Effect of BIA 9-1067 on the Pharmacokinetics and Pharmacodynamics of Warfarin

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate CYP2C9 inhibition by BIA 9-1067 through the assessment of its effect on the pharmacokinetics of S-warfarin, a substrate of CYP2C9.

Detailed Description
-----------------
Single-centre, open-label, randomised, two-way crossover study in healthy young male and female volunteers. The study was to consist of 2 treatment periods separated by a washout period of 14 days or more. In one period, subjects were to receive a single-dose of 25 mg BIA 9-1067 with a single-dose of racemic 25 mg warfarin. In the other period, a 25 mg warfarin single-dose was to be administered alone.

Official Title
-----------------
Effect of BIA 9-1067 on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Volunteers

Conditions
-----------------
Parkinson's Disease (PD)

Intervention / Treatment
-----------------
* Drug: BIA 9-1067
* Drug: Warfarin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Able and willing to give written informed consent. 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. Negative tests for HBsAg, anti-HCVAb and HIV-1 and HIV-2 Ab at screening. Clinical laboratory test results clinically acceptable at screening and admission to each treatment period. Negative screen for alcohol and drugs of abuse at screening and admission to each treatment period. Non-smokers or ex-smokers for at least 3 months. (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 or intrauterine device. (If female) She had a negative urine pregnancy test at screening and admission to each treatment period. 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 have affected the safety or other study assessments, in the investigator's opinion. Had previously received BIA 9-1067. 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. Employees at BIAL - Portela & Co, SA. (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 or intra-uterine device) 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: Group 1<br>Period 1: BIA 9-1067 + warfarin Period 2: warfarin | Drug: BIA 9-1067<br>* BIA 9-1067 25 mg<br>* Other names: OPC, Opicapone;Drug: Warfarin<br>* Warfarin 25 mg<br>* Other names: Varfine®;|
| Active Comparator: Group 2<br>Period 1: warfarin Period 2: BIA 9-1067 + warfarin | Drug: BIA 9-1067<br>* BIA 9-1067 25 mg<br>* Other names: OPC, Opicapone;Drug: Warfarin<br>* Warfarin 25 mg<br>* Other names: Varfine®;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax - Maximum Observed Plasma Concentration (BIA 9-1067 + Warfarin) | Mean plasma BIA 9-1067 pharmacokinetic parameters obtained following an oral single dose of 25 mg warfarin co-administered with 25 mg BIA 9-1067 | before dose and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h post- dose. | 
| Tmax - Time to Maximum Observed Plasma Concentration (BIA 9-1067 + Warfarin) | Mean plasma BIA 9-1067 pharmacokinetic parameters obtained following an oral single dose of 25 mg warfarin co-administered with 25 mg BIA 9-1067 | before dose and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h post- dose. | 
| AUC0-t - Area Under the Plasma Concentration-time Curve From Time 0 to Last Observed Concentration (BIA 9-1067 + Warfarin) | Mean plasma BIA 9-1067 pharmacokinetic parameters obtained following an oral single dose of 25 mg warfarin co-administered with 25 mg BIA 9-1067 | before dose and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h post- dose. | 
| Cmax = Maximum Plasma Concentration (Warfarin Alone) | Mean plasma S-warfarin pharmacokinetic parameters obtained following an oral singledose of 25 mg warfarin administered alone | before dose and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h post- dose. | 
| Tmax - Time to Maximum Observed Plasma Concentration (Warfarin Alone) | Mean plasma S-warfarin pharmacokinetic parameters obtained following an oral singledose of 25 mg warfarin administered alone | before dose and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h post- dose. | 
| AUC0-t - Area Under the Plasma Concentration-time Curve From Time 0 to Last Observed Concentration (Warfarin Alone) | Mean plasma S-warfarin pharmacokinetic parameters obtained following an oral singledose of 25 mg warfarin administered alone | before dose and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h post- dose. | 
| Cmax - Maximum Observed Plasma Concentration (Warfarin + BIA 9-1067) | Mean plasma S-warfarin pharmacokinetic parameters obtained following an oral single dose of 25 mg warfarin co-administered with 25 mg BIA 9-1067 | before dose and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h post- dose. | 
| Tmax - Time to Maximum Observed Plasma Concentration (Warfarin + BIA 9-1067) | Mean plasma S-warfarin pharmacokinetic parameters obtained following an oral single dose of 25 mg warfarin co-administered with 25 mg BIA 9-1067 | before dose and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h post- dose. | 
| AUC0-t - Area Under the Plasma Concentration-time Curve From Time 0 to Last Observed Concentration (Warfarin + BIA 9-1067) | Mean plasma S-warfarin pharmacokinetic parameters obtained following an oral single dose of 25 mg warfarin co-administered with 25 mg BIA 9-1067 | before dose and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h post- dose. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Parkinson's disease (PD), BIA 9-1067, Opicapone