A Phase 1 (Ph1), Single Dose (SD), GSK961081 Absorption, Distribution, Metabolism, and Excretion (ADME) Study in Healthy Subjects

NCT02663089 | Completed Phase 1

• 1 other identifier: 201003
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

total radioactivity; [14C]-GSK961081; Pharmacokinetics; Chronic Obstructive Pulmonary Disease (COPD); Microtracer

Outcome Measures

Primary Outcomes (8)

• 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

  The following PK parameter will be measured: Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC\[0 inf\])

  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

• 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

  The following PK parameter will be measured: Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC\[0-t\]).

  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

• 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

  The following PK parameter will be measured: maximum observed plasma concentration (Cmax)

  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

• 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

  The following PK parameter will be measured: time of occurrence of Cmax (Tmax)

  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

• 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

  The following PK parameter will be measured: terminal phase half-life (t1/2)

  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 hours post-dose during Treatment Period 1 and 2

• Volume of total radioactivity (drug related material) after a single IV microtracer of [14C] GSK961081 (concomitant with an inhaled non-radiolabelled dose)

  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

• Clearance of total radioactivity (drug related material) after a single IV microtracer of [14C] GSK961081 (concomitant with an inhaled non-radiolabelled dose)

  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

• 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

  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 (17)

• 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

  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

• 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

  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

• 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

  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

• 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

  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

• 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

  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

Study Arms (1)

[14C]-GSK961081 IV+GSK961081 inhalation; [14C]-GSK961081 oral

EXPERIMENTAL

On Day 1 of Treatment Period 1, after an overnight fast of at least 8 hours, each subject will receive \[14C\] GSK961081 4 micrograms (mcg) by IV infusion over 1 hour. Within 5 minutes after the start of infusion, subjects will take 1200 mcg non-radiolabelled GSK961081 by inhalation. After Treatment Period 1, there will be a washout of at least 2 weeks. On Day 1 of Treatment Period 2, after an overnight fast of at least 8 hours, each subject will take 200 mcg \[14C\]-GSK961081 as an oral solution.

Drug: [14C]-GSK961081 solution for IV infusion; Drug: [14C]-GSK961081 oral solution; Drug: GSK961081 dry powder for inhalation

Interventions

[14C]-GSK961081 solution for IV infusion DRUG

Subjects will receive 10 mL of solution equivalent to 4 mcg of \[14C\]-GSK961081 (approximately 6.2 kilobecquerel \[kBq\]) intravenously as a single dose over 1 hour.

[14C]-GSK961081 IV+GSK961081 inhalation; [14C]-GSK961081 oral

[14C]-GSK961081 oral solution DRUG

Subjects will receive 10 mL of solution equivalent to 200 mcg of \[14C\]-GSK961081 (approximately 311 kBq) orally as a single dose with up to 250 mL of water.

[14C]-GSK961081 IV+GSK961081 inhalation; [14C]-GSK961081 oral

GSK961081 dry powder for inhalation DRUG

Subjects will receive single dose of 4 actuations of 300 mcg GSK961081 per actuation (1200 mcg GSK961081 total) as inhalation immediately after the start of infusion.

[14C]-GSK961081 IV+GSK961081 inhalation; [14C]-GSK961081 oral

Eligibility Criteria

• Age: 30 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 30 and 55 years of age inclusive, at the time of signing the informed consent.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Theravance Biopharma: lead
• Hammersmith Medicines Research: collaborator
• GlaxoSmithKline: collaborator

Study Sites (1)

GSK Investigational Site

London, NW10 7EW, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 30230263 DERIVED

Related Links

• Results for study 201003 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Infusions, Intravenous; Inhalation

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Administration, Intravenous; Drug Administration Routes; Drug Therapy; Therapeutics; Infusions, Parenteral; Respiratory Mechanics; Respiration; Respiratory Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 21, 2016
• First Posted: January 26, 2016
• Study Start: February 8, 2016
• Primary Completion: March 17, 2016
• Study Completion: March 17, 2016
• Last Updated: October 6, 2021

Record last verified: 2021-09

Locations

GB (1)