Multiple Dose Bioequivalence Study of Pramipexole Extended Release in Chinese Healthy Male Volunteers

Study Overview
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Brief Summary
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To establish bioequivalence at steady state of: 1)0.375 mg pramipexole extended release tablet q.d. in fasted status versus 0.125 mg pramipexole Immediate release tablet t.i.d. in fasted status 2)1.5 mg pramipexole extended release tablet q.d. in fasted status versus 0.5 mg pramipexole Immediate release tablet t.i.d. in fasted status To investigate dose proportionality of pharmacokinetics parameters for: 1)pramipexole extended release dosage of 0.375 to 1.5 mg q.d.

Official Title
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A Multiple Dose Bioequivalence Study of Pramipexole With Increasing Doses (0.375mg to 1.5mg q.d.) of Oral Extended Release (ER) Tablet in Two-way Cross-over Comparison of 0.375mg Extended Release Tablet q.d. Versus 0.125mg Immediate Release (IR) Tablet t.i.d and 1.5 mg Extended Release Tablet q.d. Versus 0.5mg Immediate Release Tablet t.i.d. in Chinese Healthy Male Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: pramipexole extended release
* Drug: pramipexole extended release
* Drug: pramipexole immediate release
* Drug: pramipexole immediate release


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Healthy males according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (blood pressure, pulse rate), 12-lead electrocardiogram, clinical laboratory tests Age older than or equal 18 and Age younger than or equal 40 years Body Mass Index larger than or equal 19 and Body Mass Index less than or equal 24kg/m2 Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation. Exclusion criteria: Any finding of the medical examination (including Pulse Rate and electrocardiogram) deviating from normal and of clinical relevance Any evidence of a clinically relevant concomitant disease Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Surgery of the gastrointestinal tract (except appendectomy) Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders History of relevant orthostatic hypotension, fainting spells or blackouts. Chronic or relevant acute infections History of relevant allergy/hypersensitivity (including allergy to drug or its excipients) Intake of drugs with a long half-life (longer than 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial Use of drugs which might reasonably influence the results of the trial up to 7 days before the start of drug administration in the study or during the study period Participation in another trial with an investigational drug within one months prior to administration or during the trial Smoker (more than 10 cigarettes or more than 3 cigars or more than 3 pipes/day) Inability to refrain from smoking on trial days Alcohol abuse (more than 40 g/day) Drug abuse Blood donation (more than 100 mL within four weeks prior to administration or during the trial) Excessive physical activities (within one week prior to administration or during the trial) Any laboratory value outside the reference range that is of clinical relevance Any positive results in hepatitis B surface antigen (HBsAg), anti hepatitis B core (HBc) antibodies, anti hepatitis C virus (HCV) antibodies and human immunodeficiency virus (HIV) test Exclusion criteria specific for this study: Hypersensitivity to pramipexole or other dopamine agonists Supine blood pressure at screening of systolic<100 mmHg and diastolic < 60 mmHg, or symptomatic orthostatic hypotension (i. .e. clinical symptoms of orthostatic hypotension associated with a decline >=20 mmHg in systolic BP and a decline >=10 mmHg in diastolic BP, at one minute after standing compared to the previous supine systolic and diastolic BP obtained after 5 minutes of quiet rest)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pramipexole extended release<br>0.375mg once per day for 5 days (cross-over), 0.75mg once per day for 5 days (up-titration), 1.5mg once per day for 5 days (cross-over) | Drug: pramipexole extended release<br>* 0.375mg once per day for 5 days (cross-over), 0.75mg once per day for 5 days (up-titration), 1.5mg once per day for 5 days (cross-over)<br>Drug: pramipexole immediate release<br>* 0.125mg three times a day for 5 days (crossover), 0.5mg three times a day for 5 days (cross over)<br>|
| Active Comparator: pramipexole immediate release<br>0.125mg three times a day for 5 days (crossover), 0.5mg three times a day for 5 days (cross over) | Drug: pramipexole extended release<br>* 0.375mg once per day for 5 days (cross-over), 0.75mg once per day for 5 days (up-titration), 1.5mg once per day for 5 days (cross-over)<br>Drug: pramipexole immediate release<br>* 0.125mg three times a day for 5 days (crossover), 0.5mg three times a day for 5 days (cross over)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve of Pramipexole in Plasma at Steady State Over 24 Hours (AUC0-24,ss); in Case of ER up to the Time Point of Next Dosing (AUCtau,ss) for Pharmacokinetic (PK) Population (All Subjects) | AUC0-24,ss = area under the plasma concentration-time curve between 0 and 24 hours at steady state. AUCtau,ss = area under the plasma concentration-time curve over a dosing interval at steady state | 27 days | 
| Area Under the Concentration-time Curve of Pramipexole in Plasma at Steady State Over 24 Hours (AUC0-24,ss); in Case of ER up to the Time Point of Next Dosing (AUCtau,ss) for PK Population (Excluding Subjects Due to Emesis) | AUC0-24,ss = area under the plasma concentration-time curve between 0 and 24 hours at steady state. AUCtau,ss = area under the plasma concentration-time curve over a dosing interval at steady state | 27 days | 
| Maximum Steady State Concentration (Cmax,ss) for PK Population (All Subjects) | Cmax = maximum observed concentration of the analyte in plasma at steady state | 27 days | 
| Maximum Steady State Concentration (Cmax,ss) for PK Population (Excluding Subjects Due to Emesis) | Cmax,ss = maximum observed concentration of the analyte in plasma at steady state | 27 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Dosing to the Maximum Measured Concentration of the Analyte in Plasma (Tmax) for PK Population (All Subjects) | tmax = time of maximum observed plasma concentration | 27 days | 
| Time From Dosing to the Maximum Measured Concentration of the Analyte in Plasma (Tmax) for PK Population (Excluding Subjects Due to Emesis) | tmax = time of maximum observed plasma concentration | 27 days | 
| Peak-to-trough Fluctuation (PTF) for PK Population (All Subjects) | PTF = Peak-to-trough fluctuation is measured as a percent | 27 days | 
| Peak-to-trough Fluctuation (PTF) for PK Population (Excluding Subjects Due to Emesis) | PTF = Peak-to-trough fluctuation is measured as a percent | 27 days | 
| Predose Steady State Concentration of the Analyte Immediately Before Administration of the Next Drug Administration (Cpre,ss) for PK Population (All Subjects) | Cpre,ss = pre-dose concentration of the analyte in plasma at steady state immediately before administration of the next dose | 27 days | 
| Predose Steady State Concentration of the Analyte Immediately Before Administration of the Next Drug Administration (Cpre,ss) for PK Population (Excluding Subjects Due to Emesis) | Cpre,ss = pre-dose concentration of the analyte in plasma at steady state immediately before administration of the next dose | 27 days | 
| Average Concentration in Plasma Under Steady-state Conditions (Cavg) for PK Population (All Subjects) | Cavg = Average concentration of the analyte in plasma at steady state | 27 days | 
| Average Concentration in Plasma Under Steady-state Conditions (Cavg) for PK Population (Excluding Subjects Due to Emesis) | Cavg = Average concentration of the analyte in plasma at steady state | 27 days | 
| Terminal Half-life of the Analyte in Plasma at Steady State (t1/2,ss) for PK Population (All Subjects) | t1/2,ss - Apparent plasma terminal elimination half-life at steady state | 27 days | 
| Terminal Half-life of the Analyte in Plasma at Steady State (t1/2,ss) for PK Population (Excluding Subjects Due to Emesis) | t1/2,ss - Apparent plasma terminal elimination half-life at steady state | 27 days | 
| Minimum Steady State Concentration (Cmin,ss) for PK Population (All Subjects) | Cmin,ss = Minimum observed concentration of the analyte in plasma at steady state | 27 days | 
| Minimum Steady State Concentration (Cmin,ss) for PK Population (Excluding Subjects Due to Emesis) | Cmin,ss = Minimum observed concentration of the analyte in plasma at steady state | 27 days | 
| The Apparent Clearance of the Analyte in Plasma at Steady State Following Oral Administration (CL/F,ss) for PK Population (All Subjects) | CL/F,ss = Apparent clearance of the analyte in the plasma at steady state following oral administration | 27 days | 
| The Apparent Clearance of the Analyte in Plasma at Steady State Following Oral Administration (CL/F,ss) for PK Population (Excluding Subjects Due to Emesis) | CL/F,ss = Apparent clearance of the analyte in the plasma at steady state following oral administration | 27 days | 
| Apparent Volume of Distribution During the Terminal Phase at Steady State Following Oral Administration (Vz/F,ss) for PK Population (All Subjects) | Vz/F,ss = Apparent volume of distribution during the terminal phase λz at steady state following oral administration | 27 days | 
| Apparent Volume of Distribution During the Terminal Phase at Steady State Following Oral Administration (Vz/F,ss) for PK Population (Excluding Subjects Due to Emesis) | Vz/F,ss = Apparent volume of distribution during the terminal phase λz at steady state following oral administration | 27 days |