Single Dose Crossover Comparative Bioavailability Study of Olmesartan Medoxomil/Hydrochlorothiazide 40 mg/25 mg Film-Coated Tablets in Healthy Adult Subjects / Fasting State
试验速览
- 阶段
- 1 期
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Cmax of olmesartan and HCTZ in plasma after administration of the test and the reference products.
研究概览
简要总结
This single dose study was designed in accordance with EMA (the European Medicines Agency) regulatory guidelines, with the aim of characterizing the bioavailability of olmesartan medoxomil/ hydrochlorothiazide in the two formulations (Olmesartan Medoxomil/ Hydrochlorothiazide (HCTZ), 40 mg/ 25 mg film-coated tablets (Manufacturer: Pharmtechnology LLC, Republic of Belarus) and Olmetec Plus® (Olmesartan Medoxomil/ Hydrochlorothiazide), 40 mg/25 mg film-coated tablets, (Manufacturer: Daiichi Sankyo Europe GmbH, Germany)) in healthy subjects. As this is a bioequivalence trial where each subject received each study treatment in a crossover fashion, a control group was not included. Within the clinical portion of the study each subject received a single oral dose of the test and the reference formulation in compliance with the generated randomization code. The primary study endpoints were the pharmacokinetic (PK) parameters Cmax and AUC0-t of olmesartan and hydrochlorothiazide.
详细描述
This is a single center, randomized, single dose, laboratory-blinded, 2-period, 2-sequence, crossover study design, in which 32 healthy adult subjects received 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 medoxomil/ HCTZ after a single oral dose administration under fasting conditions.
The intra-subject variation following a single dose of olmesartan/ HCTZ appears to be around 25% for Cmax and around 18% for AUC0-T for olmesartan and around 18% for Cmax and around 13% for AUC0-T for HCTZ. 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 for each analyte 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 CV and to conclude in favor of the hypothesis of bioequivalence with sufficient statistical power. A Caucasian population will be enrolled to minimize variability and optimize detection of differences between the Test and Reference formulations without regard to race.
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.
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. Study participants will be aware they will receive different formulations of the same drug, without being informed which product (Test or Reference) is being administered.
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
- •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 Caucasian adult male or female;
- •If female, meets one of the following criteria:
- •A. 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; or
- •B. 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; or C. Hysterectomy with FSH levels ≥ 40 mIU/mL at screening. If the postmenopausal subject has an FSH of < 40 mIU/mL, but meets the above criteria in either (A), (B) or (C) and all the other inclusion criteria, the subject may be included in the study if the estradiol serum level measured at screening is equal to or below 150 pmol/L;
- •Aged at least 18 years but not older than 50 years;
- •Body mass index (BMI) within 18.50 kg/m2 to 30.00 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 (CS) diseases captured in the medical history or evidence of CS findings on the physical examination (including vital signs) and/or electrocardiogram (ECG), as determined by an investigator.
排除标准
- •Female who is lactating at screening;
- •Female who is 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 and prior to the first study drug administration;
- •Seated blood pressure below 110/60 mmHg at the screening visit and prior to the first study drug administration;
- •History of significant hypersensitivity to olmesartan and HCTZ or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs;
- •Presence or history of significant gastrointestinal, liver or kidney disease, or any other condition that is known to interfere with drug absorption, distribution, metabolism or excretion, or known to potentiate or predispose to undesired effects;
- •History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease;
- •Presence of CS 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 [1 unit = 10 mL of pure alcohol], intake of excessive alcohol, acute or chronic);
- •Any CS 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 participant 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;
- •Inclusion in a previous group for this clinical study;
- •Intake of olmesartan medoxomil or HCTZ in the 28 days prior to the first study drug administration;
- •Intake of an Investigational Product (IP) in the 28 days prior to the first study drug administration;
- •Donation of 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/25 mg dose of the test product Olmesartan Medoxomil/ Hydrochlorothiazide (1 x 40 mg/ 25 mg tablet), marked as A in the sequence, in Period 1 and a single 40 mg/25 mg dose of the reference product Olmetec® Plus (1 x 40 mg/ 25 mg tablet), marked as B in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.
干预措施: Olmesartan Medoxomil/Hydrochlorothiazide 40 Mg/25 Mg film-coated tablets for oral use (Drug)
Sequence AB
16 subjects assigned to the sequence AB will receive a single 40 mg/25 mg dose of the test product Olmesartan Medoxomil/ Hydrochlorothiazide (1 x 40 mg/ 25 mg tablet), marked as A in the sequence, in Period 1 and a single 40 mg/25 mg dose of the reference product Olmetec® Plus (1 x 40 mg/ 25 mg tablet), marked as B in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.
干预措施: Olmetec® Plus 40 Mg/25 Mg film-coated tablets for oral use (Drug)
Sequence BA
16 subjects assigned to the sequence BA will receive a single 40 mg/25 mg dose of the reference product Olmetec® Plus (1 x 40 mg/ 25 mg tablet), marked as B in the sequence, in Period 1 and a single 40 mg/25 mg dose of the test product Olmesartan Medoxomil/ Hydrochlorothiazide (1 x 40 mg/ 25 mg tablet), marked as A in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.
干预措施: Olmesartan Medoxomil/Hydrochlorothiazide 40 Mg/25 Mg film-coated tablets for oral use (Drug)
Sequence BA
16 subjects assigned to the sequence BA will receive a single 40 mg/25 mg dose of the reference product Olmetec® Plus (1 x 40 mg/ 25 mg tablet), marked as B in the sequence, in Period 1 and a single 40 mg/25 mg dose of the test product Olmesartan Medoxomil/ Hydrochlorothiazide (1 x 40 mg/ 25 mg tablet), marked as A in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.
干预措施: Olmetec® Plus 40 Mg/25 Mg film-coated tablets for oral use (Drug)
结局指标
主要结局
Cmax of olmesartan and HCTZ in plasma after administration of the test and the reference products.
时间窗: Time points 0.00 (prior to each drug administration) and 0.33, 0.67, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 48.00 hours after each drug administration.
Maximum observed concentration in plasma
AUC0-t of olmesartan and HCTZ in plasma after administration of the test and the reference products.
时间窗: Time points 0.00 (prior to each drug administration) and 0.33, 0.67, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 48.00 hours after each drug administration.
Cumulative area under the concentration time curve calculated from 0 to TLQC using the linear trapezoidal method, where TLQC represents time of last observed quantifiable concentration
次要结局
- Tmax of olmesartan and HCTZ in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.33, 0.67, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 48.00 hours after each drug administration.)
- TLQC of olmesartan and HCTZ in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.33, 0.67, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 48.00 hours after each drug administration.)
- AUC0-∞ of olmesartan and HCTZ in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.33, 0.67, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 48.00 hours after each drug administration.)
- Residual area of olmesartan and HCTZ in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.33, 0.67, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 48.00 hours after each drug administration.)
- Time point where the log-linear elimination phase begins (TLIN) of olmesartan and HCTZ in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.33, 0.67, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 48.00 hours after each drug administration.)
- λZ of olmesartan and HCTZ in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.33, 0.67, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 48.00 hours after each drug administration.)
- Terminal elimination half-life (Thalf) of olmesartan and HCTZ in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.33, 0.67, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 24.00, 48.00 hours after each drug administration.)
- Number of treatment-emergent adverse events for the test and the reference products.(Up to 11 days (after the first drug administration until the end of the period of 1 day following the last blood sample of the study))