Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Rotigotine Transdermal Patch in Healthy Chinese Subjects

Study Overview
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Brief Summary
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This study is to characterize the Pharmacokinetics (PK) of unconjugated and total Rotigotine after single and multiple doses of Rotigotine transdermal patch, and also to investigate the safety and tolerability of Rotigotine transdermal patch in healthy Chinese subjects.

Official Title
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A Single-site, Single-dose and Multiple-dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Rotigotine Transdermal Patch in Healthy Chinese Subjects.

Conditions
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Healthy

Intervention / Treatment
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* Drug: Rotigotine, Period 1
* Drug: Rotigotine, Period 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chinese subjects Healthy volunteers with normal body weight, female subject is willing to use a double contraceptive barrier method or an oral hormonal contraceptive during the entire study Exclusion Criteria: Previously participated in any Rotigotine study or participated in another clinical study for an investigational drug History of drug or alcohol abuse within the last 2 years Suicide attempt or suicidal ideation in the past 6 months Transient ischemic attack or stroke within the last 12 months Current condition of epilepsy and / or seizures History of significant skin hypersensitivity to adhesives or other transdermal products or recently unsolved contact dermatitis History or present condition of an atopic or eczematous dermatitis, psoriasis and / or an active skin disease Female subject is pregnant or lactating Subject has any medical or psychiatric condition that, in the opinion of the investigator, could jeopardize or would compromise the subject's wellbeing or ability to participate in this study Subject has a QTcB (QT interval corrected for heart rate according to Bazett's formula) interval of ≥ 450 ms for female or ≥ 430 ms for male Subject has a relevant hepatic dysfunction (total bilirubin > 2 mg / dL or alanine aminotransferase [ALT] or aspartate aminotransferase [AST] greater than 2 times the upper limit of the normal reference range) Subject has tested positive for human immunodeficiency virus antibodies (HIV)-1 / 2Ab, hepatitis B surface antigen (HBsAg) or hepatitis C virus antibody (HCV-Ab) Subject has a positive urine drug screen and / or alcohol breath test on Day 1 Subject has made a blood donation or had a comparable blood loss (> 400 mL) Subject smokes or has done so within 6 months prior to Eligibility Assessment (EA) Subject has a clinically relevant allergy Subject is currently taking any medication Female subject is currently taking an oral hormonal contraceptive Subject has symptomatic orthostatic hypotension Subject has a pulse rate at rest less than 45 beats per minute (bpm) or more than 100 bpm Subject has a systolic blood pressure (SBP) lower than 100 mmHg or higher than 140 mmHg or diastolic blood pressure (DBP) higher than 90 mmHg Subject has a current or a history of clinically relevant motor disturbance, impairment of memory, sleep disturbance or neurodegenerative disease Subject has consumed more than 3 cups (more than 450 ml) of caffeinated beverages per day Subject's abdomen is thickly covered with hair resulting in difficulties in finding appropriate patch application sites

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rotigotine, Period 1<br>In Period 1 (Day 1 to Day 3) all 24 subjects will receive only 1 dose 2 mg / 24 hours. | Drug: Rotigotine, Period 1<br>* Formulation: transdermal Dosage: 2 mg / 24 hours once at Day 2 Frequency: once every 24 hours Duration: from Day 1 to Day 3<br>* Other names: Neupro;|
| Experimental: Rotigotine, Period 2<br>In Period 2 (Day 7 to Day 14) all 24 subjects will receive 2 mg / 24 hours for 3 days then 4 mg / 24 hours for 3 days. | Drug: Rotigotine, Period 2<br>* Formulation: transdermal Dosage: 2 mg / 24 hours for 3 days from Day 7 to Day 9, 4 mg / 24 hours for 3 days from Day 10 to Day 12 Frequency: once every 24 hours Duration: from Day 1 to Day 3<br>* Other names: Neupro;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of unconjugated Rotigotine for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Plasma concentrations of unconjugated Rotigotine for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 7, 8, 9, 11 and 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and 12 and 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 12 | Period 2; Day 7 to Day 14 of study | 
| Plasma concentrations of total Rotigotine for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Plasma concentrations of total Rotigotine for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 7, 8, 9, 11 and 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and 12 and 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 12 | Period 2; Day 7 to Day 14 of study | 
| Area under the plasma concentration-time curve from zero up to the last analytically quantifiable concentration (AUC 0-tz) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Maximum plasma concentration (Cmax) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Area under the plasma concentration-time curve from zero to 24 hours at steady state (AUC(0-24h),ss) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 | Period 2; Day 9 to Day 12 of study for this Primary Outcome Measure | 
| Maximum plasma concentration at steady state (Cmax,ss) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 | Period 2; Day 9 to Day 12 of study for this Primary Outcome Measure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Terminal half-life (t½) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Time to reach a maximum plasma concentration (tmax) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day1 to Day 3 of study | 
| Lag time until first concentration ≥ limit of quantitation (LOQ) (tlag) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Maximum plasma concentration normalized by Body Weight (kg) (Cmax, norm (BW)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Maximum plasma concentration normalized by apparent dose (mg)(Cmax, norm (apparent dose)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Maximum plasma concentration normalized by drug content of patch (mg) (Cmax, norm (mgdc)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Area under the plasma concentration-time curve from zero up to the last analytically quantifiable concentration normalized by body weight (kg) (AUC(0-tz), norm (BW)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Perion 1; Day 1 to Day 3 of study | 
| Area under the plasma concentration-time curve from zero up to the last analytically quantifiable concentration normalized by apparent dose (mg) (AUC(0-tz), norm (apparent dose)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Area under the plasma concentration-time curve from zero up to the last analytically quantifiable concentration normalized by drug content of patch (mg) (AUC(0-tz), norm (mgdc)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Area under the plasma concentration-time curve from zero up to infinity (AUC(0-∞)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Area under the plasma concentration-time curve from zero up to infinity normalized by apparent dose (mg) (AUC(0-∞), norm (apparent dose)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Area under the plasma concentration-time curve from zero up to infinity normalized by body weight (kg) (AUC(0-∞), norm (BW)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Area under the plasma concentration-time curve from zero up to infinity normalized by drug content of patch (mg) (AUC(0-∞), norm (mgdc)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Apparent total body clearance (CL/F) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Apparent total body clearance normalized by body weight (kg) (CL/F norm (BW)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Apparent volume of distribution (Vz/f) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Apparent volume of distribution normalized by body weight (kg) (Vz/f norm (BW)) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Mean residence time (MRT) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Rate constant of elimination (ke) for single-dose application (Period 1) | Period 1; Pharmacokinetic (PK) samples will be taken predose and 1, 2, 3, 4, 8, 12, 16, 24, 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 1 | Period 1; Day 1 to Day 3 of study | 
| Terminal half-life (t½) for multiple-dose application | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 7, 8, 9, 11 and 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and 12 and 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours after patch application on Day 12 | Period 2; Day 7 to Day 14 of study | 
| Time to reach a maximum plasma concentration at steady state (tmax,ss) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 9 and Day 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 | Period 2; Day 9 to Day 12 of study for this Outcome Measure. | 
| Maximum plasma concentration at steady state normalized by body weight (kg) (Cmax,ss,norm(BW)) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 9 and Day 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 | Period 2; Day 9 to Day 12 of study for this Outcome Measure. | 
| Maximum plasma concentration at steady state normalized by apparent dose (mg) (Cmax, ss, norm (apparent dose)) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 9 and Day 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 | Period 2; Day 9 to Day 12 of study for this Outcome Measure. | 
| Maximum plasma concentration at steady state normalized by drug content of patch (mg) (Cmax, ss, norm (mgdc)) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 9 and Day 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 | Period 2; Day 9 to Day 12 of study for this Outcome Measure | 
| Minimum plasma concentration at steady state (Cmin, ss) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 9 and Day 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 | Period 2; Day 9 to Day 12 of study for this Outcome Measure | 
| Area under the plasma concentration-time curve from zero to 24 hours at steady state normalized by body weight (kg) (AUC(0-24h), ss, norm (BW)) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 9 and Day 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 | Period 2; Day 9 to Day 12 of study for this Outcome Measure | 
| Area under the plasma concentration-time curve from zero to 24 hours at steady state normalized by apparent dose (mg) (AUC(0-24), ss, norm (apparent dose)) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 9 and Day 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 | Period 2; Day 9 to Day 12 of study for this Outcome Measure | 
| Area under the plasma concentration-time curve from zero to 24 hours at steady state normalized by drug content of patch (mg) (AUC(0-24), ss, norm (mgdc)) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 9 and Day 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 | Period 2; Day 9 to Day 12 of study for this Outcome Measure | 
| Apparent total body clearance (CL/F) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 7, 8, 9, 11 and 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 and 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours on Day 12. | Period 2; Day 7 to Day 14 of study | 
| Apparent total body clearance normalized by body weight (kg) (CL/F norm (BW)) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 7, 8, 9, 11 and 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 and 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours on Day 12. | Period 2; Day 7 to Day 14 of study | 
| Apparent volume of distribution (Vz/f) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 7, 8, 9, 11 and 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 and 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours on Day 12. | Period 2; Day 7 to Day 14 of study | 
| Apparent volume of distribution normalized by body weight (kg) (Vz/f norm (BW)) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 7, 8, 9, 11 and 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 and 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours on Day 12. | Period 2; Day 7 to Day 14 of study | 
| Mean residence time (MRT) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 7, 8, 9, 11 and 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 and 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours on Day 12. | Period 2; Day 7 to Day 14 of study | 
| Rate constant of elimination (ke) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 7, 8, 9, 11 and 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12 and 25, 26, 28, 30, 32, 36, 40, 48, 60 and 72 hours on Day 12. | Period 2; Day 7 to Day 14 of study | 
| Peak to trough fluctuation (PTF) for multiple-dose application (Period 2) | Period 2; Pharmacokinetic (PK) samples will be taken prior to patch application on Day 9 and Day 12 and 1, 2, 3, 4, 8, 12, 16 and 24 hours after patch application on Day 9 and Day 12. | Period 2; Day 9 to Day 12 of study for this Outcome Measure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neupro, Pharmacokinetics, healthy Chinese subjects