Effect of BIA 3-202 on the Pharmacokinetics and Pharmacodynamics of Warfarin

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether multiple-dose administration of nebicapone affects the pharmacokinetics of warfarin.

Detailed Description
-----------------
Study design and methodology: This was a single-centre, open-label, randomised, two-way crossover study in healthy young male and female volunteers. The study consisted of 2 treatment periods separated by a washout period of 14 days or more. In one period, subjects received nebicapone 200 mg thrice-daily (tid) for 9 days, and a warfarin 25 mg single-dose concomitantly with the morning dose of nebicapone on Day 4. In the other period, a warfarin 25 mg single-dose was administered alone. Warfarin pharmacokinetic and pharmacodynamic profiles were characterised following warfarin dosing.

Official Title
-----------------
Effect of BIA 3-202 on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Volunteers

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: BIA 3-202
* Drug: warfarin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects were eligible for entry into the study if they fulfilled the following inclusion criteria: Male or female subjects aged between 18 and 45 years, inclusive. Subjects of body mass index (BMI) between 19 and 30 kg/m2, inclusive. Healthy as determined by pre-study medical history, physical examination, vital signs, complete neurological examination and 12-lead ECG. Clinical laboratory test results clinically acceptable at screening and admission to first treatment period. Negative tests for HBsAg, anti-HCVAb and HIV-1 and HIV-2 Ab at screening. Negative screen for alcohol and drugs of abuse at screening and admission to each treatment period. Non-smokers or who smoked ≤ 10 cigarettes or equivalent per day. Able and willing to give written informed consent. (If female) She was not of childbearing potential by reason of surgery or, if of childbearing potential, she used one of the following methods of contraception: double barrier, intrauterine device or abstinence. (If female) She had a negative urine pregnancy test at screening and admission to each treatment period. Exclusion Criteria: Subjects were not eligible for entry into the study if they fulfilled the following exclusion criteria: Clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, endocrine, connective tissue diseases or disorders. Clinically relevant surgical history. Personal or family history of haemostatic disorder. Personal or family history of bleeding complications after surgery or tooth extraction, nose or gingival bleeding, or haemorrhagic diathesis. Any abnormality in the coagulation tests. Any abnormality in the liver function tests. A history of relevant atopy or drug hypersensitivity. History of alcoholism or drug abuse. Consumed more than 14 units of alcohol a week. Significant infection or known inflammatory process at screening or admission to each treatment period. Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, heartburn) at the time of screening or admission to each treatment period. Had used medicines within 2 weeks of admission to first period that may affect the safety or other study assessments, in the investigator's opinion. Had previously received BIA 3-202. Had used any investigational drug or participated in any clinical trial within 6 months prior to screening. Had participated in more than 2 clinical trials within the 12 months prior to screening. Had donated or received any blood or blood products within the 3 months prior to screening. Vegetarians, vegans or had medical dietary restrictions. Cannot communicate reliably with the investigator. Unlikely to co-operate with the requirements of the study. Unwilling or unable to gave written informed consent. (If female) She was pregnant or breast-feeding. (If female) She was of childbearing potential and she did not used an approved effective contraceptive method (double-barrier, intra-uterine device or abstinence) or she used oral contraceptives.

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

Sexes Eligible for Study
-----------------
All

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nebicapone plus warfarin<br>BIA 3-202 200 mg tid + Warfarin 25 mg | Drug: BIA 3-202<br>* Nebicapone tablets 200 mg<br>* Other names: Nebicapone;Drug: warfarin<br>* Varfine® 5 mg (warfarin 5 mg) tablets<br>|
| Experimental: Warfarin<br>Warfarin 25 mg | Drug: warfarin<br>* Varfine® 5 mg (warfarin 5 mg) tablets<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Cmax of S-warfarin | Maximum observed plasma drug concentration (Cmax) | before the warfarin dose, and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours post-warfarin dose | 
| Mean tmax of S-warfarin | Time of occurrence of Cmax (tmax) | before the warfarin dose, and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours post-warfarin dose | 
| Mean AUC0-144 of S-warfarin | Area under the plasma concentration-time curve (AUC) from time zero to 144 h post-warfarin dose (AUC0-144), calculated by the linear trapezoidal rule | before the warfarin dose, and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours post-warfarin dose | 
| Mean λz of S-warfarin | Apparent terminal rate constant calculated by log-linear regression of the terminal segment of the concentration versus time curve (λz) | before the warfarin dose, and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours post-warfarin dose | 
| Mean t1/2 of S-warfarin | Apparent terminal half-life, calculated from ln 2/λz (t1/2). | before the warfarin dose, and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours post-warfarin dose | 
| Mean Cmax of R-warfarin | Maximum observed plasma drug concentration (Cmax) | before the warfarin dose, and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours post-warfarin dose | 
| Mean tmax of R-warfarin | Time of occurrence of Cmax (tmax) | before the warfarin dose, and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours post-warfarin dose | 
| Mean AUC0-144 of R-warfarin | Area under the plasma concentration-time curve (AUC) from time zero to 144 h post-warfarin dose (AUC0-144), calculated by the linear trapezoidal rule | before the warfarin dose, and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours post-warfarin dose | 
| Mean λz of R-warfarin | Apparent terminal rate constant calculated by log-linear regression of the terminal segment of the concentration versus time curve (λz) | before the warfarin dose, and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours post-warfarin dose | 
| Mean t1/2 of R-warfarin | Apparent terminal half-life, calculated from ln 2/λz (t1/2). | before the warfarin dose, and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours post-warfarin dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nebicapone, Warfarin