Epilepsy
Conditions
Keywords
Eslicarbazepine acetate, simvastatin
Brief summary
The primary objective was to investigate whether multiple-dose administration of ESL 800 mg once daily affects the pharmacokinetics of simvastatin, a substrate of CYP34A.
Detailed description
This was a single centre, two-way crossover, randomised, open-label study in 24 healthy volunteers. The volunteers will receive an oral single-dose of simvastatin 80 mg on two occasions - once administered alone and once after treatment with an oral once-daily dose of 800 mg of ESL for 14 days -, separated by a washout period of 3 weeks or more
Interventions
DRUGSimvastatin
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Male and female subjects aged 18 to 45 years, inclusive * Body mass index (BMI) between 18 and 30 kg/m2, inclusive * Healthy as determined by pre-study medical history, physical examination, vital signs, 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 * Able and willing to give written informed consent; * If female, not of childbearing potential by reason of surgery or, if of childbearing potential, she uses one of the following methods of contraception: double barrier method: 1 male barrier method \[male condom\] plus 1 female barrier method (diaphragm, spermicide, or intrauterine device); * If female, has 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; * History of relevant atopy or any drug hypersensitivity (including known hypersensitivity to ESL or other carboxamide derivatives, simvastatin or other statins or any of its excipients * History of fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain * Second or third-degree atrioventricular blockade not corrected with a pacemaker or any other clinically significant abnormality in the 12-lead electrocardiogram (ECG) as determined by the investigator * History of alcoholism or drug abuse * Consume more than 14 units of alcohol a week * Significant infection or known inflammatory process on 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 * Use of medicines within two weeks of admission to first period that may affect the safety or other study assessments, in the investigator's opinion * Have donated or received any blood or blood products within the 3 months prior to screening * Vegetarians, vegans or have other medical dietary restrictions * Cannot communicate reliably with the investigator * Unlikely to co-operate with the requirements of the study * Unwilling or unable to give written informed consent * If female, is pregnant or breast-feeding * If female, is of childbearing potential and does not use an approved effective contraceptive method (double-barrier method: 1 male barrier method \[male condom\] plus 1 female barrier method (diaphragm, spermicide, or intra-uterine device) or uses hormonal contraceptives * Have received an investigational drug within 3 months of screening or is currently participating in another study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Simvastatin Cmax (Maximum Plasma Concentration) | Day 1 and Day 14 | Simvastatin (Reference) ESL + Simvastatin (Test) |
| Simvastatin Tmax (Time of Occurrence of Cmax) | Day 1 and Day 14 | Simvastatin (Reference) ESL + Simvastatin (Test) |
| Simvastatin AUC0-t | Day 1 and Day 14 | AUC0-t - area under the plasma concentration versus time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification Simvastatin (Reference) ESL + Simvastatin (Test) |
| Simvastatin AUC0-∞ (AUC From Time Zero to Infinity) | Day 1 and Day 14 | Simvastatin (Reference) ESL + Simvastatin (Test) |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eslicarbazepine Acetate + Simvastatin Simvastatin 80 mg + eslicarbazepine acetate 800 mg
Simvastatin + ESL: Oral single-dose of simvastatin 80 mg on two occasions - once administered alone and once after treatment with an oral once-daily dose of 800 mg of ESL for 14 days - separated by a washout period of 3 weeks or more. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Eslicarbazepine Acetate + Simvastatin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 30 | 23 / 30 | 5 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 | 0 / 30 |
Outcome results
Primary
Simvastatin AUC0-∞ (AUC From Time Zero to Infinity)
Simvastatin (Reference) ESL + Simvastatin (Test)
Time frame: Day 1 and Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin (Reference) | Simvastatin AUC0-∞ (AUC From Time Zero to Infinity) | 108 ng.h/mL | Standard Deviation 68.6 |
| ESL + Simvastatin (Test) | Simvastatin AUC0-∞ (AUC From Time Zero to Infinity) | 54.6 ng.h/mL | Standard Deviation 46.6 |
Primary
Simvastatin AUC0-t
AUC0-t - area under the plasma concentration versus time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification Simvastatin (Reference) ESL + Simvastatin (Test)
Time frame: Day 1 and Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin (Reference) | Simvastatin AUC0-t | 93.9 ng.h/mL | Standard Deviation 47.7 |
| ESL + Simvastatin (Test) | Simvastatin AUC0-t | 43.3 ng.h/mL | Standard Deviation 22.5 |
Primary
Simvastatin Cmax (Maximum Plasma Concentration)
Simvastatin (Reference) ESL + Simvastatin (Test)
Time frame: Day 1 and Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin (Reference) | Simvastatin Cmax (Maximum Plasma Concentration) | 17.7 ng/mL | Standard Deviation 14 |
| ESL + Simvastatin (Test) | Simvastatin Cmax (Maximum Plasma Concentration) | 6.89 ng/mL | Standard Deviation 5.21 |
Primary
Simvastatin Tmax (Time of Occurrence of Cmax)
Simvastatin (Reference) ESL + Simvastatin (Test)
Time frame: Day 1 and Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin (Reference) | Simvastatin Tmax (Time of Occurrence of Cmax) | 1.50 hours | Standard Deviation 3.29 |
| ESL + Simvastatin (Test) | Simvastatin Tmax (Time of Occurrence of Cmax) | 1.62 hours | Standard Deviation 3.4 |