Evaluating the Pharmacokinetic Parameters and Relative Bioavailability of Sorafenib (XS005) in Healthy Male Subjects
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: 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. |
Drug: Sorafenib - Period 1
Sorafenib (Nexavar®) Tablet, 200 mg
Other Names:
|
| Experimental: 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. |
Drug: XS005 Sorafenib Capsule A - Period 1
XS005 Sorafenib Capsule A, 100 mg (2 x 50 mg)
Other Names:
|
| Experimental: 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. |
Drug: XS005 Sorafenib Tablet A - Period 1
XS005 Sorafenib Tablet A, 100 mg
Other Names:
|
| Experimental: 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. |
Drug: XS005 Sorafenib Capsule A - Period 2
XS005 Sorafenib Capsule A, 100 mg (2 x 50 mg)
Other Names:
|
| Experimental: 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. |
Drug: XS005 Sorafenib Tablet A - Period 2
XS005 Sorafenib Tablet A, 100 mg
Other Names:
|
| Active Comparator: 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. |
Drug: Sorafenib - Period 2
Sorafenib (Nexavar®) Tablet, 200 mg
Other Names:
|
| Experimental: 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. |
Drug: XS005 Sorafenib Tablet A - Period 3
XS005 Sorafenib Tablet A, 100 mg
Other Names:
|
| Active Comparator: 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. |
Drug: Sorafenib - Period 3
Sorafenib (Nexavar®) Tablet, 200 mg
Other Names:
|
| Experimental: 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. |
Drug: XS005 Sorafenib Capsule A - Period 3
XS005 Sorafenib Capsule A, 100 mg (2 x 50 mg)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Time of Maximum Observed Plasma Concentration (Tmax) of XS005 and Nexavar® [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® [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 to the last measurable of concentration AUC(0-last) of XS005 and Nexavar® [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.
- Area Under the Plasma Concentration-Time Curve from 0 time Extrapolated to Infinity (AUC0-inf) of XS005 and Nexavar® [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.
- Plasma half-life of drug (T1/2) of XS005 and Nexavar® [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.
- Relative bioavailability (Frel) of XS005 and Nexavar® [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®).
Secondary Outcome Measures
- 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.]
The safety parameters TEAEs were were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics.
- 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.]
The safety parameters Systolic Blood Pressure (mmHg) were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics.
- 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.]
The safety parameters Diastolic Blood Pressure (mmHg) were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics.
- 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.]
The safety parameters HR summarizes were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics.
- 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.]
The safety parameters ECG - Ventricular Rate were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics.
- 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.]
The safety parameters ECG - PR Interval were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics.
- 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.]
The safety parameters ECG - QRS Duration were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics.
- 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.]
The safety parameters ECG - QT Interval were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics.
- 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.]
The safety parameters ECG - QRS Axis were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics.
- 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.]
The safety parameters ECG - QTcF Interval were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics.
- 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.]
The safety parameters Clinical Chemistry were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics and presented as number of participants with abnormal laboratory values
- 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.]
The safety parameters Haematology were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics and presented as number of participants with abnormal laboratory values
- 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.]
The safety parameters Urinalysis were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics and presented as number of participants with abnormal laboratory values.
- 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.]
The safety parameters physical examination outcome were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics and presented as number of subjects with abnormal physical examination outcome.
- 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.]
The safety parameters Skin assessment outcome were determined for XS005 Sorafenib Capsule A, 50 mg and Tablet A, 100 mg compared to reference Sorafenib tablets (Nexavar®) for each study subjects using descriptive statistics and presented as number of subjects with abnormal skin examination outcome.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Healthy males.
-
Age 18 to 55 years of age.
-
Body mass index (BMI) of 18.0 to 32.0 kg/m2.
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Must be willing and able to communicate and participate in the whole study.
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Must provide written informed consent.
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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.
Exclusion Criteria:
-
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.
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History of any drug or alcohol abuse in the past 2 years.
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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).
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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.
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Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
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Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening.
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Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator.
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Subjects has amylase or lipase result exceeding >1.5 x upper limit of normal (ULN) at screening.
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Positive drugs of abuse or alcohol breath test result.
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Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results.
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History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
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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).
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Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
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Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active.
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Donation or loss of greater than 400 mL of blood within the previous 3 months.
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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.
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Subjects with pregnant partners.
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Failure to satisfy the investigator of fitness to participate for any other reason.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Quotient Sciences | Nottingham | United Kingdom | NG11 6JS |
Sponsors and Collaborators
- Xspray Pharma AB
Investigators
- Principal Investigator: Sharan Sidhu, MBChB, BAO, MRCS, MFPM, Quotient Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- XS005-01