Single Dose Crossover Comparative Bioavailability Study of Olmesartan Medoxomil 40 mg Film-coated Tablets in Healthy Adult Subjects Under Fasting Conditions.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Cmax of olmesartan in plasma after administration of the test and the reference products
研究概览
简要总结
This single dose study is designed in accordance with EMA (the European Medicines Agency) regulatory guidelines, with the aim of characterizing the bioavailability of olmesartan in the two formulations in healthy subjects. As this is a bioequivalence trial where each subject will receive each study treatment in a crossover fashion, a control group is not included. 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 olmesartan.
详细描述
This is a single center, randomized, 2-treatment, 2-period, 2-sequence, crossover, single dose study design, in which 32 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 olmesartan after a single oral dose administration under fasting conditions.
The intra-subject variation following a single dose of olmesartan appears to be around 25% for Cmax and around 18% for AUC0-t. Statistically, given that the expected Test to Reference ratio of geometric least-squares means (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 28. Therefore, the inclusion of 32 subjects should be sufficient to account for the possibility of drop-outs, variations around the estimated intra-subject coefficient of variation (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A subject who withdraws or is withdrawn during the pretrial evaluations but before receiving the first dose (the test or the reference product) in Period 1 will not be considered as a drop-out and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 55 Years（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:
- •Physiological postmenopausal status, defined as the following:
- •absence of menses for at least one year prior to the first study drug administration (without an alternative medical condition); and
- •Follicle stimulating hormone (FSH) levels ≥ 40 mIU/mL at screening;
- •Surgical postmenopausal status, defined as the following:
- •bilateral oophorectomy; and
- •absence of menses for at least 90 days prior to the first study drug administration; and
- •FSH levels ≥ 40 mIU/mL at screening;
- •Hysterectomy with FSH levels ≥ 40 mIU/mL at screening If the postmenopausal volunteer has an FSH of < 40 mIU/mL, but meets the above criteria in either (1), (2) or (3) and all the other inclusion criteria, the volunteer may be included in the study if the estradiol serum level measured at screening is equal to or below 150 pmol/L. In the case of hysterectomy, if FSH and estradiol do not meet the criteria, inclusion of the volunteer will be based on medical judgment.
- •Volunteer aged at least 18 years but not older than 55 years
- •Volunteer with a body mass index (BMI) within 18.5 kg/m2 to 30.0 kg/m2, inclusively
- •Light-, non- or ex-smoker. A light smoker is defined as someone using 10.0 nicotine units or less per day for at least 90 days prior to the first study drug administration. 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
- •Seated pulse rate less than 50 Beats per Minute (bpm) or more than 100 bpm at the screening visit or prior to the first study drug administration
- •Seated blood pressure below 110/60 mmHg at the screening visit or prior to the first study drug administration
- •History of significant hypersensitivity to olmesartan 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, or surgery that may affect drug bioavailability, including but not limited to cholecystectomy
- •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 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 or Hepatitis C Virus tests
- •Volunteers who have already been included in a previous group for this clinical study
- •Volunteers who took olmesartan 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
16 subjects assigned to the sequence AB will receive a single 40 mg dose of the test product Olmesartan Medoxomil (1 x 40 mg film-coated tablet), marked as A in the sequence, in Period 1 and a single 40 mg dose of the reference product Olmetec® (1 x 40 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: Olmesartan Medoxomil 40 mg (Drug)
Sequence AB
16 subjects assigned to the sequence AB will receive a single 40 mg dose of the test product Olmesartan Medoxomil (1 x 40 mg film-coated tablet), marked as A in the sequence, in Period 1 and a single 40 mg dose of the reference product Olmetec® (1 x 40 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: Olmetec® (Drug)
Sequence BA
16 subjects assigned to the sequence BA will receive a single 40 mg dose of the reference product Olmetec® (1 x 40 mg film-coated tablet), marked as B in the sequence, in Period 1 and a single 40 mg dose of the test product Olmesartan Medoxomil (1 x 40 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: Olmesartan Medoxomil 40 mg (Drug)
Sequence BA
16 subjects assigned to the sequence BA will receive a single 40 mg dose of the reference product Olmetec® (1 x 40 mg film-coated tablet), marked as B in the sequence, in Period 1 and a single 40 mg dose of the test product Olmesartan Medoxomil (1 x 40 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: Olmetec® (Drug)
结局指标
主要结局
Cmax of olmesartan in plasma after administration of the test and the reference products
时间窗: Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration
Maximum observed concentration in plasma
AUC0-t of olmesartan in plasma after administration of the test and the reference products
时间窗: Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 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 olmesartan in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration)
- TLQC of olmesartan in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration)
- AUC0-INF of olmesartan in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration)
- Residual area of olmesartan in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration)
- Time point where the log-linear elimination phase begins (TLIN) of olmesartan in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration)
- λZ of olmesartan in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration)
- Terminal elimination half-life (Thalf) of olmesartan in plasma after administration of the test and the reference products(Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration)
- Number of treatment-emergent adverse events for the test and the reference products(Up to 10 days (after the first drug administration until the completion of clinical part of the study))