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

Phase 1

Completed

Conditions: Parkinson's Disease (PD)

Interventions: Drug: BIA 9-1067
Drug: Warfarin

Registration Number: NCT02169440

Lead Sponsor: Bial - Portela C S.A.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Group 1	BIA 9-1067	Period 1: BIA 9-1067 + warfarin Period 2: warfarin
Group 1	Warfarin	Period 1: BIA 9-1067 + warfarin Period 2: warfarin
Group 2	BIA 9-1067	Period 1: warfarin Period 2: BIA 9-1067 + warfarin
Group 2	Warfarin	Period 1: warfarin Period 2: BIA 9-1067 + warfarin

Primary Outcome Measures

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