Absorption & Elimination of Radiolabelled GSK2269557

NCT03315559 | Completed Phase 1 Results

• 2 other identifiers: 2067642017-002347-16
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

GSK2269557; Pharmacokinetics; Radiolabel; Healthy; Excretion; Bioavailability

Outcome Measures

Primary Outcomes (10)

• 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.

  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

• 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.

  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

• 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.

  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

• Cmax of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2

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

  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

• 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.

  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

• Tmax of Total Drug-related Material (Radioactivity) in Plasma for Treatment Period 2

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

  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

• 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.

  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

• 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.

  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

• 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.

  Up to 168 hours

• 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.

  Up to 336 hours

Secondary Outcomes (18)

• 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

• 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

• 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

• 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

• 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

Study Arms (2)

Subjects receiving GSK2269557 in treatment period 1

EXPERIMENTAL

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; Drug: GSK2269557 via DPI; Drug: [14C]-GSK2269557 oral solution

Subjects receiving GSK2269557 in treatment period 2

EXPERIMENTAL

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

Drug: [14C]-GSK2269557 IV infusion; Drug: GSK2269557 via DPI; Drug: [14C]-GSK2269557 oral solution

Interventions

[14C]-GSK2269557 IV infusion DRUG

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.

Subjects receiving GSK2269557 in treatment period 1; Subjects receiving GSK2269557 in treatment period 2

GSK2269557 via DPI DRUG

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.

Subjects receiving GSK2269557 in treatment period 1; Subjects receiving GSK2269557 in treatment period 2

[14C]-GSK2269557 oral solution DRUG

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.

Subjects receiving GSK2269557 in treatment period 1; Subjects receiving GSK2269557 in treatment period 2

Eligibility Criteria

• Age: 30 Years - 55 Years
• Gender Eligibility Details: This study will include 6 healthy male subjects.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject must be 30 to 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 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

London, NW10 7EW, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 31649125 BACKGROUND

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: This will be an open-label study. Hence, masking will not be provided to the subjects.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: October 17, 2017
• First Posted: October 20, 2017
• Study Start: November 14, 2017
• Primary Completion: December 22, 2017
• Study Completion: December 22, 2017
• Last Updated: March 13, 2020
• Results First Posted: March 20, 2019

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• 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.

Locations

GB (1)