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Absorption & Elimination of Radiolabelled GSK2269557

Primary Purpose

Pulmonary Disease, Chronic Obstructive

Status
Completed
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
[14C]-GSK2269557 IV infusion
GSK2269557 via DPI
[14C]-GSK2269557 oral solution
Sponsored by
GlaxoSmithKline
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Disease, Chronic Obstructive focused on measuring GSK2269557, Pharmacokinetics, Radiolabel, Healthy, Excretion, Bioavailability

Eligibility Criteria

30 Years - 55 Years (Adult)MaleAccepts Healthy Volunteers

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

Sites / Locations

  • GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Subjects receiving GSK2269557 in treatment period 1

Subjects receiving GSK2269557 in treatment period 2

Arm Description

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.

Eligible subjects will receive [14C]-GSK2269557 with a single dose of 800 µg, administered as an oral solution.

Outcomes

Primary Outcome Measures

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
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.
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
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.
Maximum Observed Concentration (Cmax) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1
Blood samples were collected at indicated time points for pharmacokinetic analysis.
Cmax of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2
Blood samples were collected at indicated time points for pharmacokinetic analysis.
Time of Occurrence of Cmax (Tmax) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1
Blood samples were collected at indicated time points for pharmacokinetic analysis.
Tmax of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2
Blood samples were collected at indicated time points for pharmacokinetic analysis.
Terminal Phase Half-life (t1/2) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1
Blood samples were collected at indicated time points for pharmacokinetic analysis.
Terminal Phase Half-life (t1/2) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2
Blood samples were collected at indicated time points for pharmacokinetic analysis. NA indicates that data is not available as single participant was analyzed.
Urinary and Faecal Cumulative Excretion as a Percentage of the Total Radioactive Dose Administered Over Time for Treatment Period 1
Urine samples and fecal samples were collected to measure total radiolabeled drug-related material excreted in urine and feces respectively.
Urinary and Fecal Cumulative Excretion as a Percentage of the Total Radioactive Dose Administered Over Time for Treatment Period 2
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

AUC (0 to Inf) and AUC (0 to t) of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
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.
AUC (0 to Inf) and AUC (0 to t) of [14C]-GSK2269557 in Plasma for Treatment Period 2
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.
Cmax of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
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.
Cmax of [14C]-GSK2269557 in Plasma for Treatment Period 2
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.
Tmax of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
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.
Tmax of [14C]-GSK2269557 in Plasma for Treatment Period 2
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.
t1/2 of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
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.
t1/2 of [14C]-GSK2269557 in Plasma for Treatment Period 2
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.
Volume of Distribution of Parent [14C]-GSK2269557 After IV Dose Only in Plasma
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.
Clearance of Parent [14C]-GSK2269557 After IV Dose Only in Plasma
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.
Inhaled Absolute Bioavailability (F) for Treatment Period 1
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.
Oral Absolute Bioavailability (F) for Treatment Period 2
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.
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
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.
Number of Participants With Hematology Parameters of Potential Clinical Concern
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.
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern
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.
Number of Participants With Clinically Significant Urinalysis Findings
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.
Number of Participants With Electrocardiogram Findings of Clinical Significance
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.
Number of Participants With Vital Signs of Potential Clinical Concern
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.

Full Information

First Posted
October 17, 2017
Last Updated
March 2, 2020
Sponsor
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT03315559
Brief Title
Absorption & Elimination of Radiolabelled GSK2269557
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
November 14, 2017 (Actual)
Primary Completion Date
December 22, 2017 (Actual)
Study Completion Date
December 22, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Disease, Chronic Obstructive
Keywords
GSK2269557, Pharmacokinetics, Radiolabel, Healthy, Excretion, Bioavailability

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
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.
Allocation
Non-Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Subjects receiving GSK2269557 in treatment period 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Subjects receiving GSK2269557 in treatment period 2
Arm Type
Experimental
Arm Description
Eligible subjects will receive [14C]-GSK2269557 with a single dose of 800 µg, administered as an oral solution.
Intervention Type
Drug
Intervention Name(s)
[14C]-GSK2269557 IV infusion
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.
Intervention Type
Drug
Intervention Name(s)
GSK2269557 via DPI
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
[14C]-GSK2269557 oral solution
Intervention Description
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.
Primary Outcome Measure Information:
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
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
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
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
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
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
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
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
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
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
Secondary Outcome Measure Information:
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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

10. Eligibility

Sex
Male
Gender Based
Yes
Gender Eligibility Description
This study will include 6 healthy male subjects.
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
London
ZIP/Postal Code
NW10 7EW
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
IPD for this study will be made available via the Clinical Study Data Request site.
IPD Sharing Time Frame
IPD is available via the Clinical Study Data Request site (click on the link provided below)
IPD Sharing Access Criteria
Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
IPD Sharing URL
https://clinicalstudydatarequest.com/Posting.aspx?ID=20278
Citations:
PubMed Identifier
31649125
Citation
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.
Results Reference
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Absorption & Elimination of Radiolabelled GSK2269557

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