the IR tablet (Period 2) will consist of 3 days and 2
      nights. There will be a minimum washout of 7 days between doses, and a follow-up visit will
      occur at 7 to 9 days after the last study treatment. The Part B of the study will be a
      7-period fixed sequence which will evaluate the selected MR prototype coated tablet
      formulation(s) at different tablet strengths or as multiple unit doses and with or without
      apertures in the tablet coatings. There will be an interim review after each period 1 to 5 of
      Part B to select the dose level, formulation and prandial status for each subsequent period.
      An interim data review after Part B Period 6 will determine if optional Period 7 is required
      and the dose level, dosing time (morning or evening), formulation and prandial status for
      that period. Each inpatient period will consist of a 4-day and 3-night with a minimum of 7
      days washout between doses. A follow-up visit will occur at 7 to 9 days after the last study
      treatment. Approximately 33 subjects will be enrolled in the study. The total duration for
      Part A will be approximately 10-12 weeks and 10-14 weeks for Part B (including screening
      period of approximately 4 weeks).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject at the time of participation must be 18 to 65 years of age.

          -  Subjects who are overtly healthy as determined by medical evaluation including medical
             history, physical examination, laboratory tests, and cardiac monitoring.

          -  Body weight greater than or equal to 50 kilogram (kg) and body mass index within the
             range 19.0 to 32.0 kg per squared meter (kg/m^2) (inclusive).

          -  Male or female subjects where male subjects are eligible to participate if they agree
             to the following during the intervention period until completion of the final follow
             up visit after the last dose of study treatment; refrain from sperm donation; plus
             either be abstinent from heterosexual or homosexual intercourse as their preferred and
             usual lifestyle (abstinent on a long term and persistent basis) and agree to remain
             abstinent; or must agree to use contraception/barrier like use a male condom and
             should also be advised of the benefit for a female partner to use a highly effective
             method of contraception as a condom may break or leak when having sexual intercourse
             with a woman of childbearing potential who is not currently pregnant; agree to use
             male condom when engaging in any activity that allows for passage of ejaculate to
             another person.

          -  The eligible female subjects can 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); is a WOCBP and using a contraceptive method that is highly
             effective (with a failure rate of less than 1 percentage per year), preferably with
             low user dependency, for at least 30 days before first dose until completion of the
             final follow up visit after the last dose of study treatment and agrees not to donate
             eggs (ova, oocytes) for the purpose of reproduction from Day 1 until 3 months after
             the last dose. The investigator should evaluate the effectiveness of the contraceptive
             method in relationship to the first dose of study intervention; a WOCBP must have a
             negative highly sensitive serum pregnancy test within 24 hours before the first dose
             of study intervention; additional requirements for pregnancy testing during and after
             study intervention must be followed; the investigator is responsible for review of
             medical history, menstrual history, and recent sexual activity to decrease the risk
             for inclusion of a woman with an early undetected pregnancy.

          -  Capable of giving an 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.

          -  Any history of suicidal behavior within the past 6 months or any history of attempted
             suicide in subject's lifetime.

          -  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. Hayfever is allowed unless it is active.

          -  Alanine transaminase (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 (QTcF) greater than 450 milliseconds (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 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 plus 5 half
             lives, of the last dose of study medication.

          -  Participation in the study would result in loss of blood or blood products in excess
             of 500 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.

          -  Current or history of renal disease or estimated glomerular filtration rate by chronic
             kidney disease epidemiology collaboration (CKD-EPI) equation calculation less than 60
             milliliter (mL) per minute per 1.73 m^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.

          -  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 than14 units for females.
             One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 mL) of
             beer or 1 (25 mL) measure of spirits, 1.5 to 2 units is 1 glass (125 mL) of wine,
             depending on type.

          -  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.

          -  Subjects who do not have suitable veins for multiple venipuncture's/cannulation as
             assessed by the investigator at screening.

          -  Total cholesterol greater than or equal to 300 mg per deciliter (mg/dL) (greater than
             or equal to 7.77 millimole 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 or sponsor employees, or immediate family members of a
             study site or sponsor employee.