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

• Area Under the Concentration-time Curve of Pramipexole in Plasma at Steady State Over 24 Hours (AUC_0-24,ss); in Case of ER up to the Time Point of Next Doing (AUC_tau,ss) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• Maximum Steady State Concentration (C_max,ss) [ Time Frame: 27 days ] [ Designated as safety issue: No ]

• 1 AUCtau, ss, AUC0-24,ss (area under the concentration-time curve of the analyte in plasma at steady state over 24 hours; in case of Extended release up to the time point of next doing) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• 2 Cmax,ss (maximum measured concentration of the analyte in plasma at steady state) [ Time Frame: 27 days ] [ Designated as safety issue: No ]

• Time From Dosing to the Maximum Measured Concentration of the Analyte in Plasma (t_max) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• Peak-to-trough Fluctuation (PTF) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
  PTF is measured as a percent.
• Predose Steady State Concentration of the Analyte Immediately Before Administration of the Next Drug Administration (C_pre,ss) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• Average Concentration in Plasma Under Steady-state Conditions (C_avg) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• Terminal Half-life of the Analyte in Plasma at Steady State (t_1/2,ss) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• Minimum Steady State Concentration (C_min,ss) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• The Apparent Clearance of the Analyte in Plasma at Steady State Following Oral Administration (CL/F,ss) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• Apparent Volume of Distribution During the Terminal Phase at Steady State Following an Extravascular Dose (V_z/F,ss) [ Time Frame: 27 days ] [ Designated as safety issue: No ]

• 1. tmax, ss (time from dosing to the maximum concentration of the analyte in plasma at steady state) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• 2. PTF (peak-trough fluctuation) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• 3. Cpre,ss (predose concentration of the analyte in plasma at steady state immediately before administration of the next dose) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• 4. Cavg (average concentration of the analyte in plasma at steady state) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• 5. t1/2,ss (terminal half-life of the analyte in plasma at steady state) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• 6. AUC0-8,ss for IR (area under the concentration-time curve of the analyte in plasma over the time interval 0 to 8 hours at steady state) [ Time Frame: 27 days ] [ Designated as safety issue: No ]
• 7. Cmin,ss (minimum measured concentration of the analyte in plasma at steady state) [ Time Frame: 27 days ] [ Designated as safety issue: No ]

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.

• Drug: pramipexole extended release
  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 immediate release
  0.125mg three times a day for 5 days (crossover), 0.5mg three times a day for 5 days (cross over)

• Experimental: pramipexole extended release
  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)
  Interventions:

  • Drug: pramipexole extended release
  • Drug: pramipexole immediate release
• Active Comparator: pramipexole immediate release
  0.125mg three times a day for 5 days (crossover), 0.5mg three times a day for 5 days (cross over)
  Interventions:

  • Drug: pramipexole extended release
  • Drug: pramipexole immediate release

Inclusion criteria:

1. 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

2. Age older than or equal 18 and Age younger than or equal 40 years
3. Body Mass Index larger than or equal 19 and Body Mass Index less than or equal 24kg/m2
4. Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation.

Exclusion criteria:

1. Any finding of the medical examination (including Pulse Rate and electrocardiogram) deviating from normal and of clinical relevance
2. Any evidence of a clinically relevant concomitant disease
3. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
4. Surgery of the gastrointestinal tract (except appendectomy)
5. Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
6. History of relevant orthostatic hypotension, fainting spells or blackouts.
7. Chronic or relevant acute infections
8. History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
9. 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
10. 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
11. Participation in another trial with an investigational drug within one months prior to administration or during the trial
12. Smoker (more than 10 cigarettes or more than 3 cigars or more than 3 pipes/day)
13. Inability to refrain from smoking on trial days
14. Alcohol abuse (more than 40 g/day)
15. Drug abuse
16. Blood donation (more than 100 mL within four weeks prior to administration or during the trial)
17. Excessive physical activities (within one week prior to administration or during the trial)
18. Any laboratory value outside the reference range that is of clinical relevance

19. 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:

20. Hypersensitivity to pramipexole or other dopamine agonists
21. 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)