Single Dose Crossover Comparative Bioavailability Study of Febuxostat 120 mg Film-Coated Tablets in Healthy Adult Subjects / Fasting State
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Cmax of febuxostat in plasma after administration of the test and the reference products
研究概览
简要总结
This study is designed in accordance with the European Medicines Agency (EMA) regulatory guidelines, with the aim of characterizing the bioavailability of febuxostat in the two formulations in healthy adult subjects. Within the clinical portion of the study each subject will receive a single oral dose of the test and the reference formulation in compliance with the generated randomization code. The primary study endpoints are the pharmacokinetic (PK) parameters Cmax and AUC0-T of febuxostat.
详细描述
This is a single center, randomized, 2-treatment, 2-period, 2-sequence, crossover, single dose study design, in which 50 healthy adult subjects will receive one of the study treatments during each study period.
The objective of this study is to determine the bioequivalence of two different formulations of febuxostat after a single oral dose administration under fasting conditions.
The intra-subject variation following a single dose of febuxostat appears to be up to 34% for Cmax and up to 12% for AUC0-T. Statistically, given that the expected Test to Reference ratio of geometric LSmeans should fall within 95 and 105%, it is estimated that the lowest number of subjects to meet the 80 to 125% bioequivalence range with a statistical a priori power of at least 80% is about 46. Therefore, the inclusion of 50 subjects should be sufficient to account for the possibility of drop-outs, variations around the estimated intra-subject CV and to conclude in favor of the hypothesis of bioequivalence with sufficient statistical power.
Subject eligibility for this study will be determined at the screening visit and eligible subjects will be admitted to the clinical research unit at least 10 hours prior to drug administration for each study period.
A subject who withdraws or is withdrawn during the pretrial evaluations but before receiving the investigational product (IP) will not be considered as a drop-out and will not be included in the final database. Standbys should be recruited and available to replace any subject who withdraws prior to the first drug administration. On-study drop-outs will not be replaced.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- Single (Outcomes Assessor)
盲法说明
The randomization code will not be available to the personnel of the bioanalytical facility until the bioanalytical tables have been finalized and audited by the Quality Assurance (QA) department.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Provision of signed and dated informed consent form (ICF)
- •Stated willingness to comply with all study procedures and availability for the duration of the study
- •Healthy male or female adult volunteer
- •A female volunteer meeting one of the following criteria:
- •Participant is of childbearing potential and agrees to use one of the accepted contraceptive regimens from at least 28 days prior to the first study drug administration through to at least 30 days after the last dose of the study drug. An acceptable method of contraception includes one of the following:
- •Abstinence from heterosexual intercourse
- •Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
- •Intrauterine device (IUD) (with or without hormones)
- •Male condom with spermicide or male condom with a vaginal spermicide (gel, foam, or suppository)
- •Male partner vasectomized at least 6 months prior to the first study drug administration
- •Participant whose partner has had a vasectomy less than 6 months prior to dosing, and agrees to use an additional acceptable method of contraception from the first study drug administration through to at least 30 days after the last dose of the study drug
- •Participant is of non-childbearing potential, defined as surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is in a postmenopausal state (i.e. at least 1 year without menses without an alternative medical condition prior to the first study drug administration)
- •Volunteer aged at least 18 years
- •Volunteer with a body mass index (BMI) within 18.5 kg/m2 to 30.0 kg/m2, inclusively
- •Non- or ex-smoker; an ex-smoker is defined as someone who completely stopped using nicotine products for at least 180 days prior to the first study drug administration
- •Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be without clinical significance, as determined by an investigator
- •Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination (including vital signs) and/or ECG, as determined by an investigator
排除标准
- •Females who are lactating at screening
- •Females who are pregnant according to the pregnancy test at screening or prior to the first study drug administration
- •History of significant hypersensitivity to febuxostat or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs
- •Presence of significant gastrointestinal, liver or kidney disease, or any other condition known to interfere with drug absorption, distribution, metabolism or excretion, or known to potentiate or predispose to undesired effects
- •History of significant gastrointestinal, liver or kidney disease that may affect drug bioavailability
- •History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease
- •Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment
- •History of rare hereditary problems of galactose and/or lactose intolerance, lactase deficiency or glucose-galactose malabsorption
- •Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic)
- •Any clinically significant illness in the 28 days prior to the first study drug administration
- •Use of any prescription drugs (with the exception of hormonal contraceptives or hormone replacement therapy) in the 28 days prior to the first study drug administration, that in the opinion of an investigator would put into question the status of the volunteer as healthy
- •Any history of tuberculosis
- •Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration
- •Positive screening results to HIV Ag/Ab Combo, Hepatitis B surface Antigen (HBsAG (B) (hepatitis B)) or Hepatitis C Virus (HCV (C)) tests
- •Volunteers who have already been included in a previous group for this clinical study
- •Volunteers who took febuxostat in the 28 days prior to the first study drug administration
- •Volunteers who took an Investigational Product (IP) in the 28 days prior to the first study drug administration
- •Volunteers who donated 50 mL or more of blood in the 28 days prior to the first study drug administration
- •Donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the 56 days prior to the first study drug administration
研究组 & 干预措施
Sequence AB
25 subjects assigned to the sequence AB will receive a single 120 mg dose of the test product Febuxostat (1 x 120 mg film-coated tablet), marked as A in the sequence, in Period 1 and a single 120 mg dose of the reference product Adenuric (1 x 120 mg film-coated tablet), marked as B in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.
干预措施: Febuxostat (Drug)
Sequence AB
25 subjects assigned to the sequence AB will receive a single 120 mg dose of the test product Febuxostat (1 x 120 mg film-coated tablet), marked as A in the sequence, in Period 1 and a single 120 mg dose of the reference product Adenuric (1 x 120 mg film-coated tablet), marked as B in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.
干预措施: Adenuric (Drug)
Sequence BA
25 subjects assigned to the sequence BA will receive a single 120 mg dose of the reference product Adenuric (1 x 120 mg film-coated tablet), marked as B in the sequence, in Period 1 and a single 120 mg dose of the test product Febuxostat (1 x 120 mg film-coated tablet), marked as A in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.
干预措施: Febuxostat (Drug)
Sequence BA
25 subjects assigned to the sequence BA will receive a single 120 mg dose of the reference product Adenuric (1 x 120 mg film-coated tablet), marked as B in the sequence, in Period 1 and a single 120 mg dose of the test product Febuxostat (1 x 120 mg film-coated tablet), marked as A in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.
干预措施: Adenuric (Drug)
结局指标
主要结局
Cmax of febuxostat in plasma after administration of the test and the reference products
时间窗: Time points 0.00 (prior to each drug administration) and 0.25, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 18.00, 24.00, 36.00 hours after each drug administration
Maximum observed concentration in plasma
AUC0-T of febuxostat in plasma after administration of the test and the reference products
时间窗: Time points 0.00 (prior to each drug administration) and 0.25, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 18.00, 24.00, 36.00 hours after each drug administration
Cumulative area under the concentration time curve calculated from 0 to time of last observed quantifiable concentration (TLQC) using the linear trapezoidal method
次要结局
- Tmax of febuxostat in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.25, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 18.00, 24.00, 36.00 hours after each drug administration)
- TLQC of febuxostat in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.25, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 18.00, 24.00, 36.00 hours after each drug administration)
- AUC0-∞ of febuxostat in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.25, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 18.00, 24.00, 36.00 hours after each drug administration)
- Residual area of febuxostat in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.25, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 18.00, 24.00, 36.00 hours after each drug administration)
- Time point where the log-linear elimination phase begins (TLIN) of febuxostat in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.25, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 18.00, 24.00, 36.00 hours after each drug administration)
- λZ of febuxostat in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.25, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 18.00, 24.00, 36.00 hours after each drug administration)
- Terminal elimination half-life (Thalf) of febuxostat in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.25, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 15.00, 18.00, 24.00, 36.00 hours after each drug administration)
- Number of treatment-emergent adverse events for the test and the reference products(Up to 9 days (after the first drug administration until the completion of clinical part of the study)])