A Pilot, Phase 1, Randomized, Open-Label, Single-Dose, Four-Way Crossover Study to Compare the Pharmacokinetics of Sapropterin Dihydrochloride 100 mg/mL Oral Suspension (Product Code: RLF-OD032) (Test) With Kuvan® (Sapropterin Dihydrochloride) 100 mg Powder for Oral Solution (Reference) and to Evaluate the Effect of Food and the Effect of Water on the Bioavailability of Sapropterin Dihydrochloride 100 mg/mL Oral Suspension in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Uncorrected Sapropterin AUC0-t
研究概览
简要总结
This is a single center, Phase 1, randomized, open-label, single-dose, 4 treatment, 4-period, 4-sequence, crossover study designed to compare the pharmacokinetics (PK) of sapropterin from the Test and Reference products, and to evaluate the effect of food and the effect of water administration on the bioavailability of sapropterin from the Test product in healthy subjects.
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详细描述
In each period, subjects will receive a single 10 mg/kg dose of sapropterin dihydrochloride on Day 1, under fasting or fed conditions, and with or without water, followed by 24 hours of PK sampling. The study will include a screening visit from Day -30 to Day -1. In each period, eligible subjects will be admitted to the clinical site on Day -1 and will be confined until completion of the assessments on Day 2. There will be a washout period of at least 7 days between doses.
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
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Male or female, light smoker (no more than 10 cigarettes daily) or non smoker, ≥18 and ≤50 years of age, with body mass index (BMI) ≥18.5 and ≤30.0 kg/m2 and body weight ≥50.0 kg for males and ≥45.0 kg for females.
- •Healthy as defined by:
- •the absence of clinically significant illness and surgery within 30 days prior to dosing.
- •the absence of clinically significant history of neurological, endocrine, cardiovascular, respiratory, hematological, immunological, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.
- •Female subjects of non-childbearing potential must be:
- •post-menopausal (no menstrual period at least 12 consecutive months without any other medical cause and FSH and LH values consistent with being menopausal); or
- •surgically sterile (bilateral oophorectomy, bilateral salpingectomy, hysterectomy or tubal ligation) at least 3 months prior to dosing.
- •Sexually active female subjects of childbearing potential must be willing to use an acceptable contraceptive method throughout the study as detailed in the protocol.
- •Willing to take off dentures or mouth piercing at the time of dosing.
- •Able to understand the study procedures and provide signed informed consent to participate in the study.
排除标准
- •Any clinically significant abnormal finding at physical examination at screening.
- •Clinically significant abnormal laboratory test results (may be repeated up to two times) or positive serology test results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV)-1 and HIV-2 antibodies at screening.
- •Positive pregnancy test or lactating female subject.
- •Positive urine drug screen.
- •Known allergic reactions to sapropterin dihydrochloride or other related drugs, or to any excipient in the formulation.
- •Clinically significant ECG abnormalities or vital signs abnormalities (systolic blood pressure lower than 90 or over 150 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or pulse rate less than 50 or over 100 bpm) at screening. ECG and vitals signs may be repeated up to two times, to determine if the values are significantly abnormal.
- •Recreational use of soft drugs (such as marijuana) within 1 month or hard drugs (such as cocaine, phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine derivatives) within 3 months prior to screening.
- •History of alcohol addiction requiring treatment.
- •History of abuse of medicinal product or drugs within the last 3 years.
- •History or presence of alcoholism within the last 3 years. (>40 g ethanol/day or more than 10 units per week [1 unit =150 mL of wine, or 360 mL of beer, or 45 mL of 45% alcohol]).
- •Use of medications within the timeframes specified in the protocol
- •Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to dosing, administration of a biological product in the context of a clinical research study within 90 days prior to dosing, or concomitant participation in an investigational study involving no drug or device administration.
- •Known predisposition to seizures.
- •Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of whole blood within 8 weeks prior to dosing.
- •Presence of orthodontic braces or orthodontic retention wires, or any physical findings in the mouth or tongue that would be likely to interfere with successful completion of the dosing procedure.
- •Females who:
- •Have discontinued or changed the use of implanted, intrauterine, intravaginal, or injected hormonal contraceptives within 6 months prior to study treatment administration.
- •Have discontinued or changed the use of oral or patch hormonal contraceptives within 1 month prior to study treatment administration.
- •Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.
研究组 & 干预措施
Sequence DCAB
Where the Subject receives in this order
D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions
C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.
A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.
B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.
干预措施: RLF-OD032 (Drug)
Sequence DCAB
Where the Subject receives in this order
D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions
C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.
A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.
B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.
干预措施: Kuvan (Drug)
Sequence ADBC
Where the Subject receives in this order
A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.
D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions
B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.
C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.
干预措施: RLF-OD032 (Drug)
Sequence ADBC
Where the Subject receives in this order
A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.
D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions
B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.
C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.
干预措施: Kuvan (Drug)
Sequence BACD
Where the Subject receives in this order
B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.
A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.
C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.
D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions
干预措施: RLF-OD032 (Drug)
Sequence BACD
Where the Subject receives in this order
B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.
A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.
C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.
D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions
干预措施: Kuvan (Drug)
Sequence CBDA
Where the Subject receives in this order
C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.
B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.
D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions
A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.
干预措施: RLF-OD032 (Drug)
Sequence CBDA
Where the Subject receives in this order
C is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.
B is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.
D is 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions
A is 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.
干预措施: Kuvan (Drug)
结局指标
主要结局
Uncorrected Sapropterin AUC0-t
时间窗: Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Area under the concentration-time curve from time zero until the last observed concentration, as calculated by the linear up/log down variant of the trapezoidal method
Baseline-corrected Sapropterin AUC0-t
时间窗: Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Area under the concentration-time curve from time zero until the last observed concentration, as calculated by the linear up/log down variant of the trapezoidal method
Uncorrected Sapropterin Cmax
时间窗: Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Maximum observed concentration
Baseline-corrected Sapropterin Cmax
时间窗: Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Maximum observed concentration
Uncorrected Sapropterin AUC0-inf
时间窗: Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Area under the concentration-time curve from time zero to infinity (extrapolated)
Baseline-corrected Sapropterin AUC0-inf
时间窗: Time points 1, 0.5, pre-dose (0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.
Area under the concentration-time curve from time zero to infinity (extrapolated)
次要结局
未报告次要终点