Absorption and Elimination of Radiolabeled Daprodustat

NCT03239522 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 2002322017-001729-42
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

Absorption, metabolism and excretion of daprodustat (GSK1278863) have been studied in previous clinical trials; however, the elimination routes and metabolic pathways of daprodustat have not been fully elucidated in humans. This is an open-label, single-center, non-randomized, 2-period, single-sequence, crossover, mass balance study in 6 healthy male participants. The aim of the study is to assess the excretion balance of daprodustat using \[14C\]-radiolabeled drug substance administered orally, and as an intravenous (IV) infusion, administered as a microtracer dose (concomitant with an oral, non-radiolabeled dose). Absolute bioavailability of an oral dose will also be assessed. Each participant will be involved in the study for up to 10 weeks which include a screening visit, two treatment periods (treatment periods 1 and 2), separated by about 7 days (at least 14 days between oral doses), and a follow up visit 1-2 weeks after the last assessment in treatment period 2. The primary objective of the study is to gain a better understanding of the compound's excretory and metabolic profile. This study will include sampling of duodenal bile to conduct qualitative assessment of drug metabolites in this matrix in order to characterize biliary elimination pathways.

Conditions

Anaemia

Keywords

GSK1278863; pharmacokinetics; mass balance; daprodustat

Outcome Measures

Primary Outcomes (17)

• Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-Inf]) of Total Drug-related Material (Radioactivity) in Plasma Following Administration of GSK1278863

  Plasma samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in plasma. Pharmacokinetic analysis was conducted using standard non-compartmental methods. Pharmacokinetic Population comprised of all participants in the Safety Population who had at least 1 non-missing pharmacokinetic assessment (Non-quantifiable \[NQ\] values were considered as non-missing values).

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• AUC (0-Inf) of Total Drug-related Material (Radioactivity) in Blood Following Administration of GSK1278863

  Blood samples were planned to be collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in blood. Data were not collected for blood total radioactivity concentration following administration of radiolabeled IV dose of GSK1278863 because of an error (deviation). The deviation is due to a processing error: labels for whole blood draws, and aliquots for shipment were not generated in error. Data were not analyzed for radiolabeled oral dose of GSK1278863 as there were not enough data points captured for a terminal slope required to calculate AUC (0-inf). The blood assay could not detect radiation levels at the time points blood was drawn to go into these calculations.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Participant Across All Treatments (AUC [0-t]) of Total Drug-related Material (Radioactivity) in Plasma Following Administration of GSK1278863

  Plasma samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in plasma. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• AUC (0-t) of Total Drug-related Material (Radioactivity) in Blood Following Administration of GSK1278863

  Blood samples were collected from participants at indicated time points after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in blood. Pharmacokinetic analysis was conducted using standard non-compartmental methods. Data were not collected for blood total radioactivity concentration following administration of radiolabeled IV dose of GSK1278863 because of an error (deviation). The deviation is due to a processing error: labels for whole blood draws, and aliquots for shipment were not generated in error.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• Maximum Observed Plasma Concentration (Cmax) of Total Drug-related Material (Radioactivity) in Plasma Following Administration of GSK1278863

  Plasma samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in plasma. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• Cmax of Total Drug-related Material (Radioactivity) in Blood Following Administration of GSK1278863

  Blood samples were collected from participants at indicated time points after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in blood. Pharmacokinetic analysis was conducted using standard non-compartmental methods. Data were not collected for blood total radioactivity concentration following administration of radiolabeled IV dose of GSK1278863 because of an error (deviation). The deviation is due to a processing error: labels for whole blood draws, and aliquots for shipment were not generated in error.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• Time of Occurrence of Cmax (Tmax) of Total Drug-related Material (Radioactivity) in Plasma Following Administration of GSK1278863

  Plasma samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in plasma. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• Tmax of Total Drug-related Material (Radioactivity) in Blood Following Administration of GSK1278863

  Blood samples were collected from participants at indicated time points after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in blood. Pharmacokinetic analysis was conducted using standard non-compartmental methods. Data were not collected for blood total radioactivity concentration following administration of radiolabeled IV dose of GSK1278863 because of an error (deviation). The deviation is due to a processing error: labels for whole blood draws, and aliquots for shipment were not generated in error.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• Apparent Terminal Phase Half-life (t1/2) of Total Drug-related Material (Radioactivity) in Plasma Following Administration of GSK1278863

  Plasma samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in plasma. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• T1/2 of Total Drug-related Material (Radioactivity) in Blood Following Administration of GSK1278863

  Blood samples were planned to be collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in blood. Data were not collected for blood total radioactivity concentration following administration of radiolabeled IV dose of GSK1278863 because of an error (deviation). The deviation is due to a processing error: labels for whole blood draws, and aliquots for shipment were not generated in error. Data were not analyzed for radiolabeled oral dose of GSK1278863 as there were not enough data points captured for a terminal slope required to calculate t1/2. The blood assay could not detect radiation levels at the time points blood was drawn to go into these calculations.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• Volume of Distribution at Steady State (Vss) of Total Drug-related Material (Radioactivity) in Plasma Following IV Dose of GSK1278863

  Plasma samples were collected from participants at indicated time points in treatment period 1, after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in plasma. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1

• Vss of Total Drug-related Material (Radioactivity) in Blood Following IV Dose of GSK1278863

  Blood samples were planned to be collected from participants at indicated time points in treatment period 1, after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in blood. Data were not collected for blood total radioactivity concentration following administration of radiolabeled IV dose of GSK1278863 because of an error (deviation). The deviation is due to a processing error: labels for whole blood draws, and aliquots for shipment were not generated in error.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1

• Total Systemic Clearance (CL) of Total Drug-related Material (Radioactivity) in Plasma Following IV Dose of GSK1278863

  Plasma samples were collected from participants at indicated time points in treatment period 1 after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in plasma. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1

• CL of Total Drug-related Material (Radioactivity) in Blood Following IV Dose of GSK1278863

  Blood samples were planned to be collected from participants at indicated time points in treatment period 1 after administration of study treatment to investigate the pharmacokinetics of GSK1278863 in blood. Data were not collected for blood total radioactivity concentration following administration of radiolabeled IV dose of GSK1278863 because of an error (deviation). The deviation is due to a processing error: labels for whole blood draws, and aliquots for shipment were not generated in error.

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1

• Percentage of the Total Radioactive Dose Excreted in Urine Over Time Following a Single, Oral Dose of [14C]-GSK1278863

  Urine samples were collected at the indicated time points to determine the rate and extent of excretion of total radioactivity in urine. All participants were asked to void their bladders before study treatment administration.

  Pre-dose and then over 24 hours collection periods as follows: 0-24, 24-48, 48-72, 72-96, 96-120,120-144 and 144-168 hours post-dose in treatment period 2

• Percentage of the Total Radioactive Dose Excreted in Feces Over Time Following a Single, Oral Dose of [14C]-GSK1278863

  Fecal samples were collected at the indicated time points to determine the rate and extent of excretion of total radioactivity in feces.

  Pre-dose and then over 24 hour collection periods as follows: 0-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours post-dose in treatment period 2

• Percentage of the Total Radioactive Dose Excreted in Urine and Feces Determined as Total Excretion Over Time

  Urine and fecal samples were collected at the indicated time points to determine the rate and extent of cumulative excretion of total radioactivity in urine and feces.

  Pre-dose and then over 24 hour collection periods as follows: 0-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours post-dose in treatment period 2

Secondary Outcomes (29)

• AUC (0-Inf) of GSK1278863 in Plasma Following Administration IV and Both Oral Doses

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• AUC(0-t) of GSK1278863 in Plasma Following Administration of IV and Both Oral Doses

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• Cmax of GSK1278863 in Plasma Following Administration of IV and Both Oral Doses

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• Tmax of GSK1278863 in Plasma Following Administration of IV and Both Oral Doses

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

• T1/2 of GSK1278863 in Plasma Following Administration of IV and Both Oral Doses

  Pre-dose, 0.5, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 1; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose in treatment period 2

Study Arms (1)

All participants receiving treatment

EXPERIMENTAL

Each participant will receive a single 6 milligram (mg) oral dose of daprodustat on Day 1 of period 1. After approximately 1 hour, participants will receive 50 microgram (µg) of \[14C\]-GSK1278863 by IV infusion over 1 hour. On Day 1 of period 2, each participant will receive 25 mg \[14C\]-GSK1278863 as an oral solution.

Drug: [14C]-GSK1278863 solution for IV infusion; Drug: [14C]-GSK1278863 oral solution; Drug: Daprodustat 6 mg oral tablet

Interventions

[14C]-GSK1278863 solution for IV infusion DRUG

It is a clear, colorless solution free from visible particulate matter. Participants will receive 10 mL of 5 µg/mL of \[14C\]-GSK1278863 IV solution (total dose: 50 µg) by IV infusion over 1 hour.

All participants receiving treatment

[14C]-GSK1278863 oral solution DRUG

It is a clear, colorless solution. Participants will receive 125 mL of 200 µg/mL of \[14C\]-GSK1278863 oral solution (total dose: 25 mg).

All participants receiving treatment

Daprodustat 6 mg oral tablet DRUG

It is a 9.0 millimeter (mm) round, white film coated tablet.

All participants receiving treatment

Eligibility Criteria

• Age: 30 Years - 55 Years
• Gender Eligibility Details: Only male participants, aged 30 to 55 years (inclusive) will be enrolled into the study.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Aged 30 to 55 years, 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 ECG. A participant with a clinical abnormality or laboratory parameter (i.e., outside the reference range for the population being studied), which is not specifically listed in the eligibility criteria, 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.
• Hemoglobin value at screening greater than the lower limit of the laboratory reference range and less than or equal to 16.0 gram (g) per deciliter (dL).
• History of regular bowel movements (averaging one or more bowel movements per day).
• Non-smoker, or ex-smoker who hasn't regularly smoked for the 6 months before screening.
• Body weight of 50 kilogram (kg) and above, and body mass index (BMI) within the range 19.0-31 kg per meter (m)\^2 (inclusive).
• Participants must agree to use contraception as follows: participants with female partners of childbearing potential must agree to use a condom from the time of first dose of study treatment until 1 month after their last dose.
• Capable of giving signed informed consent.
• Willingness to give written consent to have data entered into The Over-volunteering Prevention System.

You may not qualify if:

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Participants with a history of cholecystectomy must be excluded.
• Any clinically relevant abnormality identified at the screening medical assessment (physical examination/medical history), clinical laboratory tests, or 12-lead ECG.
• Myocardial infarction or acute coronary syndrome \<=12 weeks prior to screening through to enrollment (Day 1, treatment period 1).
• History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal (GI), endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs, or which could constitute a risk when taking the study treatment, or interfere with the interpretation of data.
• Evidence of actively bleeding gastric, duodenal or esophageal ulcer disease OR clinically significant GI bleeding \<=12 weeks prior to screening through to enrollment (Day 1, treatment period 1).
• History of malignancy within the two years before dosing, with the exception of localized squamous cell or basal cell carcinoma of the skin that has been definitively treated prior to screening; currently receiving treatment for cancer; has a strong family history of cancer (e.g., familial cancer disorders).
• Mentally or legally incapacitated.
• Heart Failure: Class II, III or IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
• Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
• Daprodustat is a substrate of cytochrome P4502C8 (CYP2C8). Co-administration of drugs that are inhibitors of this enzyme are prohibited.
• Past or intended use of over-the-counter or prescription medication including herbal medications prior to dosing except occasional use of paracetamol (acetaminophen), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study treatment until completion of the follow-up visit, unless in the opinion of the investigator and GSK medical monitor the medication will not interfere with the study.
• Current enrolment in a clinical trial; recent participation in a clinical trial and has received an investigational product within 3 months before their first dose in the current study.
• Exposure to more than 4 new chemical entities within 12 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 participant's previous effective dose will be reviewed by the medical investigator to ensure there is no risk of contamination/carryover into the current study.
• Received a total body radiation dose of greater than 10.0 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 3 years before this study.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

London, NW10 7EW, United Kingdom

Location

MeSH Terms

Conditions

Anemia

Interventions

Infusions, Intravenous; GSK1278863; Tablets

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Administration, Intravenous; Drug Administration Routes; Drug Therapy; Therapeutics; Infusions, Parenteral; Dosage Forms; Pharmaceutical Preparations

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
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2017
• First Posted: August 4, 2017
• Study Start: October 10, 2017
• Primary Completion: November 28, 2017
• Study Completion: November 28, 2017
• Last Updated: December 3, 2019
• Results First Posted: March 18, 2019

Record last verified: 2019-11

Locations

GB (1)