Daprodustat Bioequivalence and Food Effect Study

NCT03493386 | Completed Phase 1 Results

• 1 other identifier: 207727
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

Brief Summary

This is two-way crossover study to compare pharmacokinetic (PK) of daprodustat 2 milligram (mg) versus 4 mg tablets and food effect on the PK of daprodustat following single oral doses in healthy Japanese male subjects. This study will be conducted in two parts. Part 1 is the bioequivalence part in which subjects will receive single dose of 2 tablets of 2 mg daprodustat and single dose of 1 tablet of 4 mg daprodustat in crossover manner. Part 2 is Food effect part. In this part, subjects will receive single dose of 4 mg daprodustat tablet in fasting and fed state in a crossover manner. There will 5-day wash-out period between each intervention period. There will be approximately 52 subjects in Part 1 and 12 subjects in Part 2. The study will last for 6 weeks.

Conditions

Anaemia

Keywords

Japan; Crossover; Daprodustat; Bioequivalence; Pharmacokinetics

Outcome Measures

Primary Outcomes (16)

• Part 1:Area Under Plasma Concentration-time Curve (AUC) From Zero Hours to Last Measurable Concentration (AUC[0-t]) and AUC From Zero Hours Extrapolated to Infinity AUC [0-inf] of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3. PK population comprised of all participants in the Safety population (all randomized participants) who received at least one dose of study intervention) who had at least 1 non-missing PK assessment.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 1:Maximum Observed Drug Concentration (Cmax) of Daprodustat

  Blood samples were collected at indicated timepoints and pharmacokinetic (PK) analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 1:Terminal Phase Half-life (T1/2) of Daprodustat and Mean Residence Time (MRT)

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 1: Time of Occurrence of Cmax (Tmax) of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 1: Percentage of AUC (0-inf) Obtained by Extrapolation (Percentage AUCex)

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 1:Apparent Clearance (CL/F) of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 1:Apparent Oral Volume of Distribution (Vz/F) of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 1: Elimination Rate Constant (Kel) of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12hours post-dose on Day 1, 24hours post-dose on Day 2

• Part 2:AUC[0-t] andAUC [0-inf] of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12hours post-dose on Day 1, 24hours post-dose on Day 2

• Part 2: Cmax of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12hours post-dose on Day 1, 24hours post-dose on Day 2

• Part 2: T1/2 and MRT of Daprodustat

  Blood samples were collected at indicated time points and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12hours post-dose on Day 1, 24hours post-dose on Day 2

• Part 2: Tmax of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 2: Percentage AUCex of Dapordustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 2: CL/F of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 2: Vz/F of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

• Part 2: Kel of Daprodustat

  Blood samples were collected at indicated timepoints and PK analysis was performed. PK parameters were determined by non-compartmental methods with Phoenix WinNonlin version 6.3.

  Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 24 hours post-dose on Day 2

Secondary Outcomes (40)

• Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Up to Day 16

• Part 1: Change From Baseline Chemistry Paramters: Glucose, Calcium, Cholesterol, Chloride, High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, Potassium, Phosphate, Sodium, Triglycerides, and Urea.

  Baseline (Day -1), 24hours post-dose

• Part 1: Change From Baseline in Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase, Lactate Dehydrogenase and Gamma Glutamyl Transferase (GGT).

  Baseline (Day -1), 24hours post-dose

• Part 1: Change From Baseline in Chemistry Parameters; Albumin, Protein.

  Baseline (Day -1), 24hours post-dose

• Part 1: Change From Baseline in Chemistry Parameters; Direct Bilirubin, Bilirubin, Creatinine, Urate

  Baseline (Day -1), 24hours post-dose

Study Arms (4)

Treatment Group A: Part 1

EXPERIMENTAL

Subjects will be randomized to receive single dose of two tablets of 2 mg daprodustat in Period 1 and in Period 2 subjects will receive single dose of 4 mg daprodustat. There will be a wash-out period of 5 days between the Periods.

Drug: Daprodustat 2 mg tablet; Drug: Daprodustat 4 mg tablet

Treatment Group B: Part 1

EXPERIMENTAL

Subjects will be randomized to receive single dose of 4 mg daprodustat in Period 1 and in Period 2 subjects will receive single dose of two tablets of 2 mg daprodustat. There will be a wash-out period of 5 days between the Periods.

Drug: Daprodustat 2 mg tablet; Drug: Daprodustat 4 mg tablet

Treatment Group C: Part 2

EXPERIMENTAL

Subjects will be randomized to receive single dose of 4 mg daprodustat in fed state during Period 1 and in Period 2 subjects will receive single dose of 4 mg daprodustat in fasted state. There will be a wash-out period of 5 days between the Periods.

Drug: Daprodustat 4 mg tablet

Treatment Group D: Part 2

EXPERIMENTAL

Subjects will be randomized to receive single dose of 4 mg daprodustat in fasted state during period 1 and in Period 2 subjects will receive single dose of 4 mg daprodustat in fed state. There will be a wash-out period of 5 days between the Periods.

Drug: Daprodustat 4 mg tablet

Interventions

Daprodustat 2 mg tablet DRUG

Daprodustat is available as 2 mg tablet. Subjects will receive daprodustat orally as tablet. A single dose of 2 tablets of 2 mg daprodustat will be administered in a fasted state during Part 1 of the study.

Treatment Group A: Part 1; Treatment Group B: Part 1

Daprodustat 4 mg tablet DRUG

Daprodustat is available as 4 mg tablet. Subjects will receive daprodustat orally as tablet. A single dose of 4 mg daprodustat will be administered in a fasted state during Part 1 and in fed and fasted state in Part 2 of the study.

Treatment Group A: Part 1; Treatment Group B: Part 1; Treatment Group C: Part 2; Treatment Group D: Part 2

Eligibility Criteria

• Age: 20 Years - 55 Years
• Gender Eligibility Details: Japanese male subjects who will be overtly healthy as determined by medical evaluation will be included in the study.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject must be 20 to 55 years of age inclusive, at the time of signing the informed consent.
• Japanese subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
• Body weight \> = 50 kilogram (kg) and body mass index (BMI) within the range 18.5 - 24.9 kilogram per meter square (kg/m\^2).
• Male subjects.
• Subjects capable of giving signed informed consent.

You may not qualify if:

• History or presence of cardiovascular(CV), respiratory, hepatic, renal, gastrointestinal (GI), endocrine, haematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
• Abnormal blood pressure as determined by the investigator.
• ALT \>1.5x upper limit of normal (ULN).
• Bilirubin \>1.5xULN
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• QTcF \> 500 millisecond (msec). The QTcF is the QT interval corrected for heart rate according to Fridericia's formula, machine-read or manually over-read. The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QT correction (QTc) for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.
• The values of Hgb at screening: \>=16.0 gram per deciliter (g/dL).
• History of deep vein thrombosis, pulmonary embolism or other thrombosis related condition.
• History of myocardial infarction (MI) or acute coronary syndrome, stroke or transient ischemic attack.
• Subjects that have undergone cholecystectomy.
• History of malignancy within the prior 2 years or currently receiving treatment for cancer.
• Any evidence of heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
• Past or intended use of over-the-counter or prescription medication including vitamins, diet foods and herbal medications within 14 days prior to first dosing.
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
• Current enrolment or past participation (that is administration of last dose of investigational study intervention) within the last 30 days (or 5 half-lives, whichever is longer) before signing of consent in this clinical study involving an investigational study intervention or any other type of medical research.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Fukuoka, 813-0017, Japan

Location

Related Publications (1)

• Yamada M, Osamura M, Ogura H, Onoue T, Wakamatsu A, Numachi Y, Caltabiano S, Mahar KM. A Single-Dose, Open-Label, Randomized, Two-Way Crossover Study in Healthy Japanese Participants to Evaluate the Bioequivalence and the Food Effect on the Pharmacokinetics of Daprodustat. Clin Pharmacol Drug Dev. 2020 Nov;9(8):978-984. doi: 10.1002/cpdd.793. Epub 2020 Apr 6.

  PMID: 32250021 BACKGROUND

MeSH Terms

Conditions

Anemia

Interventions

GSK1278863; Tablets

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

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: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This study will be conducted in two parts. Part 1 is the bioequivalence part in which subjects will receive single dose of 2 tablets of 2 mg daprodustat and single dose of 1 tablet of 4 mg daprodustat in crossover manner. Part 2 is Food effect part. In this part, subjects will receive single dose of 4 mg daprodustat tablet in fasting and fed state in a crossover manner.

Study Record Dates

• First Submitted: April 4, 2018
• First Posted: April 10, 2018
• Study Start: April 24, 2018
• Primary Completion: June 9, 2018
• Study Completion: June 9, 2018
• Last Updated: July 8, 2020
• Results First Posted: August 6, 2019

Record last verified: 2020-06

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

JP (1)