Clinical trial NCT02663089: A Phase 1 (Ph1), Single Dose (SD), GSK961081 Absorption, Distribution, Metabolism, and Excretion (ADME) Study in Healthy Subjects
Official title: An Open-label Study in Healthy Male Subjects, to Determine the Excretion Balance and Pharmacokinetics of [14C]-GSK961081, 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: total radioactivity
[14C]-GSK961081
Pharmacokinetics
Chronic Obstructive Pulmonary Disease (COPD)
Microtracer
Lead sponsor: Theravance Biopharma
Sponsor class: INDUSTRY
Collaborators: name: Hammersmith Medicines Research
name: GlaxoSmithKline
First posted: 2016-01-26
Enrollment: 6
Sex: MALE
Minimum age (years): 30
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Batefenterol (GSK961081) is a bifunctional bronchodilator that is being developed for the treatment of Chronic Obstructive Pulmonary Disease (COPD). Absorption, metabolism and excretion of batefenterol have been studied in animals, in vitro, and in previous clinical studies; however, the elimination routes and metabolic pathways of batefenterol have not been fully elucidated in humans. This is an open-label, single centre, non-randomised, 2-period single-sequence crossover, mass balance study to determine total radioactivity (drug related material) in plasma, the rate and extent of excretion of total radioactivity in urine and faeces and the total recovery of radioactivity of \[14C\] GSK961081 administered as a single IV dose (concomitant with an inhaled non-radiolabelled dose) and a single oral dose, in healthy male subjects. A total of 6 healthy male subjects will be enrolled. The duration of each subject in the study is up to 11 weeks, which consists of a screening visit, 2 Treatment Periods, and a follow up visit.


Eligibility criteria: Inclusion Criteria:

* Between 30 and 55 years of age inclusive, at the time of signing the informed consent.
* Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, vital signs, laboratory tests, and 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/square metre (m\^2) (inclusive)
* Sex: Male
* Subjects with female partners of child bearing potential must use a condom from the time of first dose of study medication until follow-up.
* Capable of giving signed informed consent as described in protocol which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

* Alanine aminotransferase (ALT) and bilirubin \>1.5xupper limit of normal (ULN) (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 corrected QT interval (QTc) \> 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 blood pressure (BP) that is persistently higher (triplicate measurements at least 2 min apart) than 140/90 millimetres of mercury (mmHg).
* At screening, a supine mean HR outside the range 40-90 beats per minute (BPM).
* Subject is mentally or legally incapacitated.
* A history of respiratory disease (e.g. history of asthmatic symptoms) 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.
* 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 grams (g) of alcohol: a half-pint (approximately 240 millilitres \[mL\]) 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 multiplied by number of years smoked then divided by 20.
* History of sensitivity to any of the study medications or its components, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates the subject's participation.
* Presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test result at screening or within 3 months before the first dose of study treatment.
* A positive test for Human Immunodeficiency Virus (HIV) antibody
* A positive pre-study drug/alcohol screen.
* 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.
* Exposure to more than four new chemical entities within 12 months before the subject's first dose.
* Participation in a clinical trial involving administration of 14C-labelled compound(s) within the last 12 months. A subjects' previous effective dose will be reviewed by the medical investigator to ensure there is no risk of contamination/carryover into the current study.
* Subjects who have received a total body radiation dose of greater than 5.0 millisievert (mSv) (upper limit of World Health Organization \[WHO\] category II) or exposure to significant radiation (e.g. serial x ray or computed tomography \[CT\] scans, barium meal etc) in the 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.
* Unable to refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days before the first dose of study medication until the follow-up visit.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 90 day period.
* Unwillingness or inability to follow the procedures outlined in the protocol, including the use of the enterotest capsule.

Primary outcomes:
measure: AUC(0 inf) of total drug-related material (radioactivity) in plasma after a single IV microtracer of [14C] GSK961081 (concomitant with an inhaled non-radiolabelled dose) and a single oral dose of [14C] GSK961081
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 hours post-dose during Treatment Period 1 and 2
measure: AUC(0-t) of total drug-related material (radioactivity) in plasma after a single IV microtracer of [14C] GSK961081 (concomitant with an inhaled non-radiolabelled dose) and a single oral dose of [14C] GSK961081
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 hours post-dose during Treatment Period 1 and 2
measure: Cmax of total drug-related material (radioactivity) in plasma after a single IV microtracer of [14C] GSK961081 (concomitant with an inhaled non-radiolabelled dose) and a single oral dose of [14C] GSK961081
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 hours post-dose during Treatment Period 1 and 2
measure: Tmax of total drug-related material (radioactivity) in plasma after a single IV microtracer of [14C] GSK961081 (concomitant with an inhaled non-radiolabelled dose) and a single oral dose of [14C] GSK961081
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 hours post-dose during Treatment Period 1 and 2
measure: T1/2 of total drug-related material (radioactivity) in plasma after a single IV microtracer of [14C] GSK961081 (concomitant with an inhaled non-radiolabelled dose) and a single oral dose of [14C] GSK961081
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 hours post-dose during Treatment Period 1 and 2
measure: Volume of total radioactivity (drug related material) after a single IV microtracer of [14C] GSK961081 (concomitant with an inhaled non-radiolabelled dose)
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 hours post-dose during Treatment Period 1 and 2
measure: Clearance of total radioactivity (drug related material) after a single IV microtracer of [14C] GSK961081 (concomitant with an inhaled non-radiolabelled dose)
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 hours post-dose during Treatment Period 1 and 2
measure: Urinary and faecal cumulative excretion as a percentage of the total radioactive dose administered over time after a single IV microtracer of [14C] GSK961081 (concomitant with an inhaled non-radiolabelled dose) and a single oral dose of [14C] GSK961081
timeFrame: Pre-dose and at 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168 hours post-dose during Treatment Period 1 and 2
Secondary outcomes:
measure: AUC(0-inf) of parent GSK961081 and [14C] GSK961081 in plasma after a single IV microtracer of [14C]-GSK961081 concomitant with an inhaled non-radiolabelled GSK961081 dose and a single oral dose of [14C] GSK961081
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 hours post-dose during Treatment Period 1 and 2
measure: AUC(0-t) of parent GSK961081 and [14C] GSK961081 in plasma after a single IV microtracer of [14C]-GSK961081 concomitant with an inhaled non-radiolabelled GSK961081 dose and a single oral dose of [14C] GSK961081
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 hours post-dose during Treatment Period 1 and 2
measure: Cmax of parent GSK961081 and [14C] GSK961081 in plasma after a single IV microtracer of [14C]-GSK961081 concomitant with an inhaled non-radiolabelled GSK961081 dose and a single oral dose of [14C] GSK961081
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 hours post-dose during Treatment Period 1 and 2
measure: Tmax of parent GSK961081 and [14C] GSK961081 in plasma after a single IV microtracer of [14C]-GSK961081 concomitant with an inhaled non-radiolabelled GSK961081 dose and a single oral dose of [14C] GSK961081
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 hours post-dose during Treatment Period 1 and 2
measure: T1/2 of parent GSK961081 and [14C] GSK961081 in plasma after a single IV microtracer of [14C]-GSK961081 concomitant with an inhaled non-radiolabelled GSK961081 dose and a single oral dose of [14C] GSK961081
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 hours post-dose during Treatment Period 1 and 2
measure: Volume of parent GSK961081 and [14C] GSK961081 after a single IV microtracer of [14C]-GSK961081 concomitant with an inhaled non-radiolabelled GSK961081 dose
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 hours post-dose during Treatment Period 1 and 2
measure: Clearance of parent GSK961081 and [14C] GSK961081 after a single IV microtracer of [14C]-GSK961081 concomitant with an inhaled non-radiolabelled GSK961081 dose
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 hours post-dose during Treatment Period 1 and 2
measure: Oral and inhaled absolute bioavailability (F)
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 hours post-dose during Treatment Period 1 and 2
measure: Number of subjects with any adverse events (AEs) as a measure of safety
timeFrame: Up to 7 weeks
measure: Composite of Hematology parameters as a measure of safety
timeFrame: Up to 11 weeks
measure: Composite of Clinical Chemistry parameters as a measure of safety
timeFrame: Up to 11 weeks
measure: Composite of Urinalysis parameters as a measure of safety
timeFrame: Up to 11 weeks
measure: Electrocardiogram (ECG) as a measure of safety
timeFrame: Up to 11 weeks
measure: Temperature as a measure of safety
timeFrame: Up to 11 weeks
measure: Systolic and diastolic blood pressure as a measure of safety
timeFrame: Up to 11 weeks
measure: Pulse rate as a measure of safety
timeFrame: Up to 11 weeks
measure: Respiratory rate as a measure of safety
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: Ambery C, Young G, Fuller T, Lazaar AL, Pereira A, Hughes A, Ramsay D, van den Berg F, Daley-Yates P. Pharmacokinetics, Excretion, and Mass Balance of [14 C]-Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men. Clin Pharmacol Drug Dev. 2018 Nov;7(8):901-910. doi: 10.1002/cpdd.616. Epub 2018 Sep 19.