Sorafenib Drug Drug Interaction Study in Healthy Male Subjects

Study Overview
=================
Brief Summary
-----------------
To evaluate the effect of levothyroxine on the absorption, distribution, metabolization and elimination of sorafenib and safety in healthy male subjects

Official Title
-----------------
An Open-label Study in Healthy Male Subjects to Assess the Effect of Hyperthyroidism Mimicked by Oral Dosing of Levothyroxine on the Pharmacokinetics of Sorafenib

Conditions
-----------------
Drug Interactions

Intervention / Treatment
-----------------
* Drug: Sorafenib (Nexavar, BAY43-9006)
* Drug: Levothyroxine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male subjects between the ages of 18 (inclusive) and 45 years (inclusive) at the first screening visit. Body mass index (BMI) between 18.5 (inclusive) to 30.0 kg / m² (inclusive) with body weight ≥ 65kg. Normal thyroid function indicated by thyroid examination to include total and free T3 (Triiodothyronine) , T4 (total and free Thyroxine, levothyroxine), TSH (Thyroid stimulating hormone), anti-TSH-receptor (anti-TSHR) antibody, anti-thyroperoxidase (anti-TPO) antibody, anti-thyroglobulin antibody (anti-ATA) as well as thyroid ultrasound. Exclusion Criteria: History of clinically significant metabolic, renal, hepatic, or central nervous system disorder such as seizure, psychosis and sleep disorders. History of cardiovascular diseases including arrhythmia, hypertension, ischemia, etc. Known or suspected cardiovascular disease including potential risk of atrioventricular (AV) block, arrhythmia, etc. with or without a formal cardiologist consultation. Subjects who had received iodine containing contrast medium within 2 months before first study drug administration. Use of systemic or topical medicines or substances which might affect the study drug(s) must be avoided

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib (Nexavar, BAY43-9006) & Levothyroxine<br>Sorafenib be administrated without and with levothyroxine orally | Drug: Sorafenib (Nexavar, BAY43-9006)<br>* Single dose of 400 mg orally on Period 1 Day 1 and Period 2 Day 11<br>Drug: Levothyroxine<br>* Single dose of 300 mcq orally from Period 2 Day 1 to Period 2 Day 14<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration vs. time curve from zero to infinity after single (first) dose (AUC) of sorafenib |  | Period 1 Day 1 and Period 2 Day 11: Predose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC from time 0 to the last data point > LLOQ (AUC(0-tlast))of Sorafenib and metabolite M-2 |  | Period 1 Day 1 and Period 2 Day 11: Predose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose | 
| Maximum observed drug concentration in measured matrix after single dose administration (Cmax) of Sorafenib and metabolite M-2 |  | Period 1 Day 1 and Period 2 Day 11: Predose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose | 
| Time to reach Cmax (in case of two identical Cmax values, the first tmax will be used) (Tmax Sorafenib) and metabolite M-2 |  | Period 1 Day 1 and Period 2 Day 11: Predose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose | 
| Half-life associated with the terminal slope (t1/2) of Sorafenib and metabolite M-2 |  | Period 1 Day 1 and Period 2 Day 11: Predose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose | 
| Apparent volume of distribution at steady state after extravascular administration (Vss/F) of Sorafenib |  | Period 1 Day 1 and Period 2 Day 11: Predose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose | 
| Total body clearance of Sorafenib calculated after extravascular administration (CL/F) |  | Period 1 Day 1 and Period 2 Day 11: Predose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose | 
| AUC of metabolite M-2 |  | Period 1 Day 1 and Period 2 Day 11: Predose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose | 
| Metabolite to parent AUC(0-tlast) ratios |  | Period 1 Day 1 and Period 2 Day 11: Predose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose | 
| Number of participants with adverse events as a measure of safety and tolerability |  | Up to 15 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sorafenib, levothyroxine, drug interaction, pharmacokinetics, healthy volunteer