Clinical trial NCT03493386: Daprodustat Bioequivalence and Food Effect Study
Official title: A Single Centre, Single Dose, Open-label, Randomised, 2-way Crossover Study in Healthy Japanese Male Subjects to Evaluate the Bioequivalence of Daprodustat Tablets (2 mg Tablet vs. 4 mg Tablet) (Part 1) and the Food Effect on the Pharmacokinetics of Daprodustat (Part 2)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Anaemia
Keywords: Japan
Crossover
Daprodustat
Bioequivalence
Pharmacokinetics
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2018-04-10
Enrollment: 64
Sex: MALE
Minimum age (years): 20
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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.
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.
* The subject with positive serological test for syphilis (Rapid Plasma Reagin \[RPR\] and Treponema pallidum haemagglutination test \[TPHA\]), Human immunodeficiency virus (HIV) Antigen/Antibody, Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV) antibody, or Human T-cell lymphotropic virus type 1 (HTLV-1) antibody at screening.
* Positive pre-study drug screen.
* Regular alcohol consumption within 6 months prior to the study defined as:for an average weekly intake of \>14 units for males. One unit is equivalent to 350 milliliter (mL) of beer, 150 mL of wine or 45 mL of 80 proof distilled spirits.
* Smoking or history of regular use of tobacco- or nicotine-containing products (example nicotine patch, electronic cigarette) within 6 months prior to screening.
* Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
* History of donation of blood or blood products \>= 400 mL within 3 months or \>= 200 mL within 1 month prior to the first dosing day.

Primary outcomes:
measure: 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
timeFrame: 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
measure: Part 1:Maximum Observed Drug Concentration (Cmax) of Daprodustat
timeFrame: 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
measure: Part 1:Terminal Phase Half-life (T1/2) of Daprodustat and Mean Residence Time (MRT)
timeFrame: 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
measure: Part 1: Time of Occurrence of Cmax (Tmax) of Daprodustat
timeFrame: 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
measure: Part 1: Percentage of AUC (0-inf) Obtained by Extrapolation (Percentage AUCex)
timeFrame: 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
measure: Part 1:Apparent Clearance (CL/F) of Daprodustat
timeFrame: 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
measure: Part 1:Apparent Oral Volume of Distribution (Vz/F) of Daprodustat
timeFrame: 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
measure: Part 1: Elimination Rate Constant (Kel) of Daprodustat
timeFrame: 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
measure: Part 2:AUC[0-t] andAUC [0-inf] of Daprodustat
timeFrame: 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
measure: Part 2: Cmax of Daprodustat
timeFrame: 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
measure: Part 2: T1/2 and MRT of Daprodustat
timeFrame: 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
measure: Part 2: Tmax of Daprodustat
timeFrame: 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
measure: Part 2: Percentage AUCex of Dapordustat
timeFrame: 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
measure: Part 2: CL/F of Daprodustat
timeFrame: 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
measure: Part 2: Vz/F of Daprodustat
timeFrame: 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
measure: Part 2: Kel of Daprodustat
timeFrame: 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:
measure: Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 16
measure: 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.
timeFrame: Baseline (Day -1), 24hours post-dose
measure: 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).
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Chemistry Parameters; Albumin, Protein.
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Chemistry Parameters; Direct Bilirubin, Bilirubin, Creatinine, Urate
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1:Change From Baseline in Hematology Parameter; Hematocrit
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1:Change From Baseline in Hematology Parameter; Reticulocytes
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Hematology Parameters; Hemoglobin (Hb), Erythrocyte Mean Corpuscular Hb Concentration (MCHC)
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Hematology Parameters; Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Hematology Parameter Erythrocyte MCHC
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Hematology Parameter Erythrocyte Mean Corpuscular Volume (EMCV)
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Hematology Parameters Platelets, Leukocytes
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Hematology Parameter: Erythrocytes
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Urinalysis Parameter; Potential of Hydrogen (pH)
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Urinalysis Parameter; Specific Gravity
timeFrame: Baseline (Day -1), 24hours post-dose
measure: Part 1: Change From Baseline in Vital Signs; Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Baseline (Day -1), 3 and 24 hours (post-dose)
measure: Part 1: Change From Baseline in Pulse Rate
timeFrame: Baseline (Day -1), 3 and 24 hours (post-dose)
measure: Part 1: Change From Baseline in Temperature
timeFrame: Baseline (Day -1), 3 and 24 hours (post-dose)
measure: Part 1: Change From Baseline in Electrocardiogram (ECG) Parameter; Mean Heart Rate (HR)
timeFrame: Baseline (Day -1), 3 and 24 hours (post-dose)
measure: Part 1: Change From Baseline in ECG Parameter; PR Interval, QRS Interval, QT Interval, QT Duration Corrected for Heart Rate by Friderician Formula (QTcF) Interval
timeFrame: Baseline (Day -1), 3 and 24 hours (post-dose)
measure: Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 16
measure: Part 2: Change From Baseline Chemistry Parameters; Glucose, Calcium, Cholesterol, Chloride, HDL Cholesterol, LDL Cholesterol, Potassium, Phosphate, Sodium, Triglycerides, and Urea
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Chemistry Paremeters; ALP, ALT, AST, Creatine Kinase, Lactate Dehydrogenase, GGT
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Chemistry Parameters; Albumin, Protein
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Chemistry Parameters; Direct Bilirubin, Bilirubin, Creatinine, Urate
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Hematology Parameters; Hematocrit
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Hematology Parameters; Reticulocytes
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Hematology Parameters; Hb, Erythrocyte MCHC
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Hematology Parameters; Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Hematology Parameter: EMCH
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Hematology Parameter EMCV
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Hematology Parameters Platelets, Leukocytes
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Hematology Parameter Erythrocytes
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Urinalysis Parameter; Potential of Hydrogen (pH)
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Urinalysis Parameter; Specific Gravity
timeFrame: Baseline (Day -1), 24 hours (post-dose)
measure: Part 2: Change From Baseline in Vital Signs; Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Baseline (Day -1),3 and 24hours (pre-dose)
measure: Part 2: Change From Baseline in Pulse Rate
timeFrame: Baseline (Day -1),3 and 24hours (pre-dose)
measure: Part 2: Change From Baseline in Temperature
timeFrame: Baseline (Day -1),3 and 24hours (pre-dose)
measure: Part 2: Change From Baseline in ECG Parameter; Mean Heart Rate (HR)
timeFrame: Baseline (Day -1),3 and 24hours (pre-dose)
measure: Part 2: Change From Baseline in ECG Parameter; PR Interval, QRS Interval, QT Interval, QTcF Interval
timeFrame: Baseline (Day -1),3 and 24hours (pre-dose)
Other outcomes:
Locations:
city: Fukuoka
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.