Clinical trial NCT03315559: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: GSK2269557
Pharmacokinetics
Radiolabel
Healthy
Excretion
Bioavailability
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-10-20
Enrollment: 6
Sex: MALE
Minimum age (years): 30
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: Maximum Observed Concentration (Cmax) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1
timeFrame: 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
measure: Cmax of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2
timeFrame: 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
measure: Time of Occurrence of Cmax (Tmax) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1
timeFrame: 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
measure: Tmax of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2
timeFrame: 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
measure: Terminal Phase Half-life (t1/2) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 1
timeFrame: 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
measure: Terminal Phase Half-life (t1/2) of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2
timeFrame: 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
measure: Urinary and Faecal Cumulative Excretion as a Percentage of the Total Radioactive Dose Administered Over Time for Treatment Period 1
timeFrame: Up to 168 hours
measure: Urinary and Fecal Cumulative Excretion as a Percentage of the Total Radioactive Dose Administered Over Time for Treatment Period 2
timeFrame: Up to 336 hours
Secondary outcomes:
measure: AUC (0 to Inf) and AUC (0 to t) of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
timeFrame: 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
measure: AUC (0 to Inf) and AUC (0 to t) of [14C]-GSK2269557 in Plasma for Treatment Period 2
timeFrame: 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
measure: Cmax of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
timeFrame: 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
measure: Cmax of [14C]-GSK2269557 in Plasma for Treatment Period 2
timeFrame: 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
measure: Tmax of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
timeFrame: 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
measure: Tmax of [14C]-GSK2269557 in Plasma for Treatment Period 2
timeFrame: 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
measure: t1/2 of Parent GSK2269557 and [14C]-GSK2269557 in Plasma for Treatment Period 1
timeFrame: 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
measure: t1/2 of [14C]-GSK2269557 in Plasma for Treatment Period 2
timeFrame: 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
measure: Volume of Distribution of Parent [14C]-GSK2269557 After IV Dose Only in Plasma
timeFrame: 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
measure: Clearance of Parent [14C]-GSK2269557 After IV Dose Only in Plasma
timeFrame: 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
measure: Inhaled Absolute Bioavailability (F) for Treatment Period 1
timeFrame: 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
measure: Oral Absolute Bioavailability (F) for Treatment Period 2
timeFrame: 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
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to 11 weeks
measure: Number of Participants With Hematology Parameters of Potential Clinical Concern
timeFrame: Up to 11 weeks
measure: Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern
timeFrame: Up to 11 weeks
measure: Number of Participants With Clinically Significant Urinalysis Findings
timeFrame: Up to 168 hours
measure: Number of Participants With Electrocardiogram Findings of Clinical Significance
timeFrame: Up to 11 weeks
measure: Number of Participants With Vital Signs of Potential Clinical Concern
timeFrame: Up to 11 weeks
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
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.