Single Dose Crossover Comparative Bioavailability Study of Candesartan Cilexetil 32 mg 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
- 40
- 试验地点
- 1
- 主要终点
- Cmax of candesartan 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 candesartan in the two formulations 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 candesartan.
详细描述
This is a single center, randomized, 2-treatment, 2-period, 2-sequence, crossover, single dose study design, in which 40 healthy adult subjects received one of the study treatments during each study period.
The objective of this study was to determine the bioequivalence of two different formulations of candesartan after a single oral dose administration under fasting conditions.
The intra-subject variation following a single dose of candesartan cilexetil appeared to be around 28.8% for Cmax and around 24% 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 36. Therefore, the inclusion of 40 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A subject who withdraws or is withdrawn during the pretrial evaluations but before receiving the first dose (the test or the reference product) in Period 1 will not be considered as a drop-out and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. 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 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 Caucasian adult male or female
- •If female, meets one of the following criteria:
- •(1) Physiological postmenopausal status, defined as the following:
- •a) absence of menses for at least one year prior to the first study drug administration (without an alternative medical condition); and b) Follicle stimulating hormone (FSH) levels ≥ 40 mIU/mL at screening; or (2) 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 (3) Hysterectomy with FSH levels ≥ 40 mIU/mL at screening If postmenopausal and has an FSH of < 40 mIU/mL, but meets all other criteria in (1), (2) or (3) above as well as all the other inclusion criteria, screening estradiol serum level must be equal to or below 150 pmol/L. In the case of hysterectomy, if FSH and estradiol do not meet the criteria, eligibility for study participation will be based on medical judgment.
- •Aged at least 18 years but not older than 55 years
- •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
- •Female who is lactating at screening
- •Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration
- •Seated pulse rate less than 50 Beats per Minute (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 candesartan 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 (including but not limited to cholecystectomy) 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 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 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 (HBsAG) or Hepatitis C Virus (HCV) tests
- •Inclusion in a previous group for this clinical study
- •Intake of candesartan 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
20 subjects assigned to the sequence AB will receive a single 32 mg dose of the test product Candesartan Cilexetil (1 x 32 mg tablet), marked as A in the sequence, in Period 1 and a single 32 mg dose of the reference product Atacand® PROTECT (1 x 32 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: Candesartan Cilexetil 32mg (Drug)
Sequence AB
20 subjects assigned to the sequence AB will receive a single 32 mg dose of the test product Candesartan Cilexetil (1 x 32 mg tablet), marked as A in the sequence, in Period 1 and a single 32 mg dose of the reference product Atacand® PROTECT (1 x 32 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: Atacand® PROTECT (Drug)
Sequence BA
20 subjects assigned to the sequence BA will receive a single 32 mg dose of the reference product Atacand® PROTECT (1 x 32 mg tablet), marked as B in the sequence, in Period 1 and a single 32 mg dose of the test product Candesartan Cilexetil (1 x 32 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: Candesartan Cilexetil 32mg (Drug)
Sequence BA
20 subjects assigned to the sequence BA will receive a single 32 mg dose of the reference product Atacand® PROTECT (1 x 32 mg tablet), marked as B in the sequence, in Period 1 and a single 32 mg dose of the test product Candesartan Cilexetil (1 x 32 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: Atacand® PROTECT (Drug)
结局指标
主要结局
Cmax of candesartan 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, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration.
Maximum observed concentration in plasma.
AUC0-t of candesartan 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, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 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
- AUC0-INF of candesartan in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration.)
- Residual area of candesartan in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 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 candesartan in plasma after administration of the test and the reference. products.(Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration.)
- λZ of candesartan in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration.)
- Tmax of candesartan in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration.)
- TLQC of candesartan in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration.)
- Terminal elimination half-life (Thalf) of candesartan in plasma after administration of the test and the reference products.(Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 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 11 days (after the first drug administration until the end of the period of 1 day following the last blood sample of the study))