Epilepsy
Conditions
Brief summary
Single centre, open-label, multiple doses, two parallel study groups each receiving two formulations in a one-sequence design
Detailed description
Single centre, open-label, multiple doses, two parallel study groups each receiving two formulations in a one-sequence design: Group A: Pre-treatment with ESL, treatment with ESL and ascending doses of phenytoin (PHT) in last phases; Group B: Pre-treatment with PHT, treatment with PHT and ascending doses of ESL in last phases
Interventions
DRUGBIA 2-093
DRUGPhenytoin
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Availability of volunteer for the entire study period and willingness to adhere to protocol requirements as evidenced by the informed consent form (ICF) duly read, signed and dated by the volunteer * Non-black male aged of at least 18 years but not older than 45 years with a body mass index (BMI) greater than or equal to 19 and below 30 kg/m2 * Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be without any clinical significance (laboratory tests are presented in section 6.1.1.3) * Healthy according to the medical history, laboratory results and physical examination * Light-, non- or ex-smokers. A light smoker is defined as someone smoking 10 cigarettes or less per day, and an ex-smoker is defined as someone who completely stopped smoking for at least 12 months before day 1 of this study
Exclusion criteria
* Significant history of hypersensitivity to phenytoin, eslicarbazepine, oxcarbazepine, carbamazepine or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs * Presence of significant gastrointestinal, liver or kidney disease, or any other conditions known to interfere with the absorption, distribution, metabolism or excretion of drugs or known to potentiate or predispose to undesired effects * History of significant gastrointestinal, liver or kidney disease, or surgery that may affect drug bioavailability, including but not limited to cholecystectomy * Presence of significant cardiovascular, pulmonary, hematologic, neurologic, psychiatric, endocrine, immunologic or dermatologic disease * Presence of significant heart disease or disorder according to ECG * Presence or history of significant central nervous system disorder like convulsion or depression * Hemoglobin count below 135 g/L (at screening) * Use of valproic acid in the previous 7 days prior to Day 1 of the study. * Maintenance therapy with any drug, or significant history of drug dependency or alcohol abuse (\> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) * Any clinically significant illness in the previous 28 days before day 1 of this study * Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 (CYP) enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids,phenytoin and rifampin), in the previous 28 days before Day 1 of this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax - the Maximum Plasma Concentration | Day 8 and 27: within 5 minutes prior to dosing and 0.5,1,1.5,2,2.5,3,3.5,4,6,9,12,16 and 24 hours after drug administration | BIA 2-194 and BIA 2-195 are metabolites of eslicarbazepine acetate |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-t - the Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time | Day 8 and 27: within 5 minutes prior to dosing and 0.5,1,1.5,2,2.5,3,3.5,4,6,9,12,16 and 24 hours after drug administration | AUC0-t - the Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time BIA 2-194 and BIA 2-195 are metabolites of eslicarbazepine acetate |
| Tmax - the Time of Occurrence of Cmax | Day 8 and 27: within 5 minutes prior to dosing and 0.5,1,1.5,2,2.5,3,3.5,4,6,9,12,16 and 24 hours after drug administration | BIA 2-194 and BIA 2-195 are metabolites of eslicarbazepine acetate |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A BIA 2-093 + Phenytoin (PHT) Pre-treatment: 600 mg ESL, 2 days; Treatment 1: 1200 mg ESL 6 days Treatment 2: 1200 mg ESL and PHT 100 mg for 2 days Treatment 3: 1200 mg ESL and PHT 300 mg for17 days | 16 |
| Group B BIA 2-093 + Phenytoin (PHT) Pre-treatment: 100 mg PHT for 2 days; Treatment 1: 300 mg PHT 6 days; Treatment 2: 600 mg ESL + PHT 300 mg for 2 days; Treatment 3: 1200 mg ESL and PHT 300 mg for 17 days | 16 |
| Total | 32 |
Baseline characteristics
| Characteristic | Group A BIA 2-093 + Phenytoin (PHT) | Group B BIA 2-093 + Phenytoin (PHT) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 16 Participants | 32 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 16 | 12 / 16 | 7 / 16 | 27 / 32 | 7 / 16 | 10 / 16 | 8 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 32 | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Cmax - the Maximum Plasma Concentration
BIA 2-194 and BIA 2-195 are metabolites of eslicarbazepine acetate
Time frame: Day 8 and 27: within 5 minutes prior to dosing and 0.5,1,1.5,2,2.5,3,3.5,4,6,9,12,16 and 24 hours after drug administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BIA 2-093 + Phenytoin | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-194) | 16350.6 ng/mL | Standard Deviation 2060.2 |
| BIA 2-093 + Phenytoin | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-195) | 976.9 ng/mL | Standard Deviation 194.4 |
| BIA 2-093 + Phenytoin | Cmax - the Maximum Plasma Concentration | Cmax (PHT) | 12868.5 ng/mL | Standard Deviation 6292.7 |
| BIA 2-093 | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-194) | 23806.5 ng/mL | Standard Deviation 3047.2 |
| BIA 2-093 | Cmax - the Maximum Plasma Concentration | Cmax (BIA 2-195) | 954.3 ng/mL | Standard Deviation 189.9 |
| BIA 2-093 | Cmax - the Maximum Plasma Concentration | Cmax (PHT) | 9405.1 ng/mL | Standard Deviation 3621 |
Secondary
AUC0-t - the Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time
AUC0-t - the Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time BIA 2-194 and BIA 2-195 are metabolites of eslicarbazepine acetate
Time frame: Day 8 and 27: within 5 minutes prior to dosing and 0.5,1,1.5,2,2.5,3,3.5,4,6,9,12,16 and 24 hours after drug administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BIA 2-093 + Phenytoin | AUC0-t - the Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time | AUC0-t (BIA 2-195) | 19471.2 ng*h/mL | Standard Deviation 4069.5 |
| BIA 2-093 + Phenytoin | AUC0-t - the Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time | AUC0-t (BIA 2-194) | 251055.2 ng*h/mL | Standard Deviation 34143.1 |
| BIA 2-093 + Phenytoin | AUC0-t - the Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time | AUC0-t (PHT) | 264784.8 ng*h/mL | Standard Deviation 137688.1 |
| BIA 2-093 | AUC0-t - the Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time | AUC0-t (BIA 2-194) | 371574.9 ng*h/mL | Standard Deviation 43474.3 |
| BIA 2-093 | AUC0-t - the Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time | AUC0-t (BIA 2-195) | 20675.0 ng*h/mL | Standard Deviation 4362.4 |
| BIA 2-093 | AUC0-t - the Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time | AUC0-t (PHT) | 186826.5 ng*h/mL | Standard Deviation 81643.2 |
Secondary
Tmax - the Time of Occurrence of Cmax
BIA 2-194 and BIA 2-195 are metabolites of eslicarbazepine acetate
Time frame: Day 8 and 27: within 5 minutes prior to dosing and 0.5,1,1.5,2,2.5,3,3.5,4,6,9,12,16 and 24 hours after drug administration
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| BIA 2-093 + Phenytoin | Tmax - the Time of Occurrence of Cmax | Tmax (BIA 2-194) | 3.00 hours | Standard Deviation 1.02 |
| BIA 2-093 + Phenytoin | Tmax - the Time of Occurrence of Cmax | Tmax (BIA 2-195) | 9.00 hours | Standard Deviation 1.49 |
| BIA 2-093 + Phenytoin | Tmax - the Time of Occurrence of Cmax | Tmax (PHT) | 4.00 hours | Standard Deviation 1.96 |
| BIA 2-093 | Tmax - the Time of Occurrence of Cmax | Tmax (BIA 2-194) | 2.50 hours | Standard Deviation 0.95 |
| BIA 2-093 | Tmax - the Time of Occurrence of Cmax | Tmax (BIA 2-195) | 9.00 hours | Standard Deviation 4.03 |
| BIA 2-093 | Tmax - the Time of Occurrence of Cmax | Tmax (PHT) | 4.00 hours | Standard Deviation 2.35 |