A Single Part, Open-Label, Randomised, Three-Way Crossover Study Designed to Evaluate the Pharmacokinetic Parameters and Relative Bioavailability of Sorafenib From Sorafenib (XS005) Tablets and Capsules Compared With Nexavar® (Reference Product) in Healthy Male Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Plasma half-life of drug (T1/2) of XS005 and Nexavar®
研究概览
简要总结
This is a single centre, open-label, randomised, single dose, 3-way crossover comparative (PK) and bioavailability study in healthy male subjects comparing a 200 mg Sorafenib (Nexavar®) reference tablet (Regimen A) to XS005 Sorafenib Capsule A, 2 x 50 mg (Regimen B) and XS005 Sorafenib Tablet A,100 mg (Regimen C) formulation. It is planned to enroll 15 subjects who will receive single oral doses of investigational medicinal product (IMP) across 3 treatment periods.
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
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Healthy males.
- •Age 18 to 55 years of age.
- •Body mass index (BMI) of 18.0 to 32.0 kg/m
- •Must be willing and able to communicate and participate in the whole study.
- •Must provide written informed consent.
- •Good state of health (mentally and physically) as indicated by a comprehensive clinical assessment (detailed medical history and a complete physical examination), ECG and laboratory investigations (haematology, biochemistry and urinalysis).
- •Must adhere to the contraception requirements.
排除标准
- •Subjects who have received any IMP in a clinical research study within the previous 3 months.
- •Subjects who are study site employees, or immediate family members of a study site or sponsor employee.
- •Subjects who have previously been enrolled in this study.
- •History of any drug or alcohol abuse in the past 2 years.
- •Regular alcohol consumption >21 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type).
- •Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission.
- •Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
- •Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening.
- •Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator.
- •Subjects has amylase or lipase result exceeding >1.5 x upper limit of normal (ULN) at screening.
- •Positive drugs of abuse or alcohol breath test result.
- •Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results.
- •History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
- •Subject has a QT interval corrected by Fredericia (QTcF) >450 ms based on ECG at screening or at pre-dose Period 1 or a history of additional risk factors for Torsades de Pointe (eg hypokalaemia, hypomagnesia, a family history of long QT syndrome).
- •Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
- •Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active.
- •Donation or loss of greater than 400 mL of blood within the previous 3 months.
- •Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than 4 g per day paracetamol) or herbal remedies in the 14 days before IMP administration. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the PI and sponsor's medical monitor.
- •Subjects with pregnant partners.
- •Failure to satisfy the investigator of fitness to participate for any other reason.
研究组 & 干预措施
Sorafenib - Period 1
Subjects were admitted to the clinical unit in the morning of Day 1, and dosed with 200 mg Sorafenib (Nexavar®) in the morning of Day 1 following an overnight fast of a minimum of 10 h. Subjects remained in clinical unit until 24 h post dose (Day 2) when they were discharged from the clinical unit, and then returned to the clinical unit at 48 h and 72 h post-dose (Days 3 and 4) for a PK blood sample.The minimum washout before the next dosing period was 10 days.
干预措施: Sorafenib - Period 1 (Drug)
XS005 Sorafenib Capsule A - Period 1
Subjects were admitted to the clinical unit in the morning of Day 1, and dosed with 100 mg (2 x 50 mg) XS005 Sorafenib Capsule A in the morning of Day 1 following an overnight fast of a minimum of 10 h. Subjects remained in clinical unit until 24 h post dose (Day 2) when they were discharged from the clinical unit, and then returned to the clinical unit at 48 h and 72 h post-dose (Days 3 and 4) for a PK blood sample.The minimum washout before the next dosing period was 10 days.
干预措施: XS005 Sorafenib Capsule A - Period 1 (Drug)
XS005 Sorafenib Tablet A - Period 1
Subjects were admitted to the clinical unit in the morning of Day 1, and dosed with 100 mg XS005 Sorafenib Tablet A in the morning of Day 1 following an overnight fast of a minimum of 10 h. Subjects remained in clinical unit until 24 h post dose (Day 2) when they were discharged from the clinical unit, and then returned to the clinical unit at 48 h and 72 h post-dose (Days 3 and 4) for a PK blood sample.The minimum washout before the next dosing period was 10 days.
干预措施: XS005 Sorafenib Tablet A - Period 1 (Drug)
XS005 Sorafenib Capsule A - Period 2
Subjects were admitted to the clinical unit in the morning of Day 1, and dosed with 100 mg (2 x 50 mg) XS005 Sorafenib Capsule A in the morning of Day 1 following an overnight fast of a minimum of 10 h. Subjects remained in clinical unit until 24 h post dose (Day 2) when they were discharged from the clinical unit, and then returned to the clinical unit at 48 h and 72 h post-dose (Days 3 and 4) for a PK blood sample.The minimum washout before the next dosing period was 10 days.
干预措施: XS005 Sorafenib Capsule A - Period 2 (Drug)
XS005 Sorafenib Tablet A - Period 2
Subjects were admitted to the clinical unit in the morning of Day 1, and dosed with 100 mg XS005 Sorafenib Tablet A in the morning of Day 1 following an overnight fast of a minimum of 10 h. Subjects remained in clinical unit until 24 h post dose (Day 2) when they were discharged from the clinical unit, and then returned to the clinical unit at 48 h and 72 h post-dose (Days 3 and 4) for a PK blood sample.The minimum washout before the next dosing period was 10 days.
干预措施: XS005 Sorafenib Tablet A - Period 2 (Drug)
Sorafenib - Period 2
Subjects were admitted to the clinical unit in the morning of Day 1, and dosed with 200 mg Sorafenib (Nexavar®) in the morning of Day 1 following an overnight fast of a minimum of 10 h. Subjects remained in clinical unit until 24 h post dose (Day 2) when they were discharged from the clinical unit, and then returned to the clinical unit at 48 h and 72 h post-dose (Days 3 and 4) for a PK blood sample.The minimum washout before the next dosing period was 10 days.
干预措施: Sorafenib - Period 2 (Drug)
XS005 Sorafenib Tablet A - Period 3
Subjects were admitted to the clinical unit in the morning of Day 1, and dosed with 100 mg XS005 Sorafenib Tablet A in the morning of Day 1 following an overnight fast of a minimum of 10 h. Subjects remained in clinical unit until 24 h post dose (Day 2) when they were discharged from the clinical unit, and then returned to the clinical unit at 48 h and 72 h post-dose (Days 3 and 4) for a PK blood sample.The minimum washout before the next dosing period was 10 days.
干预措施: XS005 Sorafenib Tablet A - Period 3 (Drug)
Sorafenib - Period 3
Subjects were admitted to the clinical unit in the morning of Day 1, and dosed with 200 mg Sorafenib (Nexavar®) in the morning of Day 1 following an overnight fast of a minimum of 10 h. Subjects remained in clinical unit until 24 h post dose (Day 2) when they were discharged from the clinical unit, and then returned to the clinical unit at 48 h and 72 h post-dose (Days 3 and 4) for a PK blood sample.The minimum washout before the next dosing period was 10 days.
干预措施: Sorafenib - Period 3 (Drug)
XS005 Sorafenib Capsule A - Period 3
Subjects were admitted to the clinical unit in the morning of Day 1, and dosed with 100 mg (2 x 50 mg) XS005 Sorafenib Capsule A in the morning of Day 1 following an overnight fast of a minimum of 10 h. Subjects remained in clinical unit until 24 h post dose (Day 2) when they were discharged from the clinical unit, and then returned to the clinical unit at 48 h and 72 h post-dose (Days 3 and 4) for a PK blood sample.The minimum washout before the next dosing period was 10 days.
干预措施: XS005 Sorafenib Capsule A - Period 3 (Drug)
结局指标
主要结局
Plasma half-life of drug (T1/2) of XS005 and Nexavar®
时间窗: For each study period, blood samples collected at 15 time points (including pre-dose) during the study period on Day 1 and Day 4.
The pharmacokinetic parameters (T1/2) were determined for the test and reference products (XS005 Sorafenib Capsule A, 2 x 50 mg and XS005 Tablet A, 100 mg and reference Sorafenib tablets (Nexavar®), respectively) for each subject using non-compartmental methods.
Area Under the Plasma Concentration-Time Curve from 0 time to the last measurable of concentration AUC(0-last) of XS005 and Nexavar®
时间窗: For each study period, blood samples collected at 15 time points (including pre-dose) during the study period on Day 1 and Day 4.
The pharmacokinetic parameters AUC(0-last) were determined for the test and reference products (XS005 Sorafenib Capsule A, 2 x 50 mg and XS005 Tablet A, 100 mg and reference Sorafenib tablets (Nexavar®), respectively) for each subject using non-compartmental methods.
Time of Maximum Observed Plasma Concentration (Tmax) of XS005 and Nexavar®
时间窗: For each study period, blood samples collected at 15 time points (including pre-dose) during the study period on Day 1 and Day 4.
The pharmacokinetic parameters (Tmax) were determined for the test and reference products (XS005 Sorafenib Capsule A, 2 x 50 mg and XS005 Tablet A, 100 mg and reference Sorafenib tablets (Nexavar®), respectively) for each subject using non-compartmental methods.
Maximum Observed Plasma Concentration (Cmax) of XS005 and Nexavar®
时间窗: For each study period, blood samples collected at 15 time points (including pre-dose) during the study period on Day 1 and Day 4.
The pharmacokinetic parameters (Cmax) were determined for the test and reference products (XS005 Sorafenib Capsule A, 2 x 50 mg and XS005 Tablet A, 100 mg and reference Sorafenib tablets (Nexavar®), respectively) for each subject using non-compartmental methods.
Area Under the Plasma Concentration-Time Curve from 0 time Extrapolated to Infinity (AUC0-inf) of XS005 and Nexavar®
时间窗: For each study period, blood samples collected at 15 time points (including pre-dose) during the study period on Day 1 and Day 4.
The pharmacokinetic parameters (AUC 0-inf) were determined for the test and reference products (XS005 Sorafenib Capsule A, 2 x 50 mg and XS005 Tablet A, 100 mg and reference Sorafenib tablets (Nexavar®), respectively) for each subject using non-compartmental methods.
Relative bioavailability (Frel) of XS005 and Nexavar®
时间窗: For each study period, blood samples collected at 15 time points (including pre-dose) during the study period on Day 1 and Day 4.
The relative bioavailability (Frel) of Sorafenib following administration of XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®).
次要结局
- Heart Rate (HR) (bpm)(For each study period, HR were collected at 4 time points (including pre-dose) during the study period on Day 1 and Day 2.)
- ECG (12-lead electrocardiogram) - PR Interval (msec)(For each study period, ECG were collected at 4 time points (including pre-dose) during the study period on Day 1 and Day 2.)
- Diastolic Blood Pressure (mmHg)(For each study period, Diastolic Blood Pressure were collected at 4 time points (including pre-dose) during the study period on Day 1 and Day 2.)
- ECG (12-lead electrocardiogram) - Ventricular Rate (HR) (bpm)(For each study period, ECG were collected at 4 time points (including pre-dose) during the study period on Day 1 and Day 2.)
- ECG (12-lead electrocardiogram) - QRS Duration (msec)(For each study period, ECG were collected at 4 time points (including pre-dose) during the study period on Day 1 and Day 2.)
- Systolic Blood Pressure (mmHg)(For each study period, Systolic Blood Pressure were collected at 4 time points (including pre-dose) during the study period on Day 1 and Day 2.)
- ECG (12-lead electrocardiogram) - QRS Axis (°)(For each study period, ECG were collected at 4 time points (including pre-dose) during the study period on Day 1 and Day 2.)
- ECG (12-lead electrocardiogram) - QTcF Interval (msec)(For each study period, ECG were collected at 4 time points (including pre-dose) during the study period on Day 1 and Day 2.)
- Number of participants with abnormal hematology values(For each study period, blood samples were collected at 2 time points (including pre-dose) during the study period on Day1 and Day 2.)
- Number of participants with abnormal urinalysis values(For each study period, urine samples were collected at 2 time points (including pre-dose) during the study period on Day1 and Day 2.)
- Treatment-emergent adverse events (TEAEs) (ie those beginning after dosing with study drug)(Adverse event (AE) information collected through study completion, an average of 10 weeks.)
- ECG (12-lead electrocardiogram) - QT Interval (msec)(For each study period, ECG were collected at 4 time points (including pre-dose) during the study period on Day 1 and Day 2.)
- Number of participants with abnormal physical examination outcome(For each study period, target (symptom driven) physical examination; each subject was assessed by a physician and a physical examination was performed if the subject reported any AEs, on Day 2.)
- Number of participants with abnormal laboratory values of Clinical Chemistry(For each study period, blood samples were collected at 2 time points (including pre-dose) during the study period on Day 1 and Day 2.)
- Number of participants with abnormal skin examination outcome(For each study period, skin assessments were done at 2 time points (including pre-dose) during the study period on Day 1 and Day 2.)