Pharmacokinetics (PKs) and Metabolism of Radiolabelled Linerixibat
Condition: Cholestasis
MeSH terms: Cholestasis
Intervention: Linerixibat tablet; [14C]-linerixibat intravenous infusion; Linerixibat oral solution
Intervention description: Linerixibat will be available as white to slightly colored film-coated round tablet to be administered as two tablets taken in the fasted state in the morning with 240 milliliter (mL) of room temperature water.; [14C]-linerixibat will be available as clear, colorless solution free from visible particulates to be administered 25 mL IV over 3 hours immediately after the oral dose.; Linerixibat will be available as clear, colorless solution free from visible particulates to be administered 60 mL solution in the fasted state in the morning.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Intervention model description: Subjects will receive linerixibat tablets concomitantly with [14C]-linerixibat IV infusion in treatment Period 1 and [14C]-linerixibat oral solution in treatment Period 2.
Masking: None (Open Label)
Masking description: This will be an open-label study. Hence, there will be no masking.
Enrollment: 6.0
Sex: Male
Minimum age: 30 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: [14C]-linerixibat; GSK2330672; Microtracer dose

Summary:

      Absorption, metabolism and excretion of linerixibat have been studied in previous clinical
      trials. However, no dedicated clinical studies of drug absorption, metabolism, and excretion
      have been conducted for linerixibat. The purpose of this study is to determine the PK,
      balance/excretion, and metabolism of radiolabeled 14 Carbon [14C]-linerixibat following a
      single intravenous (IV) radiolabeled microtracer dose (concomitant with a non-radiolabeled
      oral dose) and a single oral radiolabeled dose. This is a single group, two period, single
      sequence, and mass balance study will enroll 6 healthy male subjects. Each subject will be
      involved in the study for up to 10 weeks which includes screening period, two treatment
      periods (treatment Periods 1 and 2), separated by about 7 days (at least 13 days between oral
      doses), and a follow-up visit 1-2 weeks after the last assessment in treatment Period 2.
    

Eligibility criteria:

        Inclusion Criteria

          -  Aged 30 to 55 years, 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 subject 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 and documents that the finding is unlikely to introduce additional
             risk factors and will not interfere with the study procedures.

          -  History of regular bowel movements (averaging one or more bowel movements per day).

          -  Non-smoker, or ex-smoker who hasn't regularly smoked for the 6 months before
             screening.

          -  Body weight of 50 kilogram and above, and body mass index (BMI) within the range 19.0
             to 31.0 kilogram per square meter (kg/m^2) (inclusive).

          -  Male only. Subjects must agree to use contraception as follows: subjects with female
             partners of childbearing potential must agree to use a condom from the time of first
             dose of study intervention until 1 month after their last dose.

          -  Capable of giving signed informed consent.

        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). Subjects with a
             history of cholecystectomy must be excluded.

          -  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, or chronic history of diarrhoea.

          -  Lymphoma, leukemia, 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 (example given [e.g.], psychiatric disorder, senility,
             dementia, or other condition), clinical or laboratory abnormality, or examination
             finding that the investigator considers would put the subjects 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 >21 units. One unit is equivalent to 8 gram of alcohol: a glass
             (approximately 240 mL) of beer, 1 small glass (approximately 100 mL) of wine or 1
             (approximately 25 mL) measure of spirits.

          -  History of or regular use of tobacco- or nicotine-containing products in the 6 months
             prior to screening.

          -  Past or intended use of over-the-counter or prescription medication, including
             analgesics (e.g., paracetamol), herbal medications, or grapefruit and Seville orange
             juices within 14 days prior to the first dose of study intervention until completion
             of the follow-up visit.

          -  Administration of any other Ileal bile acid transporter (IBAT) inhibitor in the 3
             months prior to screening.

          -  Current enrolment in a clinical trial; recent participation in a clinical trial and
             has received an investigational product within 3 months 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.

          -  Participation in a clinical trial involving administration of 14C-labelled compound(s)
             within the last 12 months. A subjects previous effective dose will be reviewed by the
             medical investigator to ensure there is no risk of contamination/carryover into the
             current study.

          -  Received a total body radiation dose of greater than 10.0 millisievert (upper limit of
             International Commission on Radiological Protection [IRCP] category II) or exposure to
             significant radiation (e.g., serial x-ray or computed tomography [CT] scans, barium
             meal, etc.) in the 3 years before this study.

          -  Alanine transaminase (ALT) >1.5* upper limit of normal (ULN).

          -  Bilirubin >1.5*ULN (isolated bilirubin >1.5*ULN is acceptable if bilirubin is
             fractionated and direct bilirubin <35 percent [%]).

          -  Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C
             antibody test result at screening or within 3 months before the first dose of study
             intervention.

          -  Screening estimated glomerular filtration rate (eGFR) <45 milliliter per minute per
             1.73 square meter (mL/min/1.73m^2) based on the Modification of Diet in Renal Disease
             (MDRD) Study equation.

          -  Positive pre-study drug/alcohol screen.

          -  Urinary cotinine levels indicative of smoking.

          -  Positive human immunodeficiency virus (HIV) antibody test.

          -  QT duration corrected for heart rate by Fridericia's formula >450 millisecond on ECG
             performed at Screening

          -  At screening or prior to the first dose, a supine blood pressure that is persistently
             higher than 140/90 millimeters of mercury (mmHg) taken in triplicate, unless deemed
             not clinically significant by the investigator.

          -  At screening or prior to the first dose, a supine mean heart rate outside the range of
             40-100 beats per minute, unless deemed not clinically significant by the investigator.

          -  Has had an occupation which requires monitoring for radiation exposure, nuclear
             medicine procedures, or excessive x-rays within the past 12 months.

          -  Unable to refrain from consumption of prohibited food and drinks from 7 days before
             the first dose of study medication until the follow up visit.

          -  Loss of more than 400 mL blood during the 3 months before screening, e.g. as a blood
             donor, or plan to donate blood or blood products in the 3 months after the end of the
             trial.

          -  Unwillingness or inability to follow the procedures outlines in the protocol,
             including the use of the string bile collection device.

          -  History of sensitivity to linerixibat, or their components thereof, or a history of
             drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline
             Medical Monitor, contraindicates their participation.