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)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 64
- 试验地点
- 1
- 主要终点
- Part 1:Apparent Clearance (CL/F) of Daprodustat
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 55 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Treatment Group A: Part 1
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.
干预措施: Daprodustat 2 mg tablet (Drug)
Treatment Group A: Part 1
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.
干预措施: Daprodustat 4 mg tablet (Drug)
Treatment Group B: Part 1
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.
干预措施: Daprodustat 2 mg tablet (Drug)
Treatment Group B: Part 1
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.
干预措施: Daprodustat 4 mg tablet (Drug)
Treatment Group C: Part 2
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.
干预措施: Daprodustat 4 mg tablet (Drug)
Treatment Group D: Part 2
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.
干预措施: Daprodustat 4 mg tablet (Drug)
结局指标
主要结局
Part 1:Apparent Clearance (CL/F) of Daprodustat
时间窗: 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
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.
Part 1: Percentage of AUC (0-inf) Obtained by Extrapolation (Percentage AUCex)
时间窗: 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
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.
Part 1:Terminal Phase Half-life (T1/2) of Daprodustat and Mean Residence Time (MRT)
时间窗: 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
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.
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
时间窗: 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
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.
Part 1:Apparent Oral Volume of Distribution (Vz/F) of Daprodustat
时间窗: 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
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.
Part 1: Elimination Rate Constant (Kel) of Daprodustat
时间窗: 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
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.
Part 1: Time of Occurrence of Cmax (Tmax) of Daprodustat
时间窗: 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
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.
Part 2: T1/2 and MRT of Daprodustat
时间窗: 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
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.
Part 2: Percentage AUCex of Dapordustat
时间窗: 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
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.
Part 1:Maximum Observed Drug Concentration (Cmax) of Daprodustat
时间窗: 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
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.
Part 2: CL/F of Daprodustat
时间窗: 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
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.
Part 2:AUC[0-t] andAUC [0-inf] of Daprodustat
时间窗: 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
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.
Part 2: Vz/F of Daprodustat
时间窗: 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
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.
Part 2: Kel of Daprodustat
时间窗: 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
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.
Part 2: Tmax of Daprodustat
时间窗: 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
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.
Part 2: Cmax of Daprodustat
时间窗: 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
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.
次要结局
- Part 1: Change From Baseline in Chemistry Parameters; Direct Bilirubin, Bilirubin, Creatinine, Urate(Baseline (Day -1), 24hours post-dose)
- Part 1: Change From Baseline in Hematology Parameters Platelets, Leukocytes(Baseline (Day -1), 24hours post-dose)
- Part 1: Change From Baseline in Urinalysis Parameter; Potential of Hydrogen (pH)(Baseline (Day -1), 24hours post-dose)
- 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 Hematology Parameter; Hematocrit(Baseline (Day -1), 24hours post-dose)
- Part 1: Change From Baseline in Hematology Parameter Erythrocyte MCHC(Baseline (Day -1), 24hours post-dose)
- Part 1: Change From Baseline in Hematology Parameter: Erythrocytes(Baseline (Day -1), 24hours post-dose)
- Part 1:Change From Baseline in Hematology Parameter; Reticulocytes(Baseline (Day -1), 24hours post-dose)
- Part 1: Change From Baseline in Hematology Parameter Erythrocyte Mean Corpuscular Volume (EMCV)(Baseline (Day -1), 24hours post-dose)
- Part 1: Change From Baseline in Temperature(Baseline (Day -1), 3 and 24 hours (post-dose))
- Part 2: Change From Baseline in Hematology Parameter EMCV(Baseline (Day -1), 24 hours (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 Pulse Rate(Baseline (Day -1), 3 and 24 hours (post-dose))
- Part 1: Change From Baseline in Electrocardiogram (ECG) Parameter; Mean Heart Rate (HR)(Baseline (Day -1), 3 and 24 hours (post-dose))
- 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(Baseline (Day -1), 3 and 24 hours (post-dose))
- Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to Day 16)
- Part 1: Change From Baseline in Hematology Parameters; Hemoglobin (Hb), Erythrocyte Mean Corpuscular Hb Concentration (MCHC)(Baseline (Day -1), 24hours post-dose)
- Part 1: Change From Baseline in Hematology Parameters; Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils(Baseline (Day -1), 24hours post-dose)
- Part 2: Change From Baseline in Chemistry Parameters; Albumin, Protein(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Chemistry Parameters; Direct Bilirubin, Bilirubin, Creatinine, Urate(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Hematology Parameters Platelets, Leukocytes(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Urinalysis Parameter; Specific Gravity(Baseline (Day -1), 24 hours (post-dose))
- Part 1: Change From Baseline in Urinalysis Parameter; Specific Gravity(Baseline (Day -1), 24hours post-dose)
- Part 1: Change From Baseline in Vital Signs; Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)(Baseline (Day -1), 3 and 24 hours (post-dose))
- Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to Day 16)
- Part 2: Change From Baseline Chemistry Parameters; Glucose, Calcium, Cholesterol, Chloride, HDL Cholesterol, LDL Cholesterol, Potassium, Phosphate, Sodium, Triglycerides, and Urea(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Hematology Parameters; Hematocrit(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Hematology Parameters; Reticulocytes(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Hematology Parameter: EMCH(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Hematology Parameter Erythrocytes(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Chemistry Paremeters; ALP, ALT, AST, Creatine Kinase, Lactate Dehydrogenase, GGT(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Hematology Parameters; Hb, Erythrocyte MCHC(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Hematology Parameters; Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Urinalysis Parameter; Potential of Hydrogen (pH)(Baseline (Day -1), 24 hours (post-dose))
- Part 2: Change From Baseline in Vital Signs; Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)(Baseline (Day -1),3 and 24hours (pre-dose))
- Part 2: Change From Baseline in Temperature(Baseline (Day -1),3 and 24hours (pre-dose))
- Part 2: Change From Baseline in ECG Parameter; Mean Heart Rate (HR)(Baseline (Day -1),3 and 24hours (pre-dose))
- Part 2: Change From Baseline in Pulse Rate(Baseline (Day -1),3 and 24hours (pre-dose))
- Part 2: Change From Baseline in ECG Parameter; PR Interval, QRS Interval, QT Interval, QTcF Interval(Baseline (Day -1),3 and 24hours (pre-dose))