Absorption & Elimination of Radiolabelled GSK2269557
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Pulmonary Disease, Chronic Obstructive
Intervention: [14C]-GSK2269557 IV infusion; GSK2269557 via DPI; [14C]-GSK2269557 oral solution
Intervention description: The [14C]-GSK2269557 solution will be available in dosing strength of 10 µg, administered as single dose IV infusion over 15 minutes. It will be prepared by dissolving a hemisuccinate salt (GSK2269557T) in normal saline.; GSK2269557 DPI will be available with dosing strength of 1000 µg, administered as oral inhalation intended to inhale twice. It will be prepared by blending GSK2269557 hemisuccinate salt (GSK2269557H) with lactose and magnesium stearate.; The [14C]-GSK2269557 solution will be available with dosing strength of 800 µg, administered as single dose orally. It will be prepared by dissolving [14C]-GSK2269557 hemisuccinate salt (GSK2269557T) in water.
Intervention MeSH terms: Nemiralisib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Intervention model description: This will be a 2-period, single-sequence crossover study. Subjects will receive IV and inhaled doses of GSK2269557 in treatment period 1 and oral dose of GSK2269557 in treatment period 2.
Masking: None (Open Label)
Masking description: This will be an open-label study. Hence, masking will not be provided to the subjects.
Enrollment: 6.0
Sex: Male
Minimum age: 30 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: GSK2269557; Pharmacokinetics; Radiolabel; Healthy; Excretion; Bioavailability

Summary:

      GSK2269557 is being developed as an anti-inflammatory agent for the treatment of chronic
      obstructive pulmonary disease (COPD) and other inflammatory lung diseases such as asthma.
      This study is designed to investigate the recovery, excretion, and pharmacokinetics (PK) of
      (14 Carbon [C])-GSK2269557 administered as a single intravenous (IV) dose (concomitant with
      an inhaled non-radiolabelled dose) and as a single oral dose in 6 healthy male subjects.
      Subjects will receive [14C] radiolabelled GSK2269557 administered as IV infusion, with a
      nonradiolabelled dose of GSK2269557 via dry powder inhaler (DPI) in treatment period 1 and a
      single dose of [14C]-GSK2269557, administered as an oral solution in treatment period 2.
      There will be a washout period of at least 14 days after inhaled and IV dosing before
      subjects takes part in treatment period 2. The IV microtracer dose of GSK2269557 will be
      administered concomitant to an inhaled non-radiolabelled dose to ensure that the
      pharmacokinetics represent a clinically relevant dose. The total study duration will be up to
      11 weeks, including a screening visit, 2 treatment periods and a follow-up visit.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject must be 30 to 55 years of age inclusive, at the time of signing the informed
             consent.

          -  Subjects who are overtly 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 cardiac monitoring; A subject with a
             clinical abnormality or laboratory parameter(s) which is/are not specifically listed
             in the inclusion or exclusion criteria, outside the reference range for the population
             being studied 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.

          -  A history of regular bowel movements (averaging one or more bowel movements per day).

          -  Body weight >= 50 kilograms (Kg) and body mass index (BMI) within the range 19.0-31.0
             kg per meter square (kg/m^2) (inclusive).

          -  Male subjects will be included.

          -  Subjects with female partners of childbearing potential must agree to use
             contraception during the treatment period, from the time of first dose of study
             medication until follow-up, and refrain from donating sperm during this period.

          -  Capable of giving signed informed consent.

        Exclusion Criteria:

          -  Alanine aminotransferase (ALT) > 1.5x Upper limit of normal (ULN).

          -  Bilirubin > 1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is
             fractionated and direct bilirubin < 35%).

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Mean QT duration corrected for heart rate by Fridericia's formula (QTCF) > 450
             milliseconds (msec).

          -  Any clinically relevant abnormality identified at the screening medical assessment
             (physical examination/medical history), clinical laboratory tests, or 12-lead ECG.

          -  A pre-existing condition(s) interfering with normal gastrointestinal (GI) anatomy or
             motility, including constipation, malabsorption or other GI dysfunction which may
             interfere with the absorption, distribution, metabolism or elimination of the study
             drug. Subjects with a history of cholecystectomy must be excluded.

          -  At screening, a supine or semi-supine BP that is persistently higher (triplicate
             measurements at least 2 minutes apart than 140/90 millimeters of mercury (mmHg).

          -  At screening, a supine or semi-supine mean heart rate (HR) outside the range 40-90
             beats per minute (BPM).

          -  Subject is mentally or legally incapacitated.

          -  A history of respiratory disease (example given [e.g.] history of asthma) in the last
             10 years.

          -  Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
             supplements (including St John's Wort) within 7 days (or 14 days if the drug is a
             potential enzyme inducer) or 5 half-lives (whichever is longer) before the first dose
             of study medication, unless in the opinion of the investigator and GlaxoSmithKline
             (GSK) Medical Monitor the medication will not interfere with the study procedures or
             compromise subject safety.

          -  Need of Paracetamol or Acetaminophen, at doses of > 2 grams (g)/day. Other concomitant
             medication may be considered on a case by case basis by the GSK Medical Monitor.

          -  The subject has participated in a clinical trial and has received an investigational
             product (IP) within 3 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 subject's previous effective dose will be reviewed by the
             medical investigator to ensure there is no risk of contamination/carryover into the
             current study.

          -  Presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test
             result at screening.

          -  Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3
             months prior to first dose of study treatment.

          -  A positive test for Human Immunodeficiency Virus (HIV) antibody.

          -  A positive pre-study drug/alcohol screen.

          -  Exposure to more than four new chemical entities within 12 months before the subject's
             first dose.

          -  Subjects have received a total body radiation dose of greater than 5.0 micro sievert
             (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 12 months before this study.

          -  An occupation which requires monitoring for radiation exposure, nuclear medicine
             procedures or excessive x-rays within the past 12 months.

          -  Participation in the study would result in donation of blood or blood products in
             excess of 500 milliliters (mL) within a 90 day period.

          -  Unwillingness or known inability to follow the procedures outlined in the protocol,
             including the use of the Enterotest capsule.

          -  History of regular alcohol consumption within 6 months of the study, defined as an
             average weekly intake of >21 units. One unit is equivalent to 8 g of alcohol: a
             halfpint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure
             of spirits.

          -  Urinary cotinine levels indicative of smoking; current smoker; or ex-smokers who gave
             up less than 6 months ago or who have a history of more than 10 pack-years. Pack-years
             = cigarettes per day x number of years smoked/20