Parkinson's Disease (PD)
Conditions
Keywords
Parkinson's disease (PD), BIA 9-1067, Opicapone
Brief summary
The purpose of this study is to determine the effect of repeated dosing of once-daily 25, 50 and 75 mg opicapone (OPC, development code BIA 9-1067) on the levodopa pharmacokinetics (PK), in comparison to placebo and 200 mg entacapone (ENT).
Detailed description
This study was a single-centre, randomized, double-blind, gender-balanced, placebo-controlled study in 4 groups of 20 healthy subjects each (10 male and 10 female). The clinical part included a screening examination within 3 weeks before the first institutionalization, an ambulatory period of 11 days (from Day 1 evening to Day 11 evening), during which the subjects returned to the clinical unit every evening, followed by an institutionalization of 1.5 days (from Day 11 evening to Day 13 morning (i.e. 14 h after the third administration of levodopa/carbidopa). Then, a follow-up visit at 5 to 9 days after collection of the last PK blood sample (i.e. Day 13). The maximum total duration of the clinical study, including the 21-day screening period and the post-study follow-up, was expected to be about 39 to 43 days.
Interventions
DRUGBIA 9-1067
BIA 9-1067 25 mg and 50 mg
DRUGEntacapone
Entacapone (ENT), over-encapsulated tablet 200 mg
DRUGPlacebo
PLC, placebo
Levodopa/carbidopa, tablet 100/25 mg
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and female volunteers 18 to 45 years old (inclusive), * Body Mass Index (BMI) in normal range (18-30 kg/m²), * Healthy as determined by the Investigator on the basis of medical history, physical examination, clinical laboratory test results, vital signs, complete neurological examination and 12-lead ECG (electrocardiogram), * Negative tests for Hepatitis B surface antigen (HBsAG), anti-Hepatitis C virus (HCV) antibodies and Human immunodeficiency virus (HIV) -1 and HIV-2 antibodies at screening, * Negative screen for drugs of abuse and alcohol at screening and admission to the treatment period, * If of childbearing potential (i.e. except if they had been sterilized for at least 3 months or postmenopausal for at least one year - the menopause was defined by a follicule stimulating hormone (FSH) level \> 30 IU/L): used a non hormonal acceptable contraception method, i.e. intra-uterine device, condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository for all the duration of the study, * If female of childbearing potential, had a negative human chorionic gonadotropin (HCG) beta serum pregnancy test at screening and urinary pregnancy test at admission to both ambulatory and confinement periods, * Non-smokers or ex-smokers for at least 3 months, * Able to communicate well with the Investigator and research staff and to comply with the requirements of the entire study, * Provision of written informed consent to participate as shown by a signature on the volunteer consent form, * Registered with the French Social Security in agreement with the French law on biomedical experimentation
Exclusion criteria
* Did not conform to the above inclusion criteria, or in case of volunteers who had a clinically relevant surgical history, a clinically relevant family history; had a history of relevant atopy, * Had a significant infection or known inflammatory process at screening or admission to the treatment period; acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, heartburn) at the time of screening or admission to the treatment period, * Were vegetarians, vegans or had medical dietary restrictions, * Could not communicate reliably with the Investigator, * Were unlikely to co-operate with the requirements of the study; history of hypersensitivity to OPC, tolcapone, ENT, levodopa, carbidopa, benserazide or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs, * Had any significant cardiovascular (e.g. hypertension), hepatic, renal, respiratory (e.g. childhood asthma), gastrointestinal, endocrine (e.g. diabetes, dyslipidemia), immunologic, dermatological, hematological, neurological, or psychiatric disease, * Presented any clinically significant illness in the previous 28 days before Day 1 of this study; history of drug abuse within 1 year before study Day 1; history of alcoholism within 1 year before Day 1, * Had taken any prescribed or over the counter drug (including antacid drug), with the exception of paracetamol (up to 3 g per day) within 2 weeks prior to the dose administration, * Consumed more than 50 g of ethanol per day (12.5 cL glass of 10° \[10%\] wine = 12 g; 4 cL of aperitif, 42° \[42%\] whiskey = 17 g; 25 cL glass of 3° \[3%\] beer = 7.5 g; 25 cL glass of 6° \[6%\] beer = 15 g, * Drank more than 8 cups daily of beverage containing caffeine, * Had poor motivation, intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with the protocol requirements or inability to cooperate adequately, inability to understand and to observe the instructions of the physician, * Had received any experimental drug within the exclusion period defined in the National Register for Healthy Volunteers of the French Ministry of Health, * Forfeited their freedom by administrative or legal award or were under guardianship, * Had undergone surgery or had donated blood (i.e. 450 mL) within 12 weeks before study Day 1, * Had positive urine screening of ethyl alcohol or drugs of abuse upon admission to the treatment period, * Had any history of tuberculosis and/or prophylaxis for tuberculosis; positive results to HIV, HBsAg or anti-HCV tests; participation in any previous clinical study with OPC, * If female, was pregnant or breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| t1/2 - Terminal Plasma Half-life | pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration | t1/2 - Terminal plasma half-life of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone. |
| Cmax - Maximum Plasma Concentration of Levodopa | pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration | Cmax - Maximum plasma concentration of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone. |
| Tmax - Time of Occurrence of Maximum Plasma Concentration | pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration | Tmax - Time to Reach maximum plasma concentration of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone |
| AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration | AUC0-∞ of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone. |
| AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration | AUC0-t - of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone. |
| AUC0-5 - AUC Over 5 Hours | pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration | AUC0-5 - of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Placebo once-daily for 11 days 200 mg entacapone concomitantly with levodopa/carbidopa on Day 12
Entacapone: Entacapone (ENT), over-encapsulated tablet 200 mg
Placebo: PLC, placebo
Levodopa/carbidopa: Levodopa/carbidopa, tablet 100/25 mg | 16 |
| Group 2 25 mg BIA 9-1067 once-daily for 11 days Placebo concomitantly with levodopa/carbidopa on Day 12
BIA 9-1067: BIA 9-1067 25 mg and 50 mg
Placebo: PLC, placebo
Levodopa/carbidopa: Levodopa/carbidopa, tablet 100/25 mg | 16 |
| Group 3 50 mg 9-1067 once-daily for 11 days Placebo concomitantly with levodopa/carbidopa on Day 12
BIA 9-1067: BIA 9-1067 25 mg and 50 mg
Placebo: PLC, placebo
Levodopa/carbidopa: Levodopa/carbidopa, tablet 100/25 mg | 16 |
| Group 4 75 mg 9-1067 once-daily for 11 days placebo concomitantly with levodopa/carbidopa on Day 12
BIA 9-1067: BIA 9-1067 25 mg and 50 mg
Placebo: PLC, placebo
Levodopa/carbidopa: Levodopa/carbidopa, tablet 100/25 mg | 16 |
| Group 5 placebo once-daily for 11 days placebo concomitantly with levodopa/carbidopa on Day 12
Placebo: PLC, placebo
Levodopa/carbidopa: Levodopa/carbidopa, tablet 100/25 mg | 16 |
| Total | 80 |
Baseline characteristics
| Characteristic | Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 16 Participants | 16 Participants | 16 Participants | 16 Participants | 80 Participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 40 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 40 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 16 | 5 / 16 | 8 / 16 | 8 / 16 | 11 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
AUC0-5 - AUC Over 5 Hours
AUC0-5 - of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone.
Time frame: pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | AUC0-5 - AUC Over 5 Hours | Post Second Dose | 2774 ng.h/mL | Standard Deviation 353 |
| Placebo | AUC0-5 - AUC Over 5 Hours | Post First Dose | 1985 ng.h/mL | Standard Deviation 346 |
| Placebo | AUC0-5 - AUC Over 5 Hours | Post Third Dose | 2719 ng.h/mL | Standard Deviation 492 |
| OPC 25 mg | AUC0-5 - AUC Over 5 Hours | Post Third Dose | 3802 ng.h/mL | Standard Deviation 1549 |
| OPC 25 mg | AUC0-5 - AUC Over 5 Hours | Post First Dose | 2665 ng.h/mL | Standard Deviation 867 |
| OPC 25 mg | AUC0-5 - AUC Over 5 Hours | Post Second Dose | 3678 ng.h/mL | Standard Deviation 1455 |
| OPC 50 mg | AUC0-5 - AUC Over 5 Hours | Post Second Dose | 4151 ng.h/mL | Standard Deviation 1070 |
| OPC 50 mg | AUC0-5 - AUC Over 5 Hours | Post First Dose | 2383 ng.h/mL | Standard Deviation 699 |
| OPC 50 mg | AUC0-5 - AUC Over 5 Hours | Post Third Dose | 3940 ng.h/mL | Standard Deviation 1022 |
| OPC 75 mg | AUC0-5 - AUC Over 5 Hours | Post First Dose | 2829 ng.h/mL | Standard Deviation 794 |
| OPC 75 mg | AUC0-5 - AUC Over 5 Hours | Post Third Dose | 4882 ng.h/mL | Standard Deviation 1246 |
| OPC 75 mg | AUC0-5 - AUC Over 5 Hours | Post Second Dose | 4597 ng.h/mL | Standard Deviation 1041 |
| ENT 200 mg | AUC0-5 - AUC Over 5 Hours | Post Third Dose | 3468 ng.h/mL | Standard Deviation 1108 |
| ENT 200 mg | AUC0-5 - AUC Over 5 Hours | Post Second Dose | 3446 ng.h/mL | Standard Deviation 1125 |
| ENT 200 mg | AUC0-5 - AUC Over 5 Hours | Post First Dose | 2042 ng.h/mL | Standard Deviation 669 |
Primary
AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase
AUC0-∞ of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone.
Time frame: pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post First Dose | 2305 ng.h/mL | Standard Deviation 391 |
| Placebo | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post Third Dose | 3299 ng.h/mL | Standard Deviation 433 |
| Placebo | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post Second Dose | 3070 ng.h/mL | Standard Deviation 396 |
| OPC 25 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post Second Dose | 4967 ng.h/mL | Standard Deviation 2003 |
| OPC 25 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post First Dose | 3732 ng.h/mL | Standard Deviation 1418 |
| OPC 25 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post Third Dose | 5614 ng.h/mL | Standard Deviation 2467 |
| OPC 50 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post Second Dose | 5727 ng.h/mL | Standard Deviation 1495 |
| OPC 50 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post First Dose | 3363 ng.h/mL | Standard Deviation 1042 |
| OPC 50 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post Third Dose | 5912 ng.h/mL | Standard Deviation 1478 |
| OPC 75 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post First Dose | 3998 ng.h/mL | Standard Deviation 1275 |
| OPC 75 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post Third Dose | 7177 ng.h/mL | Standard Deviation 1835 |
| OPC 75 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post Second Dose | 6213 ng.h/mL | Standard Deviation 1440 |
| ENT 200 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post Second Dose | 4367 ng.h/mL | Standard Deviation 1463 |
| ENT 200 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post First Dose | 2752 ng.h/mL | Standard Deviation 540 |
| ENT 200 mg | AUC0-∞ - Area Under the Concentration-time Curve From Time Zero up to Infinity With Extrapolation of the Terminal Phase | Post Third Dose | 4707 ng.h/mL | Standard Deviation 363 |
Primary
AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration.
AUC0-t - of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone.
Time frame: pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post First Dose | 1985 ng.h/mL | Standard Deviation 346 |
| Placebo | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post Third Dose | 3123 ng.h/mL | Standard Deviation 447 |
| Placebo | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post Second Dose | 2774 ng.h/mL | Standard Deviation 353 |
| OPC 25 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post Second Dose | 3678 ng.h/mL | Standard Deviation 1455 |
| OPC 25 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post First Dose | 2665 ng.h/mL | Standard Deviation 867 |
| OPC 25 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post Third Dose | 5391 ng.h/mL | Standard Deviation 2444 |
| OPC 50 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post Second Dose | 4151 ng.h/mL | Standard Deviation 1070 |
| OPC 50 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post First Dose | 2383 ng.h/mL | Standard Deviation 699 |
| OPC 50 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post Third Dose | 5685 ng.h/mL | Standard Deviation 1466 |
| OPC 75 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post First Dose | 2829 ng.h/mL | Standard Deviation 794 |
| OPC 75 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post Third Dose | 6928 ng.h/mL | Standard Deviation 1797 |
| OPC 75 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post Second Dose | 4597 ng.h/mL | Standard Deviation 1041 |
| ENT 200 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post Second Dose | 3445 ng.h/mL | Standard Deviation 1128 |
| ENT 200 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post First Dose | 2041 ng.h/mL | Standard Deviation 671 |
| ENT 200 mg | AUC0-t - Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time (t) Corresponding to the Last Quantifiable Concentration. | Post Third Dose | 4366 ng.h/mL | Standard Deviation 1426 |
Primary
Cmax - Maximum Plasma Concentration of Levodopa
Cmax - Maximum plasma concentration of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone.
Time frame: pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Cmax - Maximum Plasma Concentration of Levodopa | Post Second Dose | 1550 ng/mL | Standard Deviation 542 |
| Placebo | Cmax - Maximum Plasma Concentration of Levodopa | Post First Dose | 1047 ng/mL | Standard Deviation 340 |
| Placebo | Cmax - Maximum Plasma Concentration of Levodopa | Post Third Dose | 1268 ng/mL | Standard Deviation 532 |
| OPC 25 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post First Dose | 1203 ng/mL | Standard Deviation 453 |
| OPC 25 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post Third Dose | 1393 ng/mL | Standard Deviation 627 |
| OPC 25 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post Second Dose | 1619 ng/mL | Standard Deviation 762 |
| OPC 50 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post First Dose | 1030 ng/mL | Standard Deviation 400 |
| OPC 50 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post Second Dose | 1974 ng/mL | Standard Deviation 847 |
| OPC 50 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post Third Dose | 1346 ng/mL | Standard Deviation 337 |
| OPC 75 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post Third Dose | 1658 ng/mL | Standard Deviation 435 |
| OPC 75 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post First Dose | 1057 ng/mL | Standard Deviation 335 |
| OPC 75 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post Second Dose | 2113 ng/mL | Standard Deviation 868 |
| ENT 200 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post Second Dose | 1437 ng/mL | Standard Deviation 569 |
| ENT 200 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post First Dose | 876 ng/mL | Standard Deviation 328 |
| ENT 200 mg | Cmax - Maximum Plasma Concentration of Levodopa | Post Third Dose | 1303 ng/mL | Standard Deviation 518 |
Primary
t1/2 - Terminal Plasma Half-life
t1/2 - Terminal plasma half-life of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone.
Time frame: pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | t1/2 - Terminal Plasma Half-life | Post Second Dose | 1.41 Hours | Standard Deviation 0.136 |
| Placebo | t1/2 - Terminal Plasma Half-life | Post First Dose | 1.46 Hours | Standard Deviation 0.406 |
| Placebo | t1/2 - Terminal Plasma Half-life | Post Third Dose | 1.74 Hours | Standard Deviation 0.349 |
| OPC 25 mg | t1/2 - Terminal Plasma Half-life | Post Second Dose | 2.23 Hours | Standard Deviation 0.385 |
| OPC 25 mg | t1/2 - Terminal Plasma Half-life | Post First Dose | 2.47 Hours | Standard Deviation 0.83 |
| OPC 25 mg | t1/2 - Terminal Plasma Half-life | Post Third Dose | 2.56 Hours | Standard Deviation 0.44 |
| OPC 50 mg | t1/2 - Terminal Plasma Half-life | Post Third Dose | 2.75 Hours | Standard Deviation 0.513 |
| OPC 50 mg | t1/2 - Terminal Plasma Half-life | Post First Dose | 2.47 Hours | Standard Deviation 0.098 |
| OPC 50 mg | t1/2 - Terminal Plasma Half-life | Post Second Dose | 2.46 Hours | Standard Deviation 0.312 |
| OPC 75 mg | t1/2 - Terminal Plasma Half-life | Post Third Dose | 2.70 Hours | Standard Deviation 0.462 |
| OPC 75 mg | t1/2 - Terminal Plasma Half-life | Post Second Dose | 2.23 Hours | Standard Deviation 0.513 |
| OPC 75 mg | t1/2 - Terminal Plasma Half-life | Post First Dose | 2.39 Hours | Standard Deviation 0.556 |
| ENT 200 mg | t1/2 - Terminal Plasma Half-life | Post Second Dose | 2.09 Hours | Standard Deviation 0.486 |
| ENT 200 mg | t1/2 - Terminal Plasma Half-life | Post Third Dose | 2.20 Hours | Standard Deviation 0.632 |
| ENT 200 mg | t1/2 - Terminal Plasma Half-life | Post First Dose | 2.11 Hours | Standard Deviation 0.626 |
Primary
Tmax - Time of Occurrence of Maximum Plasma Concentration
Tmax - Time to Reach maximum plasma concentration of levodopa (mean pharmacokinetic parameter) following first oral administration of 100/25 mg levodopa/carbidopa on Day 12 with 25, 50 and 75 mg OPC or placebo and 200 mg Entacapone
Time frame: pre-first dose and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 h post-first and -second levodopa/carbidopa administration, and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 and 14.0 h post-third levodopa/carbidopa administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post First Dose | 1.31 hours | Standard Deviation 0.854 |
| Placebo | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post Third Dose | 1.69 hours | Standard Deviation 0.964 |
| Placebo | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post Second Dose | 0.875 hours | Standard Deviation 0.465 |
| OPC 25 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post Second Dose | 1.20 hours | Standard Deviation 0.862 |
| OPC 25 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post First Dose | 1.13 hours | Standard Deviation 0.79 |
| OPC 25 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post Third Dose | 1.33 hours | Standard Deviation 0.699 |
| OPC 50 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post Second Dose | 1.06 hours | Standard Deviation 0.892 |
| OPC 50 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post First Dose | 1.34 hours | Standard Deviation 1.01 |
| OPC 50 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post Third Dose | 1.34 hours | Standard Deviation 0.65 |
| OPC 75 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post First Dose | 1.28 hours | Standard Deviation 0.515 |
| OPC 75 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post Third Dose | 1.31 hours | Standard Deviation 0.854 |
| OPC 75 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post Second Dose | 1.19 hours | Standard Deviation 0.854 |
| ENT 200 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post Second Dose | 0.906 hours | Standard Deviation 0.491 |
| ENT 200 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post First Dose | 1.13 hours | Standard Deviation 0.695 |
| ENT 200 mg | Tmax - Time of Occurrence of Maximum Plasma Concentration | Post Third Dose | 1.59 hours | Standard Deviation 0.861 |