Absorption and Elimination of Radiolabeled Daprodustat
Condition: Anaemia
Intervention: [14C]-GSK1278863 solution for IV infusion; [14C]-GSK1278863 oral solution; Daprodustat 6 mg oral tablet
Intervention description: It is a clear, colorless solution free from visible particulate matter. Participants will receive 10 mL of 5 µg/mL of [14C]-GSK1278863 IV solution (total dose: 50 µg) by IV infusion over 1 hour.; It is a clear, colorless solution. Participants will receive 125 mL of 200 µg/mL of [14C]-GSK1278863 oral solution (total dose: 25 mg).; It is a 9.0 millimeter (mm) round, white film coated tablet.
Intervention MeSH terms: Pharmaceutical Solutions; Glycine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: Male
Minimum age: 30 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: GSK1278863; pharmacokinetics; mass balance; daprodustat

Summary:

      Absorption, metabolism and excretion of daprodustat (GSK1278863) have been studied in
      previous clinical trials; however, the elimination routes and metabolic pathways of
      daprodustat have not been fully elucidated in humans. This is an open-label, single-center,
      non-randomized, 2-period, single-sequence, crossover, mass balance study in 6 healthy male
      participants. The aim of the study is to assess the excretion balance of daprodustat using
      [14C]-radiolabeled drug substance administered orally, and as an intravenous (IV) infusion,
      administered as a microtracer dose (concomitant with an oral, non-radiolabeled dose).
      Absolute bioavailability of an oral dose will also be assessed. Each participant will be
      involved in the study for up to 10 weeks which include a screening visit, two treatment
      periods (treatment periods 1 and 2), separated by about 7 days (at least 14 days between oral
      doses), and a follow up visit 1-2 weeks after the last assessment in treatment period 2. The
      primary objective of the study is to gain a better understanding of the compound's excretory
      and metabolic profile. This study will include sampling of duodenal bile to conduct
      qualitative assessment of drug metabolites in this matrix in order to characterize biliary
      elimination pathways.
    

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 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 and documents that the finding is unlikely to introduce additional
             risk factors and will not interfere with the study procedures.

          -  Hemoglobin value at screening greater than the lower limit of the laboratory reference
             range and less than or equal to 16.0 gram (g) per deciliter (dL).

          -  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 (kg) and above, and body mass index (BMI) within the range
             19.0-31 kg per meter (m)^2 (inclusive).

          -  Participants must agree to use contraception as follows: participants with female
             partners of childbearing potential must agree to use a condom from the time of first
             dose of study treatment until 1 month after their last dose.

          -  Capable of giving signed informed consent.

          -  Willingness to give written consent to have data entered into The Over-volunteering
             Prevention System.

        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). Participants
             with a history of cholecystectomy must be excluded.

          -  Any clinically relevant abnormality identified at the screening medical assessment
             (physical examination/medical history), clinical laboratory tests, or 12-lead ECG.

          -  Myocardial infarction or acute coronary syndrome <=12 weeks prior to screening through
             to enrollment (Day 1, treatment period 1).

          -  History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal
             (GI), endocrine, hematological, or neurological disorders capable of significantly
             altering the absorption, metabolism, or elimination of drugs, or which could
             constitute a risk when taking the study treatment, or interfere with the
             interpretation of data.

          -  Evidence of actively bleeding gastric, duodenal or esophageal ulcer disease OR
             clinically significant GI bleeding <=12 weeks prior to screening through to enrollment
             (Day 1, treatment period 1).

          -  History of malignancy within the two years before dosing, with the exception of
             localized squamous cell or basal cell carcinoma of the skin that has been definitively
             treated prior to screening; currently receiving treatment for cancer; has a strong
             family history of cancer (e.g., familial cancer disorders).

          -  Mentally or legally incapacitated.

          -  Heart Failure: Class II, III or IV heart failure, as defined by the New York Heart
             Association (NYHA) functional classification system.

          -  Any 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.

          -  Daprodustat is a substrate of cytochrome P4502C8 (CYP2C8). Co-administration of drugs
             that are inhibitors of this enzyme are prohibited.

          -  Past or intended use of over-the-counter or prescription medication including herbal
             medications prior to dosing except occasional use of paracetamol (acetaminophen),
             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 treatment until completion of
             the follow-up visit, unless in the opinion of the investigator and GSK medical monitor
             the medication will not interfere with the study.

          -  Current enrolment in a clinical trial; recent participation in a clinical trial and
             has received an investigational product within 3 months before their first dose in the
             current study.

          -  Exposure to more than 4 new chemical entities within 12 months before their first dose
             in the current study.

          -  Participation in a clinical trial involving administration of 14C-labelled compound(s)
             within the last 12 months. A participant's 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 (mSv) (upper
             limit of world health organization [WHO] 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 times 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%).

          -  QTc >500 millisecond (msec). The QTc must be the QTcB.

          -  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
             treatment.

          -  Positive pre-study drug/alcohol screen.

          -  Positive human immunodeficiency virus (HIV) antibody test.

          -  Regular use of known drugs of abuse.

          -  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 g of alcohol: a glass
             (approximately 240 milliliter [mL]) of beer, 1 small glass (approximately 100 mL) of
             wine or 1 (approximately 25 mL) measure of spirits.

          -  At screening, a supine blood pressure (BP) that is persistently higher than 140/90
             millimeters of mercury (mmHg) taken in triplicate, unless deemed not clinically
             significant by the investigator.

          -  At screening, a supine mean heart rate (HR) 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.

          -  Participation in the study would result in donation of blood or blood products in
             excess of 550 mL within a 90 day period.

          -  Unwillingness or inability to follow the procedures, including the use of the
             Entero-Test capsule.

          -  Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or
             nicotine-containing products in the 6 months prior to screening.

          -  History of drug abuse or dependence within 6 months of the study.

          -  History of sensitivity to daprodustat, or their components thereof, or a history of
             drug or other allergy that, in the opinion of the investigator or GSK medical monitor,
             contraindicates their participation.