Linerixibat and Obeticholic Acid Drug Interaction Study in Healthy Subjects
Condition: Cholestasis
MeSH terms: Cholestasis
Intervention: GSK2330672 (linerixibat); Obeticholic acid
Intervention description: GSK2330672 is available as a tablet with unit dose strength of 45 mg.; Obeticholic acid is available as a tablet with a unit dose strength of 10 mg (or 5 mg dependent on evaluation of Part A).
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Intervention model description: This will be a non-randomized study. Eligible subjects will receive OCA and OCA+linerixibat in a fixed sequence.
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: linerixibat (GSK2330672), obeticholic acid, drug interaction, primary biliary cholangitis, pharmacokinetics

Summary:

      In participants with inadequate response/intolerance to ursodeoxycholic acid (UDCA) taking
      obeticholic acid (OCA) who experience pruritus (due to primary biliary cholangitis [PBC],
      OCA, or both) the addition of linerixibat to OCA therapy may be considered following
      marketing approval. It is therefore important to characterize any potential effect of
      linerixibat on the pharmacokinetics of OCA in humans at clinically relevant dosages.
      Accordingly, a drug-drug interaction (DDI) study with linerixibat (potential perpetrator) and
      OCA (potential victim) will be conducted to inform both future clinical trials with
      linerixibat and the potential concomitant administration of these drugs in a clinical
      setting. This is a single-center, one part (with optional second part) open-label, single
      sequence crossover, drug interaction study to investigate the effect of linerixibat on plasma
      concentrations of OCA and OCA conjugates in healthy participants. Approximately 19
      participants will be enrolled in part A and further 19 participants in part B (if performed)
      in the study and will have a phone call follow-up till 7-14 days post-last linerixibat dose.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Between 18 and 80 years of age inclusive, at the time of signing the informed consent.

          -  Healthy, as determined by the investigator or medically qualified designee, based on a
             medical evaluation including medical history, physical examination, vital signs,
             laboratory tests, and ECG. A participant with a clinical abnormality or laboratory
             parameter (i.e., outside the reference range for the population being studied), which
             is not specifically listed in the eligibility criteria, may be included only if the
             investigator agrees in consultation with the GlaxoSmithKline (GSK) medical monitor and
             documents in the source documentation that the finding is unlikely to introduce
             additional risk factors and will not interfere with the study procedures or outcomes.

          -  Body weight > 50 kilogram (kg) and body mass index (BMI) within the range 18.5 to 32
             kg per square meter (inclusive).

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF) and protocol.

          -  Male and female- A female participant is eligible to participate if she is not
             pregnant not breastfeeding, and at least one of the following conditions applies; not
             a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow
             contraceptive guidance during the treatment period and until at least 4 weeks after
             the last dose of study treatment. 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.

        Exclusion Criteria:

          -  Any active dermatologic disorder leading to or with the potential to cause pruritus or
             a recent history of unexplained clinically significant itching locally or generally
             within the prior 3 months

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones) and/or confirmed
             hepatocellular carcinoma or biliary cancer

          -  Participants with a history of cholecystectomy

          -  Current symptomatic cholelithiasis or inflammatory gall bladder disease

          -  Significant history of or current cardiovascular, respiratory, hepatic, renal,
             gastrointestinal, endocrine, hematological, or neurological disorders capable of
             significantly altering the absorption, metabolism, or elimination of drugs;
             constituting a risk when taking the study intervention; or interfering with the
             interpretation of data

          -  Any clinically relevant abnormality identified at the screening medical assessment
             (physical examination/medical history) clinical laboratory tests, or 12-lead ECG

          -  Current episode, recent history (within 1 month of screening visit), or chronic
             history of clinically significant diarrhea

          -  Lymphoma, leukaemia, or any malignancy within the past 5 years except for basal cell
             or squamous epithelial carcinomas of the skin that have been resected with no evidence
             of metastatic disease for 3 years

          -  Any current medical condition (e.g. psychiatric disorder, senility, dementia, or other
             condition), clinical or laboratory abnormality, or examination finding that the
             investigator considers would put the participant at unacceptable risk, which may
             affect study compliance or prevent understanding of the aims or investigational
             procedures or possible consequences of the study

          -  Regular use of known drugs of abuse or history of drug abuse or dependence within 6
             months of the study

          -  Regular alcohol consumption within 6 months prior to the study defined as an average
             weekly intake of >14 units for females and >21 units for males. One unit is equivalent
             to 8 gram of alcohol: a glass (approximately [~] 240 milliliter [mL]) of beer, 1 small
             glass (~100 mL) of wine or 1 (~25 mL) measure of spirits

          -  History of or regular use of tobacco- or nicotine-containing products (confirmed by
             smokerlyzer test) in the 3 months prior to screening.

          -  Administration of any IBAT inhibitor (including linerixibat) or OCA in the 3 months
             prior to screening

          -  Past or intended use of over-the-counter or prescription medication (including
             vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a
             potential enzyme inhibitor) or 5 half-lives (whichever is longer) prior to the first
             dose of study medication, unless approved by the investigator in conjunction with GSK
             medical monitor.

          -  Current enrollment in a clinical trial, recent participation in a clinical trial and
             has received an investigational product within 30 days (or 5 half-lives of previous
             trial intervention, whichever is longer) before the first dose in the current study

          -  Exposure to more than 4 new chemical entities within 12 months before the first dose
             in the current study.

          -  Screening ALT or AST >1.5 times the upper limit of normal (ULN)

          -  Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin
             is fractionated and direct bilirubin <35%)

          -  Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C
             antibody test result at screening or within 3 months of the screening visit

          -  Positive serum pregnancy test at screening or positive urine pregnancy test at
             admission in WOCBP only

          -  Positive human immunodeficiency virus (HIV) antibody test

          -  QTc >450 millisecond (msec) on ECG performed at screening.

          -  Positive pre-study drug/alcohol screen or positive drug/alcohol screen at any time
             during the study.

          -  Female participants unable or unwilling to comply with specific contraception
             restrictions.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56-day period.

          -  Unwillingness or inability to follow the procedures outlined in the protocol for the
             expected duration of study participation.

          -  Sensitivity 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.