Absorption & Elimination of Radiolabelled GSK2269557

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03315559
• Collaborator: (none)
• Enrollment: 6
• Location: 1
• Arms: 2
• Actual Duration (Months): 1.2
• Patients Per Site Per Month: 4.8

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: [14C]-GSK2269557 IV infusion; Drug: GSK2269557 via DPI; Drug: [14C]-GSK2269557 oral solution	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• 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.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.
• Primary Purpose: Treatment
• Official Title: An Open-label Study in Healthy Male Subjects, to Determine the Excretion Balance and Pharmacokinetics of [14C]-GSK2269557, Administered as a Single Intravenous Microtracer (Concomitant With an Inhaled Non-radiolabelled Dose) and a Single Oral Dose
• Actual Study Start Date: Nov 14, 2017
• Actual Primary Completion Date: Dec 22, 2017
• Actual Study Completion Date: Dec 22, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Subjects receiving GSK2269557 in treatment period 1 Eligible subjects will receive IV infusion of [14C] radiolabelled GSK2269557 with a single dose of 10 micrograms (µg) administered as single microtracer, concomitantly with an inhaled nonradiolabelled 1000 µg dose of GSK2269557. There will be a washout of at least 14 days after inhaled and IV dosing before subjects receive treatment 2.	Drug: [14C]-GSK2269557 IV infusion; 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.; Drug: GSK2269557 via DPI; 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.; Drug: [14C]-GSK2269557 oral solution; 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.
Experimental: Subjects receiving GSK2269557 in treatment period 2 Eligible subjects will receive [14C]-GSK2269557 with a single dose of 800 µg, administered as an oral solution.	Drug: [14C]-GSK2269557 IV infusion; 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.; Drug: GSK2269557 via DPI; 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.; Drug: [14C]-GSK2269557 oral solution; 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.

Outcome Measures

Primary Outcome Measures

1. Area Under Concentration-time Curve (AUC) From Time 0 (Pre-dose) to Infinite Time (0 to Inf) and AUC From Time 0 (Pre-dose) to Last Time of Quantifiable Concentration (0 to t) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1 [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic (PK) Population comprised of participants in the APE Population who received at least one dose of study treatment and for whom a PK sample was obtained and analyzed. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.

2. AUC From Time Zero (Pre-dose) Extrapolated to Infinite Time (0 to Inf) and AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (0 to t) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2 [Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. Only those participants available at the specified time points were analyzed represented by n=X in the category titles. NA indicates that data is not available as single participant was analyzed.

3. Maximum Observed Concentration (Cmax) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1 [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

   Blood samples were collected at indicated time points for pharmacokinetic analysis.

4. Cmax of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2 [Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose]

   Blood samples were collected at indicated time points for pharmacokinetic analysis.

5. Time of Occurrence of Cmax (Tmax) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1 [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

   Blood samples were collected at indicated time points for pharmacokinetic analysis.

6. Tmax of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2 [Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose]

   Blood samples were collected at indicated time points for pharmacokinetic analysis.

7. Terminal Phase Half-life (t1/2) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1 [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

   Blood samples were collected at indicated time points for pharmacokinetic analysis.

8. Terminal Phase Half-life (t1/2) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2 [Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. NA indicates that data is not available as single participant was analyzed.

9. Urinary and Faecal Cumulative Excretion as a Percentage of the Total Radioactive Dose Administered Over Time for Treatment Period 1 [Up to 168 hours]

   Urine samples and fecal samples were collected to measure total radiolabeled drug-related material excreted in urine and feces respectively.

10. Urinary and Fecal Cumulative Excretion as a Percentage of the Total Radioactive Dose Administered Over Time for Treatment Period 2 [Up to 336 hours]

    Urine samples and fecal samples were collected to measure total radiolabeled drug-related material excreted in urine and feces respectively. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.

Secondary Outcome Measures

1. AUC (0 to Inf) and AUC (0 to t) of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1 [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS, whereas GSK2269557 describes the parent GSK2269557 concentration derived via LC/MS. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.

2. AUC (0 to Inf) and AUC (0 to t) of [14C]-GSK2269557 in Plasma for Treatment Period 2 [Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. Only those participants with data available at the specified time points were analyzed represented by n=X in the category titles. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.

3. Cmax of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1 [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS, whereas GSK2269557 describes the parent GSK2269557 concentration derived via LC/MS.

4. Cmax of [14C]-GSK2269557 in Plasma for Treatment Period 2 [Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.

5. Tmax of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1 [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS, whereas GSK2269557 describes the parent GSK2269557 concentration derived via LC/MS.

6. Tmax of [14C]-GSK2269557 in Plasma for Treatment Period 2 [Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.

7. t1/2 of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1 [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS, whereas GSK2269557 describes the parent GSK2269557 concentration derived via LC/MS. Only those participants available at the indicated time points were analyzed represented by n=X in the category titles.

8. t1/2 of [14C]-GSK2269557 in Plasma for Treatment Period 2 [Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.

9. Volume of Distribution of Parent [14C]-GSK2269557 After IV Dose Only in Plasma [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

   Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.

10. Clearance of Parent [14C]-GSK2269557 After IV Dose Only in Plasma [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

    Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.

11. Inhaled Absolute Bioavailability (F) for Treatment Period 1 [Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion]

    Absolute bioavailability (F) was estimated for the inhaled doses for each participant and is reported. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.

12. Oral Absolute Bioavailability (F) for Treatment Period 2 [Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose]

    Absolute bioavailability (F) was estimated for the oral doses for each participant and is reported. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.

13. Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [Up to 11 weeks]

    AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with use of a medicinal product (MP), whether or not considered related to MP. AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with use of MP. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or all events of possible drug induced liver injury with hyperbilirubinemia.

14. Number of Participants With Hematology Parameters of Potential Clinical Concern [Up to 11 weeks]

    Hematology parameters included basophils, eosinophils, erythrocytes, monocytes, hematocrit, hemoglobin, lymphocytes, neutrophil count, platelet count and white blood cells. Number of participants with hematology parameters of potential clinical concern are presented.

15. Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern [Up to 11 weeks]

    Clinical chemistry parameters included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin, chloride, cholesterol, gamma glutamyl transferase, globulin, protein, triglycerides, urate, albumin, calcium, creatinine, glucose, phosphorous, potassium, urea and sodium. Number of participants with clinical chemistry parameters of potential clinical concern are presented.

16. Number of Participants With Clinically Significant Urinalysis Findings [Up to 168 hours]

    Urine samples were collected to detect the presence of bilirubin, glucose, ketones, leukocyte esterase, nitrite, occult blood, protein and urobilinogen. Urinalysis also included measurement of specific gravity and pH. Number of participants with clinically significant urinalysis findings are presented.

17. Number of Participants With Electrocardiogram Findings of Clinical Significance [Up to 11 weeks]

    Twelve-lead electrocardiogram was measured in a supine or semi-supine position after 5 minutes rest. Number of participants with electrocardiogram findings of clinical significance are presented.

18. Number of Participants With Vital Signs of Potential Clinical Concern [Up to 11 weeks]

    Vital signs were measured in a supine or semi-supine position after 5 minutes rest and included temperature, systolic and diastolic blood pressure and pulse and respiratory rate. Number of participants with vital signs of potential clinical concern are reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	London		United Kingdom	NW10 7EW

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Oct 30, 2017
• Statistical Analysis Plan - Jan 9, 2018

More Information

Publications

• Harrell AW, Wilson R, Man YL, Riddell K, Jarvis E, Young G, Chambers R, Crossman L, Georgiou A, Pereira A, Kenworthy D, Beaumont C, Marotti M, Wilkes D, Hessel EM, Fahy WA. An Innovative Approach to Characterize Clinical ADME and Pharmacokinetics of the Inhaled Drug Nemiralisib Using an Intravenous Microtracer Combined with an Inhaled Dose and an Oral Radiolabel Dose in Healthy Male Subjects. Drug Metab Dispos. 2019 Dec;47(12):1457-1468. doi: 10.1124/dmd.119.088344. Epub 2019 Oct 24.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03315559
• Other Study ID Numbers: 206764; 2017-002347-16
• First Posted: Oct 20, 2017
• Last Update Posted: Mar 13, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: GSK2269557; Pharmacokinetics; Radiolabel; Healthy; Excretion; Bioavailability
• Additional relevant MeSH terms: Pulmonary Disease, Chronic Obstructive; Nemiralisib

Study Results

Participant Flow

Recruitment Details	The study was conducted at a single center in the United Kingdom from 14-November-2017 to 22-December-2017.
Pre-assignment Detail	A total of 7 participants were screened, of which 1 participant was a reserve participant and was not used. The remaining 6 participants were enrolled.

Arm/Group Title	All Study Participants
Arm/Group Description	Participants received intravenous (IV) infusion of [14C] radiolabeled GSK2269557 along with a single dose of 10 micrograms (µg) administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557 in Treatment Period 1. There was a washout of at least 14 days. Participants received [14C]-GSK2269557 with a single dose of 800 µg, administered as an oral solution in Treatment Period 2.
Period Title: Treatment Period 1 (8 Days)
STARTED	6
COMPLETED	6
NOT COMPLETED	0
Period Title: Treatment Period 1 (8 Days)
STARTED	6
COMPLETED	6
NOT COMPLETED	0
Period Title: Treatment Period 1 (8 Days)
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	Participants received intravenous (IV) infusion of [14C] radiolabeled GSK2269557 along with a single dose of 10 micrograms (µg) administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557 in Treatment Period 1. There was a washout of at least 14 days. Participants received [14C]-GSK2269557 with a single dose of 800 µg, administered as an oral solution in Treatment Period 2.
Overall Participants	6
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43.3 (10.03)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	6 100%
Race/Ethnicity, Customized (Count of participants) [Number]
African American/African Heritage	2 33.3%
White - White/Caucasian/European Heritage	4 66.7%

Outcome Measures

1. Primary Outcome

Title	Area Under Concentration-time Curve (AUC) From Time 0 (Pre-dose) to Infinite Time (0 to Inf) and AUC From Time 0 (Pre-dose) to Last Time of Quantifiable Concentration (0 to t) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. Pharmacokinetic (PK) Population comprised of participants in the APE Population who received at least one dose of study treatment and for whom a PK sample was obtained and analyzed. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	6
AUC (0 to inf), n=3	812.8550 (8.17885)
AUC (0 to t), n=6	770.3316 (17.70272)

2. Primary Outcome

Title	AUC From Time Zero (Pre-dose) Extrapolated to Infinite Time (0 to Inf) and AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (0 to t) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. Only those participants available at the specified time points were analyzed represented by n=X in the category titles. NA indicates that data is not available as single participant was analyzed.
Time Frame	Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	14C-Nemi Oral
Arm/Group Description	Participants received [14C]-GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6
AUC (0 to inf), n=1	34749.40 (NA)
AUC (0 to t), n=6	31730.13 (35.715)

3. Primary Outcome

Title	Maximum Observed Concentration (Cmax) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	6
Geometric Mean (Geometric Coefficient of Variation) [Picogram Equivalent per milliliter]	204.4057 (52.32698)

4. Primary Outcome

Title	Cmax of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis.
Time Frame	Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	14C-Nemi Oral
Arm/Group Description	Participants received [14C]-GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6
Geometric Mean (Geometric Coefficient of Variation) [Picogram Equivalent per milliliter]	703.5192 (24.43331)

5. Primary Outcome

Title	Time of Occurrence of Cmax (Tmax) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	6
Median (Full Range) [Hours]	0.2333

6. Primary Outcome

Title	Tmax of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis.
Time Frame	Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	14C-Nemi Oral
Arm/Group Description	Participants received [14C]-GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6
Median (Full Range) [Hours]	7.0000

7. Primary Outcome

Title	Terminal Phase Half-life (t1/2) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population. Only those participants available at the indicated time points were analyzed.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	3
Geometric Mean (Geometric Coefficient of Variation) [Hours]	56.9152 (7.69827)

8. Primary Outcome

Title	Terminal Phase Half-life (t1/2) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. NA indicates that data is not available as single participant was analyzed.
Time Frame	Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose

Outcome Measure Data

Analysis Population Description

PK Population. Only those participants available at the indicated time points were analyzed.

Arm/Group Title	14C-Nemi Oral
Arm/Group Description	Participants received [14C]-GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	1
Geometric Mean (Geometric Coefficient of Variation) [Hours]	39.6279 (NA)

9. Primary Outcome

Title	Urinary and Faecal Cumulative Excretion as a Percentage of the Total Radioactive Dose Administered Over Time for Treatment Period 1
Description	Urine samples and fecal samples were collected to measure total radiolabeled drug-related material excreted in urine and feces respectively.
Time Frame	Up to 168 hours

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	6
Fe Feces, 0 to 24 hour	0.3961 (0.83271)
Fe Feces, 24 to 48 hour	2.1998 (3.77158)
Fe Feces, 48 to 72 hour	18.1265 (12.97670)
Fe Feces, 72 to 96 hour	28.0481 (18.22334)
Fe Feces, 96 to 120 hour	33.7465 (19.02044)
Fe Feces, 120 to 144 hour	45.2398 (14.63248)
Fe Feces, 144 to 168 hour	51.6981 (15.46780)
Fe Urine, 0 to 6 hour	2.1567 (0.83754)
Fe Urine, 6 to 24 hour	5.1183 (1.53825)
Fe Urine, 24 to 48 hour	7.6850 (2.04159)
Fe Urine, 48 to 72 hour	9.3483 (2.26387)
Fe Urine, 72 to 96 hour	10.7150 (2.46640)
Fe Urine, 96 to 120 hour	11.6400 (2.52790)
Fe Urine, 120 to 144 hour	12.3607 (2.56693)
Fe Urine, 144 to 168 hour	12.9205 (2.57056)
Fe Total (Urine+Feces), 0 to 24 hour	5.5145 (1.30554)
Fe Total (Urine+Feces), 24 to 48 hour	9.8848 (3.03062)
Fe Total (Urine+Feces), 48 to 72 hour	27.4748 (13.02973)
Fe Total (Urine+Feces), 72 to 96 hour	38.7631 (18.40877)
Fe Total (Urine+Feces), 96 to 120 hour	45.3865 (19.01459)
Fe Total (Urine+Feces), 120 to 144 hour	57.6005 (14.46954)
Fe Total (Urine+Feces), 144 to 168 hour	64.6186 (15.25339)

10. Primary Outcome

Title	Urinary and Fecal Cumulative Excretion as a Percentage of the Total Radioactive Dose Administered Over Time for Treatment Period 2
Description	Urine samples and fecal samples were collected to measure total radiolabeled drug-related material excreted in urine and feces respectively. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
Time Frame	Up to 336 hours

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	14C-Nemi Oral
Arm/Group Description	Participants received [14C]-GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6
Fe Feces, 0 to 24 hour; n=6	3.81330 (7.16484)
Fe Feces, 24 to 48 hour; n=6	14.6367 (21.64607)
Fe Feces, 48 to 72 hour; n=6	40.9583 (28.48392)
Fe Feces, 72 to 96 hour; n=6	48.8217 (29.60581)
Fe Feces, 96 to 120 hour; n=6	60.7617 (18.24192)
Fe Feces, 120 to 144 hour; n=6	64.1667 (19.65337)
Fe Feces, 144 to 168 hour; n=6	72.4217 (6.66365)
Fe Feces, 168 to 192 hour; n=6	75.1117 (5.29605)
Fe Feces, 192 to 216 hour; n=6	77.0917 (4.59090)
Fe Feces, 216 to 240 hour; n=6	77.5933 (4.12513)
Fe Feces, 240 to 264 hour; n=6	78.7917 (3.82906)
Fe Feces, 264 to 288 hour; n=5	78.6820 (4.07492)
Fe Feces, 288 to 312 hour; n=3	80.9500 (3.78747)
Fe Feces, 312 to 336 hour; n=3	81.1500 (3.57979)
Fe Urine, 0 to 6 hour; n=6	0.3867 (0.09668)
Fe Urine, 6 to 24 hour; n=6	1.7017 (0.42995)
Fe Urine, 24 to 48 hour; n=6	2.7183 (0.73249)
Fe Urine, 48 to 72 hour; n=6	3.4250 (0.89063)
Fe Urine, 72 to 96 hour; n=6	3.9600 (0.97980)
Fe Urine, 96 to 120 hour; n=6	4.3617 (1.02918)
Fe Urine, 120 to 144 hour; n=6	4.6717 (1.09549)
Fe Urine, 144 to 168 hour; n=6	4.9217 (1.12583)
Fe Urine, 168 to 192 hour; n=6	5.1383 (1.16426)
Fe Urine, 192 to 216 hour; n=6	5.2950 (1.16156)
Fe Urine, 216 to 240 hour; n=6	5.4700 (1.20854)
Fe Urine, 240 to 264 hour; n=6	5.5617 (1.24856)
Fe Urine, 264 to 288 hour; n=5	5.4760 (1.35858)
Fe Urine, 288 to 312 hour; n=3	5.7800 (1.43293)
Fe Urine, 312 to 336 hour; n=3	5.8133 (1.45590)
Fe Total (Urine+Feces), 0 to 24 hour; n=6	5.5150 (7.01205)
Fe Total (Urine+Feces), 24 to 48 hour; n=6	17.3550 (21.303)
Fe Total (Urine+Feces), 48 to 72 hour; n=6	44.3833 (28.28365)
Fe Total (Urine+Feces), 72 to 96 hour; n=6	52.7817 (29.36619)
Fe Total (Urine+Feces), 96 to 120 hour; n=6	65.1233 (17.8525)
Fe Total (Urine+Feces), 120 to 144 hour; n=6	68.8383 (19.24589)
Fe Total (Urine+Feces), 144 to 168 hour; n=6	77.3433 (6.27302)
Fe Total (Urine+Feces), 168 to 192 hour; n=6	80.2500 (4.74848)
Fe Total (Urine+Feces), 192 to 216 hour; n=6	82.3867 (3.98209)
Fe Total (Urine+Feces), 216 to 240 hour; n=6	83.0633 (3.3933)
Fe Total (Urine+Feces), 240 to 264 hour; n=6	84.3533 (3.17528)
Fe Total (Urine+Feces), 264 to 288 hour; n=5	84.158 (3.25412)
Fe Total (Urine+Feces), 288 to 312 hour; n=3	86.7300 (2.44851)
Fe Total (Urine+Feces), 312 to 336 hour; n=3	86.9633 (2.16207)

11. Secondary Outcome

Title	AUC (0 to Inf) and AUC (0 to t) of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS, whereas GSK2269557 describes the parent GSK2269557 concentration derived via LC/MS. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	6
GSK2269557: AUC (0 to inf), n=6	33374.56 (33.190)
GSK2269557: AUC (0 to t), n=6	28425.82 (34.474)
[14C]-GSK2269557: AUC (0 to inf), n=4	750.5798 (48.27760)
[14C]-GSK2269557: AUC (0 to t), n=6	546.4731 (45.31868)

12. Secondary Outcome

Title	AUC (0 to Inf) and AUC (0 to t) of [14C]-GSK2269557 in Plasma for Treatment Period 2
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. Only those participants with data available at the specified time points were analyzed represented by n=X in the category titles. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.
Time Frame	Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	14C-Nemi Oral
Arm/Group Description	Participants received [14C]-GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6
AUC (0 to inf), n=4	25107.96 (46.310)
AUC (0 to t), n=6	16913.06 (53.841)

13. Secondary Outcome

Title	Cmax of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS, whereas GSK2269557 describes the parent GSK2269557 concentration derived via LC/MS.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	6
GSK2269557	5258.98 (62.819)
[14C]-GSK2269557	205.6264 (57.91419)

14. Secondary Outcome

Title	Cmax of [14C]-GSK2269557 in Plasma for Treatment Period 2
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.
Time Frame	Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	14C-Nemi Oral
Arm/Group Description	Participants received [14C]-GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6
Geometric Mean (Geometric Coefficient of Variation) [Picograms per milliliter]	398.8822 (27.81929)

15. Secondary Outcome

Title	Tmax of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS, whereas GSK2269557 describes the parent GSK2269557 concentration derived via LC/MS.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	6
GSK2269557	0.0333
[14C]-GSK2269557	0.2333

16. Secondary Outcome

Title	Tmax of [14C]-GSK2269557 in Plasma for Treatment Period 2
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.
Time Frame	Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	14C-Nemi Oral
Arm/Group Description	Participants received [14C]-GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6
Median (Full Range) [Hours]	6.0000

17. Secondary Outcome

Title	t1/2 of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS, whereas GSK2269557 describes the parent GSK2269557 concentration derived via LC/MS. Only those participants available at the indicated time points were analyzed represented by n=X in the category titles.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	6
GSK2269557	58.4408 (16.84150)
[14C]-GSK2269557	54.7223 (35.98970)

18. Secondary Outcome

Title	t1/2 of [14C]-GSK2269557 in Plasma for Treatment Period 2
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.
Time Frame	Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose

Outcome Measure Data

Analysis Population Description

PK Population. Only those participants available at the indicated time points were analyzed.

Arm/Group Title	14C-Nemi Oral
Arm/Group Description	Participants received [14C]-GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	4
Geometric Mean (Geometric Coefficient of Variation) [Hours]	50.8028 (40.16665)

19. Secondary Outcome

Title	Volume of Distribution of Parent [14C]-GSK2269557 After IV Dose Only in Plasma
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	4
Vss	727.7102 (11.24581)
Vz	851.4423 (13.98220)

20. Secondary Outcome

Title	Clearance of Parent [14C]-GSK2269557 After IV Dose Only in Plasma
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis. For measured concentrations of GSK2269557 in blood plasma, the nomenclature [14C]-GSK2269557 describes the parent GSK2269557 concentration derived via analysis by LC+AMS.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population. Only those participants available at the indicated time points were analyzed.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	4
Geometric Mean (Geometric Coefficient of Variation) [Liters per hour]	10.7849 (46.70161)

21. Secondary Outcome

Title	Inhaled Absolute Bioavailability (F) for Treatment Period 1
Description	Absolute bioavailability (F) was estimated for the inhaled doses for each participant and is reported. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
Time Frame	Pre-dose and at 0 hour (post inhalation and pre-IV infusion), at the end of infusion and at 0.33, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours after the start of infusion

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.
Measure Participants	6
Inhaled F (0 to inf); n=4	0.3807 (19.65374)
Inhaled F (0 to t); n=6	0.4213 (21.84410)

22. Secondary Outcome

Title	Oral Absolute Bioavailability (F) for Treatment Period 2
Description	Absolute bioavailability (F) was estimated for the oral doses for each participant and is reported. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
Time Frame	Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, 96 and 168 h post-dose

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	14C-Nemi Oral
Arm/Group Description	Participants received [14C]-GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6
Oral F (0 to inf); n=4	0.3515 (3.35095)
Oral F (0 to t); n=6	0.3261 (12.77892)

23. Secondary Outcome

Title	Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Description	AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with use of a medicinal product (MP), whether or not considered related to MP. AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with use of MP. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or all events of possible drug induced liver injury with hyperbilirubinemia.
Time Frame	Up to 11 weeks

Outcome Measure Data

Analysis Population Description

Safety Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV	14C-Nemi Oral
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.	Participants received solution of [14C] radiolabelled GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6	6
AE	0 0%	1 NaN
SAE	0 0%	0 NaN

24. Secondary Outcome

Title	Number of Participants With Hematology Parameters of Potential Clinical Concern
Description	Hematology parameters included basophils, eosinophils, erythrocytes, monocytes, hematocrit, hemoglobin, lymphocytes, neutrophil count, platelet count and white blood cells. Number of participants with hematology parameters of potential clinical concern are presented.
Time Frame	Up to 11 weeks

Outcome Measure Data

Analysis Population Description

Safety Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV	14C-Nemi Oral
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.	Participants received solution of [14C] radiolabelled GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6	6
Count of Participants [Participants]	2 33.3%	1 NaN

25. Secondary Outcome

Title	Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern
Description	Clinical chemistry parameters included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin, chloride, cholesterol, gamma glutamyl transferase, globulin, protein, triglycerides, urate, albumin, calcium, creatinine, glucose, phosphorous, potassium, urea and sodium. Number of participants with clinical chemistry parameters of potential clinical concern are presented.
Time Frame	Up to 11 weeks

Outcome Measure Data

Analysis Population Description

Safety Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV	14C-Nemi Oral
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.	Participants received solution of [14C] radiolabelled GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6	6
Count of Participants [Participants]	0 0%	0 NaN

26. Secondary Outcome

Title	Number of Participants With Clinically Significant Urinalysis Findings
Description	Urine samples were collected to detect the presence of bilirubin, glucose, ketones, leukocyte esterase, nitrite, occult blood, protein and urobilinogen. Urinalysis also included measurement of specific gravity and pH. Number of participants with clinically significant urinalysis findings are presented.
Time Frame	Up to 168 hours

Outcome Measure Data

Analysis Population Description

Safety Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV	14C-Nemi Oral
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.	Participants received solution of [14C] radiolabelled GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6	6
Count of Participants [Participants]	0 0%	0 NaN

27. Secondary Outcome

Title	Number of Participants With Electrocardiogram Findings of Clinical Significance
Description	Twelve-lead electrocardiogram was measured in a supine or semi-supine position after 5 minutes rest. Number of participants with electrocardiogram findings of clinical significance are presented.
Time Frame	Up to 11 weeks

Outcome Measure Data

Analysis Population Description

Safety Population.

Arm/Group Title	Nemi IH + 14C-Nemi IV	14C-Nemi Oral
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.	Participants received solution of [14C] radiolabelled GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6	6
Count of Participants [Participants]	0 0%	0 NaN

28. Secondary Outcome

Title	Number of Participants With Vital Signs of Potential Clinical Concern
Description	Vital signs were measured in a supine or semi-supine position after 5 minutes rest and included temperature, systolic and diastolic blood pressure and pulse and respiratory rate. Number of participants with vital signs of potential clinical concern are reported.
Time Frame	Up to 11 weeks

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Nemi IH + 14C-Nemi IV	14C-Nemi Oral
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.	Participants received solution of [14C] radiolabelled GSK2269557 as a single dose of 800 µg, administered as an oral solution.
Measure Participants	6	6
High respiratory rate	1 16.7%	0 NaN
Low temperature	1 16.7%	0 NaN

Adverse Events

Time Frame	Serious and non serious adverse events were evaluated up to 11 weeks
Adverse Event Reporting Description	Safety Population was analyzed to collect serious adverse events (SAE) and non-serious adverse events (nSAE).
Arm/Group Title	Nemi IH + 14C-Nemi IV		14C-Nemi Oral
Arm/Group Description	Participants received IV infusion of [14C] radiolabeled GSK2269557 as a single dose of 10 µg administered as single microtracer, concomitantly with an inhaled non-radiolabeled 1000 µg dose of GSK2269557.		Participants received solution of [14C] radiolabelled GSK2269557 as a single dose of 800 µg orally
All Cause Mortality
	Nemi IH + 14C-Nemi IV		14C-Nemi Oral
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)
Serious Adverse Events
	Nemi IH + 14C-Nemi IV		14C-Nemi Oral
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Nemi IH + 14C-Nemi IV		14C-Nemi Oral
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		1/6 (16.7%)
General disorders
Malaise	0/6 (0%)	0	1/6 (16.7%)	1
Nervous system disorders
Headache	0/6 (0%)	0	1/6 (16.7%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.