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

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

The purpose of this study is to determine whether multiple-dose administration of nebicapone affects the pharmacokinetics of warfarin.

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.

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.