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

Overview

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

Full Title of Study: “Effect of BIA 3-202 on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Volunteers”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2006

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.

Interventions

  • Drug: BIA 3-202
    • Nebicapone tablets 200 mg
  • Drug: warfarin
    • Varfine® 5 mg (warfarin 5 mg) tablets

Arms, Groups and Cohorts

  • Experimental: Nebicapone plus warfarin
    • BIA 3-202 200 mg tid + Warfarin 25 mg
  • Experimental: Warfarin
    • Warfarin 25 mg

Clinical Trial Outcome Measures

Primary Measures

  • Mean Cmax of S-warfarin
    • Time Frame: 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
    • Maximum observed plasma drug concentration (Cmax)
  • Mean tmax of S-warfarin
    • Time Frame: 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
    • Time of occurrence of Cmax (tmax)
  • Mean AUC0-144 of S-warfarin
    • Time Frame: 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
    • 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
  • Mean λz of S-warfarin
    • Time Frame: 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
    • Apparent terminal rate constant calculated by log-linear regression of the terminal segment of the concentration versus time curve (λz)
  • Mean t1/2 of S-warfarin
    • Time Frame: 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
    • Apparent terminal half-life, calculated from ln 2/λz (t1/2).
  • Mean Cmax of R-warfarin
    • Time Frame: 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
    • Maximum observed plasma drug concentration (Cmax)
  • Mean tmax of R-warfarin
    • Time Frame: 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
    • Time of occurrence of Cmax (tmax)
  • Mean AUC0-144 of R-warfarin
    • Time Frame: 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
    • 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
  • Mean λz of R-warfarin
    • Time Frame: 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
    • Apparent terminal rate constant calculated by log-linear regression of the terminal segment of the concentration versus time curve (λz)
  • Mean t1/2 of R-warfarin
    • Time Frame: 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
    • Apparent terminal half-life, calculated from ln 2/λz (t1/2).

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 45 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Bial – Portela C S.A.
  • Provider of Information About this Clinical Study
    • Sponsor

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