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Marina Braun - One of the best experts on this subject based on the ideXlab platform.
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an update on pharmacological pharmacokinetic properties and drug drug interactions of Rotigotine transdermal system in parkinson s disease and restless legs syndrome
Drugs, 2015Co-Authors: Jan-peer Elshoff, Willi Cawello, Jens Otto Andreas, Francoisxavier Mathy, Marina BraunAbstract:This narrative review reports on the pharmacological and pharmacokinetic properties of Rotigotine, a non-ergolinic D3/D2/D1 dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson’s disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied Rotigotine dose. Following a single administration of Rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300–600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1–2 days of daily dosing. The pharmacokinetics of Rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration–time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug–drug interactions were observed following co-administration of Rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by Rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile consistent with dopaminergic stimulation and use of a transdermal patch. These observations, combined with the long-term efficacy demonstrated in clinical studies, support the use of Rotigotine as a continuous non-ergot D3/D2/D1 dopamine receptor agonist in the treatment of PD and RLS.
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Pharmacokinetic Properties and Tolerability of Rotigotine Transdermal Patch After Repeated-Dose Application in Healthy Korean Volunteers
Clinical therapeutics, 2015Co-Authors: Bo Hyung Kim, Marina Braun, Jan-peer Elshoff, In-jin Jang, Kyoung Soo Lim, Jung Ryul Kim, Jens Otto Andreas, Willi CawelloAbstract:Abstract Purpose Rotigotine, a nonergolinic dopamine receptor agonist, is a once-daily transdermal patch developed for the treatment of Parkinson's disease and restless legs syndrome. The objective of the present study was to determine the pharmacokinetic characteristics and tolerability of Rotigotine transdermal patch after repeated-dose application in healthy male and female Korean subjects. Methods In this randomized, double-blind, placebo-controlled, repeated-dose study, subjects were randomly assigned to receive either Rotigotine or placebo (ratio, 20 Rotigotine to 4 placebo, per sex). Rotigotine patches were applied once daily at a dose of 2 mg/24 h on days 1 to 3, followed by 4 mg/24 h on days 4 to 6. Serial blood and urine samples were collected on days 1 to 9 for the determination of the concentrations of Rotigotine and its metabolites. Tolerability was evaluated by adverse events determined using physical examination, including vital signs with orthostatic measurements; ECG; and clinical laboratory testing. Findings A total of 48 healthy Korean subjects were enrolled (24 men, 24 women; mean age, 24 years). Approximately 50% of the total drug content was delivered within 24 hours. The mean plasma concentration of unconjugated Rotigotine increased proportionally with dose. At the 2 mg/24 h dose at steady state, the geometric mean AUC 0–24h and C max values of unconjugated Rotigotine were 5.88 ng·h/mL and 0.347 ng/mL, respectively; at the 4 mg/24 h dose, the corresponding values were 13.74 ng·h/mL and 0.838 ng/mL. The mean t ½ of Rotigotine was 4.96 hours. At the 2 mg/24 h dose at steady state, the geometric mean AUC 0–24h and C max values of total Rotigotine were 14.02 ng·h/mL and 0.776 ng/mL; at the 4-mg/24 h dose, 32.38 ng·h/mL and 1.867 ng/mL. Common adverse events reported in the Rotigotine-treated subjects included nausea (17 subjects, 42.5%), headache (11, 27.5%), and dizziness (9, 22.5%). No clinically significant changes in blood pressure, ECG, or laboratory values were observed. Implications The mean plasma exposures of unconjugated Rotigotine increased proportionally with dose. Repeated daily application of the Rotigotine patch was well tolerated in these healthy Korean volunteers. ClinicalTrials.gov identifier: NCT01964573.
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Influence of hepatic impairment on the pharmacokinetics of the dopamine agonist Rotigotine
European Journal of Drug Metabolism and Pharmacokinetics, 2014Co-Authors: Willi Cawello, Andreas Fichtner, Hilmar Boekens, Marina BraunAbstract:The transdermally applied dopamine receptor agonist Rotigotine is extensively metabolized in the liver. An open-label, parallel-group study was conducted to evaluate the effects of moderate hepatic impairment on the pharmacokinetics, safety and tolerability of Rotigotine. Eight subjects with normal hepatic function and nine with moderate hepatic impairment (Child–Pugh class B) received one Rotigotine transdermal patch (providing a dose of 2 mg/24 h) daily for 3 days with a 24-h patch-on period. Blood and urine samples were collected to evaluate pharmacokinetic parameters characterizing drug bioavailability and elimination. Primary variables included plasma and urine concentrations of unconjugated Rotigotine (active parent compound) and total Rotigotine (unconjugated Rotigotine plus sulfate and glucuronide conjugates) under steady-state (SS) conditions. For unconjugated Rotigotine, point estimates for the ratios of AUC_(0–24)SS and C _max,SS between the two groups (normal vs. impaired hepatic function) were near 1: AUC_(0–24)SS, 0.90 (90 % CI 0.59, 1.38) and C _max,SS, 0.94 (90 % CI 0.66, 1.35); t _max,SS and t _1/2 were lower in subjects with hepatic impairment, while renal clearance was unaffected and overall clearance was higher. For total Rotigotine, C _max,SS was higher in subjects with hepatic impairment compared with those with normal hepatic function ( P = 0.0239, ANOVA). A tendency to reduced non-renal clearance was observed in subjects with hepatic impairment, consistent with their higher plasma concentrations of total Rotigotine. Thus, moderate hepatic impairment did not influence the pharmacokinetics of unconjugated Rotigotine under steady-state conditions suggesting that dose adjustment will not be required for patients with mild or moderate hepatic insufficiency. In addition, the Rotigotine patch was well tolerated in subjects with moderate hepatic impairment.
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No influence of the CYP2C19-selective inhibitor omeprazole on the pharmacokinetics of the dopamine receptor agonist Rotigotine.
Clinical pharmacology in drug development, 2014Co-Authors: Jan-peer Elshoff, Willi Cawello, Jens Otto Andreas, Marina BraunAbstract:Rotigotine, a non-ergolinic dopamine receptor agonist administered transdermally via a patch, is metabolized by several cytochrome P-450 (CYP450) isoenzymes, including CYP2C19. This open-label, multiple-dose study evaluated the effect of omeprazole, a competitive inhibitor of CYP2C19, on the pharmacokinetics of Rotigotine and its metabolites under steady-state conditions in healthy male subjects (of the extensive metabolizer phenotype, CYP2C19). Subjects received Rotigotine 2 mg/24 hours on days 1-3, 4 mg/24 hours on days 4-12, and omeprazole 40 mg once daily on days 7-12 immediately after patch application. Blood and urine samples were collected on days 6 and 12 to evaluate Rotigotine pharmacokinetic parameters alone and in the presence of omeprazole. Data from 37 subjects were available for pharmacokinetic analysis. Point estimates (90% confidence intervals, CI) for the ratios of AUC(0-24)SS and Cmax,SS of unconjugated Rotigotine for the comparison Rotigotine + omeprazole:Rotigotine alone were close to 1 (0.9853 [0.9024, 1.0757] for AUC(0-24)SS and 1.0613 [0.9723, 1.1585] for Cmax,SS ) with 90% CIs within the acceptance range for bioequivalence (0.80, 1.25). Selective inhibition of CYP2C19 by omeprazole did not alter the steady-state pharmacokinetic profile of Rotigotine or its metabolites. Thus, Rotigotine dose adjustment is not required in patients receiving omeprazole, or other CYP2C19 inhibitors.
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Pharmacokinetics, Safety and Tolerability of Rotigotine Transdermal Patch in Healthy Japanese and Caucasian Subjects
Clinical Drug Investigation, 2014Co-Authors: Willi Cawello, Marina Braun, Jan-peer Elshoff, Seong R. Kim, Junji Ikeda, Tomoo FunakiAbstract:Background and Objectives Rotigotine is a dopamine receptor agonist with activity across the D_1 through to D_5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of Rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson’s disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with Rotigotine transdermal patch in Japanese and Caucasian subjects. Methods In this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h Rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total Rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration–time curve from time zero to last quantifiable concentration [AUC_last], maximum plasma concentration [ C _max], and body weight- and dose-normalized values). Results The pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of Rotigotine was 2.0 ± 0.5 mg for Japanese subjects and 2.08 ± 0.58 mg for Caucasians. Plasma concentration–time profiles of unconjugated Rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, C _max, time to C _max ( t _max), and AUC_last, for unconjugated Rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after correction for body weight. A statistically significant difference between ethnic groups was observed for total Rotigotine concentrations (total Rotigotine = unconjugated Rotigotine + conjugated Rotigotine), with slightly lower values in Caucasians after correction for body weight and apparent dose. No relevant differences were observed between males and females. Inter-individual variability was high. The terminal half-life for unconjugated Rotigotine was 5.3 h in Japanese subjects and 5.7 h in Caucasians; corresponding values for total Rotigotine were 8.6 h and 9.6 h. Less than 0.1 % of the apparent dose was renally excreted as the parent compound. Renal elimination of total Rotigotine covers 11.7 % of absorbed dose in Japanese subjects and 10.8 % of the absorbed dose in Caucasians, whereas the renal elimination via total despropyl Rotigotine was 8.2 and 7.1 %, respectively. The corresponding values for total desthienylethyl Rotigotine were 3.5 % in Japanese subjects and 4.2 % Caucasians. Most adverse events were mild in intensity and typical for dopamine agonists or for transdermal therapeutics. Conclusion Administration of a single patch delivering 2 mg/24 h Rotigotine resulted in comparable pharmacokinetic profiles in Japanese and Caucasian subjects. The Rotigotine transdermal patch was generally well-tolerated. Our findings suggest similar dose requirements for Japanese and Caucasian populations.
Babak Boroojerdi - One of the best experts on this subject based on the ideXlab platform.
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effect of using a wearable device on clinical decision making and motor symptoms in patients with parkinson s disease starting transdermal Rotigotine patch a pilot study
Parkinsonism & Related Disorders, 2019Co-Authors: Stuart Isaacson, Babak Boroojerdi, Olga Waln, Martha Mcgraw, David L Kreitzman, Kevin J Klos, Fredy J Revilla, Dustin A Heldman, Maureen PhillipsAbstract:Abstract Background Feedback from wearable biosensors may help assess motor function in Parkinson's disease (PD) patients and titrate medication. Kinesia 360 continuously monitors motor symptoms via wrist and ankle sensors. Methods PD0049 was a 12-week pilot study to investigate whether using Kinesia 360 at home could improve motor symptom management in PD patients starting transdermal dopamine agonist Rotigotine. Adults with PD and insufficiently controlled motor symptoms (prescribed Rotigotine) were randomized 1:1 to Control Group (CG) or Experimental Group (EG) before starting Rotigotine. Motor symptoms were assessed in all patients at baseline and Week 12 (W12) using Unified PD Rating Scale (UPDRS) III and Kinesia ONE, which measures standardized motor tasks via a sensor on the index finger. Between baseline and W12, EG used Kinesia 360 at home; clinicians used the data to supplement standard care in adjusting Rotigotine dosage. Results At W12, least squares mean improvements in UPDRS II (−2.1 vs 0.5, p = 0.004) and UPDRS III (−5.3 vs −1.0, p = 0.134) were clinically meaningfully greater, and mean Rotigotine dosage higher (4.8 vs 3.9 mg/24 h) in EG (n = 19) vs CG (n = 20). Mean Rotigotine dosage increase (+2.8 vs + 1.9 mg/24 h) and mean number of dosage changes (2.8 vs 1.8) during the study were higher in EG vs CG. Tolerability and retention rates were similar. Conclusion Continuous, objective, motor symptom monitoring using a wearable biosensor as an adjunct to standard care may enhance clinical decision-making, and may improve outcomes in PD patients starting Rotigotine.
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Switching from an oral dopamine receptor agonist to Rotigotine transdermal patch: a review of clinical data with a focus on patient perspective
2017Co-Authors: Sun Ju Chung, Mahnaz Asgharnejad, Lars Bauer, Babak Boroojerdi, Arturo Benitez, Tanja Heidbrede, Allison Little, Han Joon KimAbstract:Introduction: Dopamine receptor agonists (DAs) are commonly used to treat Parkinson’s disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to Rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to Rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms (‘dopamine receptor agonist’ OR ‘Rotigotine’) AND ‘switch’. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to Rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to Rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to Rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h Rotigotine) may be switched overnight.
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Rotigotine in Combination with the MAO-B Inhibitor Selegiline in Early Parkinson's Disease: A Post Hoc Analysis.
Journal of Parkinson's disease, 2016Co-Authors: Nir Giladi, Mahnaz Asgharnejad, Lars Bauer, Frank Grieger, Babak BoroojerdiAbstract:Background: Monoamine oxidase B (MAO-B) inhibitors and dopamine receptor agonists are common first-line treatment options in early Parkinson’s disease (PD). Objective: To evaluate the efficacy and safety of Rotigotine transdermal patch as an add-on therapy to an MAO-B inhibitor in patients with early-PD. Methods: In two Phase III, randomized, double-blind, placebo-controlled studies in early-PD (SP512, SP513), patients were randomized to Rotigotine (titrated to optimal dose ≤8 mg/24 h) or placebo, and maintained for 24 (SP512) or 33 (SP513) weeks. Post hoc analyses were performed on pooled data for patients receiving an MAO-B inhibitor (selegiline) at a stable dose at randomization and throughout the studies, with groups defined as “Selegiline+Rotigotine” and “Selegiline+Placebo”. Outcome measures included change from baseline in Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living), III (motor), UPDRS II+III and responders (patients achieving ≥20%, ≥25% or ≥30% decrease in UPDRS II+III). As post hoc analyses, p-values are exploratory. Results: 130 patients were evaluable for efficacy analyses (“Selegiline+Rotigotine”: 84, “Selegiline+Placebo”: 46). Combined treatment with Rotigotine and selegiline improved UPDRS III and UPDRS II+III scores versus selegiline alone (LS-mean [95% CI] treatment difference for UPDRS III: –4.89 [–7.87 to –1.91], p = 0.0015; for UPDRS II+III: –5.76 [–9.71 to –1.82], p = 0.0045). Higher proportion of patients in the “Selegiline+Rotigotine” group were classified as ≥20%, ≥25% or ≥30% responders (all p 65 years (although patient numbers in the subgroups were low). Adverse event profile was consistent with the known safety profile of Rotigotine. Conclusions: In these post hoc analyses, adjunctive treatment with Rotigotine in patients already receiving an MAO-B inhibitor improved UPDRS II+III score; this appeared to be largely driven by improvements in the motor aspects of PD.
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Rotigotine in Patients with PD and Unsatisfactory Early-morning Motor Symptom Control: a Post-hoc Analysis of Efficacy and Safety by Dose (P1.190)
Neurology, 2015Co-Authors: Babak Boroojerdi, Erwin Surmann, Mahnaz Asgharnejad, Arturo Benitez, Lars BauerAbstract:OBJECTIVE: To evaluate efficacy/safety of Rotigotine transdermal system ≤8 mg/24h (maximum approved dose for advanced-PD in US: 8 mg/24h) and >8 mg/24h (maximum approved dose for advanced-PD elsewhere: 16 mg/24h) in patients with PD and unsatisfactory early-morning motor symptom control. BACKGROUND: The RECOVER study (NCT00474058) demonstrated significant improvements in early-morning motor function and sleep disturbances with Rotigotine (2-16 mg/24h). DESIGN/METHODS: In RECOVER, patients were randomized to optimal dose (2-16 mg/24h) Rotigotine or placebo: 1-8 weeks titration; 4-week maintenance. Co-primary outcomes were early-morning motor function (UPDRS III) and nocturnal sleep disturbance (PDSS-2). Post-hoc analyses for patients receiving Rotigotine ≤8 mg/24h and >8 mg/24h (longest duration dose) were performed. As post-hoc analyses, p-values are exploratory. RESULTS: 96 patients received placebo, 84 Rotigotine ≤8 mg/24h, and 107 Rotigotine >8 mg/24h. Mean±SD UPDRS III score decreased by 6.6±7.5 with Rotigotine ≤8 mg/24h (baseline 30.6±13.2), 7.3±7.6 Rotigotine >8 mg/24h (baseline 29.1±11.9), and 3.9±7.3 placebo (baseline 31.8±13.6), representing greater improvement with both Rotigotine groups vs placebo: Rotigotine ≤8 mg/24h LS-mean (95[percnt] CI) placebo-treatment difference -3.09 (-5.23,-0.95), p=0.0050; Rotigotine >8 mg/24h -3.95 (-6.02,-1.88), p=0.0002. PDSS-2 score decreased by 5.1±6.9 with Rotigotine ≤8 mg/24h (baseline 17.9±8.1), 6.4±8.1 Rotigotine >8 mg/24h (baseline 20.4±9.9), and 1.9±8.2 placebo (baseline 20.3±10.2), representing greater improvement with both Rotigotine groups vs placebo: ≤8 mg/24h -3.84 (-6.10,-1.57), p=0.0010; >8 mg/24h -4.51 (-6.66,-2.37), p 8 mg/24h, 22[percnt]), application site reactions (4[percnt]; 14[percnt]; 16[percnt]), dizziness (6[percnt]; 10[percnt]; 11[percnt]). CONCLUSIONS: Both Rotigotine dose groups showed clinically meaningful improvements vs placebo in patients with PD and unsatisfactory early-morning motor symptom control. Study Supported by: UCB Pharma Disclosure: Dr. Boroojerdi has received personal compensation for activities with UCB Pharma as an employee. Dr. Asgharnejad has received personal compensation for activities with UCB Pharma as an employee. Dr. Benitez Diaz has received personal compensation for activities with UCB Pharma as an employee. Dr. Surmann has received personal compensation for activities with UCB Pharma as an employee. Dr. Bauer has received personal compensation for activities with UCB Pharma as an employee.
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effects of long term treatment with Rotigotine transdermal system on dyskinesia in patients with early stage parkinson s disease
Parkinsonism & Related Disorders, 2014Co-Authors: Nir Giladi, Erwin Surmann, Liesbet Ghys, Babak Boroojerdi, Joseph JankovicAbstract:Abstract Purpose In two 6-month, double-blind, placebo-controlled studies, Rotigotine transdermal system was well-tolerated and efficacious monotherapy in early-stage PD. This post hoc analysis of the long-term open-label extensions (NCT00594165; NCT00599196) of these studies assessed incidence and severity of dyskinesia in participants treated with Rotigotine, with or without concomitant levodopa, for up to 6 years. Methods Open-label Rotigotine was titrated to optimal dose (≤16 mg/24 h). Concomitant levodopa was permitted. Dyskinesia data, recorded using the Unified Parkinson's Disease Rating Scale Part IV, were pooled from the two open-label studies. Results Of 596 participants who received open-label Rotigotine, 299 (50%) remained at trial closure; no patient discontinued due to dyskinesia. In the two studies, median exposure to Rotigotine was 1910 days (∼5 years, 3 months), and 1564.5 days (∼4 years, 3 months). During up to 6 years of open-label Rotigotine, 423/596 (71%) received levodopa. Dyskinesias were reported in 115/596 (19%) participants, 90/115 (78%) of who developed dyskinesia after levodopa was added; 25 reported dyskinesia in the absence of levodopa (includes patients who never received open-label levodopa, and those who reported dyskinesia before starting concomitant levodopa). Dyskinesia severity data were available for 107 of the 115 participants. In 56/107 (52%) participants, dyskinesia was considered ‘not disabling’ for all occurrences; the worst-case severity was ‘mildly disabling’ for 33/107 (31%), and ‘moderately’ or ‘severely disabling’ for 18/107 (17%; 3% of total participants). Conclusion During treatment with Rotigotine in patients with PD for up to 6 years the incidence of dyskinesia was low, and the dyskinesia was generally ‘not disabling’ or ‘mildly disabling’.
Willi Cawello - One of the best experts on this subject based on the ideXlab platform.
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an update on pharmacological pharmacokinetic properties and drug drug interactions of Rotigotine transdermal system in parkinson s disease and restless legs syndrome
Drugs, 2015Co-Authors: Jan-peer Elshoff, Willi Cawello, Jens Otto Andreas, Francoisxavier Mathy, Marina BraunAbstract:This narrative review reports on the pharmacological and pharmacokinetic properties of Rotigotine, a non-ergolinic D3/D2/D1 dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson’s disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied Rotigotine dose. Following a single administration of Rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300–600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1–2 days of daily dosing. The pharmacokinetics of Rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration–time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug–drug interactions were observed following co-administration of Rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by Rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile consistent with dopaminergic stimulation and use of a transdermal patch. These observations, combined with the long-term efficacy demonstrated in clinical studies, support the use of Rotigotine as a continuous non-ergot D3/D2/D1 dopamine receptor agonist in the treatment of PD and RLS.
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Pharmacokinetic Properties and Tolerability of Rotigotine Transdermal Patch After Repeated-Dose Application in Healthy Korean Volunteers
Clinical therapeutics, 2015Co-Authors: Bo Hyung Kim, Marina Braun, Jan-peer Elshoff, In-jin Jang, Kyoung Soo Lim, Jung Ryul Kim, Jens Otto Andreas, Willi CawelloAbstract:Abstract Purpose Rotigotine, a nonergolinic dopamine receptor agonist, is a once-daily transdermal patch developed for the treatment of Parkinson's disease and restless legs syndrome. The objective of the present study was to determine the pharmacokinetic characteristics and tolerability of Rotigotine transdermal patch after repeated-dose application in healthy male and female Korean subjects. Methods In this randomized, double-blind, placebo-controlled, repeated-dose study, subjects were randomly assigned to receive either Rotigotine or placebo (ratio, 20 Rotigotine to 4 placebo, per sex). Rotigotine patches were applied once daily at a dose of 2 mg/24 h on days 1 to 3, followed by 4 mg/24 h on days 4 to 6. Serial blood and urine samples were collected on days 1 to 9 for the determination of the concentrations of Rotigotine and its metabolites. Tolerability was evaluated by adverse events determined using physical examination, including vital signs with orthostatic measurements; ECG; and clinical laboratory testing. Findings A total of 48 healthy Korean subjects were enrolled (24 men, 24 women; mean age, 24 years). Approximately 50% of the total drug content was delivered within 24 hours. The mean plasma concentration of unconjugated Rotigotine increased proportionally with dose. At the 2 mg/24 h dose at steady state, the geometric mean AUC 0–24h and C max values of unconjugated Rotigotine were 5.88 ng·h/mL and 0.347 ng/mL, respectively; at the 4 mg/24 h dose, the corresponding values were 13.74 ng·h/mL and 0.838 ng/mL. The mean t ½ of Rotigotine was 4.96 hours. At the 2 mg/24 h dose at steady state, the geometric mean AUC 0–24h and C max values of total Rotigotine were 14.02 ng·h/mL and 0.776 ng/mL; at the 4-mg/24 h dose, 32.38 ng·h/mL and 1.867 ng/mL. Common adverse events reported in the Rotigotine-treated subjects included nausea (17 subjects, 42.5%), headache (11, 27.5%), and dizziness (9, 22.5%). No clinically significant changes in blood pressure, ECG, or laboratory values were observed. Implications The mean plasma exposures of unconjugated Rotigotine increased proportionally with dose. Repeated daily application of the Rotigotine patch was well tolerated in these healthy Korean volunteers. ClinicalTrials.gov identifier: NCT01964573.
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Influence of hepatic impairment on the pharmacokinetics of the dopamine agonist Rotigotine
European Journal of Drug Metabolism and Pharmacokinetics, 2014Co-Authors: Willi Cawello, Andreas Fichtner, Hilmar Boekens, Marina BraunAbstract:The transdermally applied dopamine receptor agonist Rotigotine is extensively metabolized in the liver. An open-label, parallel-group study was conducted to evaluate the effects of moderate hepatic impairment on the pharmacokinetics, safety and tolerability of Rotigotine. Eight subjects with normal hepatic function and nine with moderate hepatic impairment (Child–Pugh class B) received one Rotigotine transdermal patch (providing a dose of 2 mg/24 h) daily for 3 days with a 24-h patch-on period. Blood and urine samples were collected to evaluate pharmacokinetic parameters characterizing drug bioavailability and elimination. Primary variables included plasma and urine concentrations of unconjugated Rotigotine (active parent compound) and total Rotigotine (unconjugated Rotigotine plus sulfate and glucuronide conjugates) under steady-state (SS) conditions. For unconjugated Rotigotine, point estimates for the ratios of AUC_(0–24)SS and C _max,SS between the two groups (normal vs. impaired hepatic function) were near 1: AUC_(0–24)SS, 0.90 (90 % CI 0.59, 1.38) and C _max,SS, 0.94 (90 % CI 0.66, 1.35); t _max,SS and t _1/2 were lower in subjects with hepatic impairment, while renal clearance was unaffected and overall clearance was higher. For total Rotigotine, C _max,SS was higher in subjects with hepatic impairment compared with those with normal hepatic function ( P = 0.0239, ANOVA). A tendency to reduced non-renal clearance was observed in subjects with hepatic impairment, consistent with their higher plasma concentrations of total Rotigotine. Thus, moderate hepatic impairment did not influence the pharmacokinetics of unconjugated Rotigotine under steady-state conditions suggesting that dose adjustment will not be required for patients with mild or moderate hepatic insufficiency. In addition, the Rotigotine patch was well tolerated in subjects with moderate hepatic impairment.
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No influence of the CYP2C19-selective inhibitor omeprazole on the pharmacokinetics of the dopamine receptor agonist Rotigotine.
Clinical pharmacology in drug development, 2014Co-Authors: Jan-peer Elshoff, Willi Cawello, Jens Otto Andreas, Marina BraunAbstract:Rotigotine, a non-ergolinic dopamine receptor agonist administered transdermally via a patch, is metabolized by several cytochrome P-450 (CYP450) isoenzymes, including CYP2C19. This open-label, multiple-dose study evaluated the effect of omeprazole, a competitive inhibitor of CYP2C19, on the pharmacokinetics of Rotigotine and its metabolites under steady-state conditions in healthy male subjects (of the extensive metabolizer phenotype, CYP2C19). Subjects received Rotigotine 2 mg/24 hours on days 1-3, 4 mg/24 hours on days 4-12, and omeprazole 40 mg once daily on days 7-12 immediately after patch application. Blood and urine samples were collected on days 6 and 12 to evaluate Rotigotine pharmacokinetic parameters alone and in the presence of omeprazole. Data from 37 subjects were available for pharmacokinetic analysis. Point estimates (90% confidence intervals, CI) for the ratios of AUC(0-24)SS and Cmax,SS of unconjugated Rotigotine for the comparison Rotigotine + omeprazole:Rotigotine alone were close to 1 (0.9853 [0.9024, 1.0757] for AUC(0-24)SS and 1.0613 [0.9723, 1.1585] for Cmax,SS ) with 90% CIs within the acceptance range for bioequivalence (0.80, 1.25). Selective inhibition of CYP2C19 by omeprazole did not alter the steady-state pharmacokinetic profile of Rotigotine or its metabolites. Thus, Rotigotine dose adjustment is not required in patients receiving omeprazole, or other CYP2C19 inhibitors.
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Pharmacokinetics, Safety and Tolerability of Rotigotine Transdermal Patch in Healthy Japanese and Caucasian Subjects
Clinical Drug Investigation, 2014Co-Authors: Willi Cawello, Marina Braun, Jan-peer Elshoff, Seong R. Kim, Junji Ikeda, Tomoo FunakiAbstract:Background and Objectives Rotigotine is a dopamine receptor agonist with activity across the D_1 through to D_5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of Rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson’s disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with Rotigotine transdermal patch in Japanese and Caucasian subjects. Methods In this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h Rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total Rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration–time curve from time zero to last quantifiable concentration [AUC_last], maximum plasma concentration [ C _max], and body weight- and dose-normalized values). Results The pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of Rotigotine was 2.0 ± 0.5 mg for Japanese subjects and 2.08 ± 0.58 mg for Caucasians. Plasma concentration–time profiles of unconjugated Rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, C _max, time to C _max ( t _max), and AUC_last, for unconjugated Rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after correction for body weight. A statistically significant difference between ethnic groups was observed for total Rotigotine concentrations (total Rotigotine = unconjugated Rotigotine + conjugated Rotigotine), with slightly lower values in Caucasians after correction for body weight and apparent dose. No relevant differences were observed between males and females. Inter-individual variability was high. The terminal half-life for unconjugated Rotigotine was 5.3 h in Japanese subjects and 5.7 h in Caucasians; corresponding values for total Rotigotine were 8.6 h and 9.6 h. Less than 0.1 % of the apparent dose was renally excreted as the parent compound. Renal elimination of total Rotigotine covers 11.7 % of absorbed dose in Japanese subjects and 10.8 % of the absorbed dose in Caucasians, whereas the renal elimination via total despropyl Rotigotine was 8.2 and 7.1 %, respectively. The corresponding values for total desthienylethyl Rotigotine were 3.5 % in Japanese subjects and 4.2 % Caucasians. Most adverse events were mild in intensity and typical for dopamine agonists or for transdermal therapeutics. Conclusion Administration of a single patch delivering 2 mg/24 h Rotigotine resulted in comparable pharmacokinetic profiles in Japanese and Caucasian subjects. The Rotigotine transdermal patch was generally well-tolerated. Our findings suggest similar dose requirements for Japanese and Caucasian populations.
Lars Bauer - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics, Tolerability, and Bioequivalence of Two Formulations of Rotigotine in Healthy Chinese Subjects.
Clinical therapeutics, 2018Co-Authors: Yun Liu, Erwin Surmann, Brian Tomlinson, Jiyuan Guo, Mahnaz Asgharnejad, Lars Bauer, Xiaojuan Guo, Jan-peer ElshoffAbstract:Abstract Purpose The pharmacokinetic (PK) profile of the Rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the Rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature–stable (PR2.2.1) formulations of Rotigotine in healthy Chinese men. Methods In treatment period 1 of SP0913, subjects received a single application of Rotigotine 2 mg/24 hours on day 1 followed by a washout period (days 2–6); treatment period 2 (days 6–14) involved multiple doses of Rotigotine 2 mg/24 hours (days 7–9) followed by multiple doses of Rotigotine 4 mg/24 hours (days 10–12), with patches applied for 24 hours each. In PD0011, subjects received a single dose (2 mg/24 hours) of each Rotigotine formulation (PR2.2.1 and PR2.1.1) for 24 hours each in a crossover design. Blood samples were collected at scheduled time points to determine Rotigotine plasma concentrations. Safety and tolerability were evaluated by adverse events monitoring. Results Twenty-four healthy Chinese subjects (12 males, 12 females) were enrolled and completed SP0913. Geometric mean plasma concentrations of unconjugated and total Rotigotine increased to a plateau beginning at ∼8 hours (multiple dose) to 16 hours (single dose) postdose; no characteristic Tmax was observed for unconjugated and total Rotigotine. The respective geometric mean Cmax, Cmax,ss, AUC from zero up to the last analytically quantifiable concentration, and AUC0–24,ss values for unconjugated and total Rotigotine were similar when Rotigotine 2 mg/24 hours was applied as a single dose or multiple-dose regimen. During the multiple-dose period, geometric mean Cmax,ss and AUC0–24,ss of both unconjugated and total Rotigotine were ∼2-fold higher for Rotigotine 4 mg/24 hours than for Rotigotine 2 mg/24 hours. Forty-seven of 50 male Chinese subjects completed PD0011. Primary PK parameters for the room temperature–stable formulation of Rotigotine were highly comparable to the cold-chain formulation. Common adverse events included application site pruritus, nausea, dizziness, and constipation (SP0913 only), with no clinically significant changes in other safety measures. Implications PK profiles and derived PK parameters of unconjugated and total Rotigotine in healthy Chinese subjects were consistent with findings from other ethnic groups receiving single and multiple doses of the Rotigotine transdermal patch. Single and repeated daily doses of the Rotigotine transdermal patch were well tolerated. Room temperature–stable and cold-chain formulations were bioequivalent. ClinicalTrials.gov identifiers: NCT01675024 and NCT02070796.
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Switching from an oral dopamine receptor agonist to Rotigotine transdermal patch: a review of clinical data with a focus on patient perspective
2017Co-Authors: Sun Ju Chung, Mahnaz Asgharnejad, Lars Bauer, Babak Boroojerdi, Arturo Benitez, Tanja Heidbrede, Allison Little, Han Joon KimAbstract:Introduction: Dopamine receptor agonists (DAs) are commonly used to treat Parkinson’s disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to Rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to Rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms (‘dopamine receptor agonist’ OR ‘Rotigotine’) AND ‘switch’. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to Rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to Rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to Rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h Rotigotine) may be switched overnight.
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a randomized controlled exploratory pilot study to evaluate the effect of Rotigotine transdermal patch on parkinson s disease associated chronic pain
The Journal of Clinical Pharmacology, 2016Co-Authors: Olivier Rascol, Erwin Surmann, Mahnaz Asgharnejad, Theresa A Zesiewicz, Ray K Chaudhuri, Elisabeth Dohin, Sigrid Nilius, Lars BauerAbstract:Pain is a troublesome nonmotor symptom of Parkinson's disease (PD). This double-blind exploratory pilot study (NCT01744496) was the first to specifically investigate the effect of a dopamine agonist on PD-associated pain as primary outcome. Patients with advanced PD (ie, receiving levodopa) and at least moderate PD-associated chronic pain (≥3 months, ≥4 points on 11-point Likert pain scale) were randomized to Rotigotine (optimal/maximum dose ≤16 mg/24h) or placebo and maintained for 12 weeks. Primary efficacy variable was change in pain severity (Likert pain scale) from baseline to end of maintenance. Secondary variables included percentage of responders (≥2-point Likert pain scale reduction), King's PD Pain Scale (KPPS) domains, and PD Questionnaire (PDQ-8). Statistical analyses were exploratory. Of 68 randomized patients, 60 (Rotigotine, 30; placebo, 30) were evaluable for efficacy. A numerical improvement in pain was observed in favor of Rotigotine (Likert pain scale: least-squares mean [95%CI] treatment difference, -0.76 [-1.87 to 0.34]; P = .172), and proportion of responders was 18/30 (60%) Rotigotine vs 14/30 (47%) placebo. An ∼2-fold numerical improvement in KPPS domain "fluctuation-related pain" was observed with Rotigotine vs placebo. Rotigotine improved PDQ-8 vs placebo (-8.01 [-15.56 to -0.46]; P = .038). These results suggest Rotigotine may improve PD-associated pain; a large-scale confirmatory study is needed.
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Evaluation of Rotigotine transdermal patch for the treatment of apathy and motor symptoms in Parkinson’s disease
BMC neurology, 2016Co-Authors: Robert A. Hauser, Erwin Surmann, Mahnaz Asgharnejad, Elisabeth Dohin, Jarosław Sławek, Paolo Barone, Lars BauerAbstract:This multicenter, double-blind, placebo-controlled study assessed the efficacy of Rotigotine transdermal patch on apathy and motor symptoms in patients with Parkinson’s disease (PD). Patients with PD-associated apathy (Unified Parkinson's Disease Rating Scale [UPDRS] I item 4 [motivation] ≥2 and patient-rated Apathy Scale [AS] ≥14) were randomized 1:1:1 to “low-dose” Rotigotine (≤6 mg/24 h for early PD [those not receiving levodopa] or ≤8 mg/24 h for advanced PD [those receiving levodopa]), “high-dose” Rotigotine (≤8 mg/24 h for early PD or ≤16 mg/24 h for advanced PD), or placebo, and maintained at optimal/maximal dose for 12 weeks. Coprimary efficacy variables were: change from baseline to End of Maintenance in patient-rated AS and UPDRS II + III total score. Recruitment was stopped after an interim futility analysis; therefore, all p values are exploratory. Of 122 patients randomized, 81.1 % completed the study (placebo, n = 32/40 [80.0 %]; low-dose Rotigotine, n = 30/41 [73.2 %]; high-dose Rotigotine, n = 37/41 [90.2 %]). No treatment difference was observed in the change in patient-rated AS (least squares mean [95 % confidence interval (CI)] difference: low-dose, 0.04 [−2.42, 2.50], p =0.977; high-dose, −0.22 [−2.61, 2.18], p = 0.859). Rotigotine improved UPDRS II + III total scores versus placebo (least squares mean [95 % CI] treatment difference: low-dose, −7.29 [−12.30, −2.28], p = 0.005; high-dose, −6.06 [−10.90, −1.21], p = 0.015), and the “mood/apathy” domain of the Non-Motor Symptom Scale as rated by the investigator (secondary outcome). The most frequent adverse events in Rotigotine-treated patients were application site reactions, somnolence, and nausea. Rotigotine did not improve PD-associated apathy as rated by the patient but provided clinically relevant improvement in motor control and activities of daily living. ClinicalTrials.gov identifier NCT01782222 . Trial registration date: January 30, 2013.
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evaluation of Rotigotine transdermal patch for the treatment of apathy and motor symptoms in parkinson s disease
BMC Neurology, 2016Co-Authors: Robert A. Hauser, Erwin Surmann, Mahnaz Asgharnejad, Elisabeth Dohin, Paolo Barone, Jaroslaw Slawek, Lars BauerAbstract:This multicenter, double-blind, placebo-controlled study assessed the efficacy of Rotigotine transdermal patch on apathy and motor symptoms in patients with Parkinson’s disease (PD). Patients with PD-associated apathy (Unified Parkinson's Disease Rating Scale [UPDRS] I item 4 [motivation] ≥2 and patient-rated Apathy Scale [AS] ≥14) were randomized 1:1:1 to “low-dose” Rotigotine (≤6 mg/24 h for early PD [those not receiving levodopa] or ≤8 mg/24 h for advanced PD [those receiving levodopa]), “high-dose” Rotigotine (≤8 mg/24 h for early PD or ≤16 mg/24 h for advanced PD), or placebo, and maintained at optimal/maximal dose for 12 weeks. Coprimary efficacy variables were: change from baseline to End of Maintenance in patient-rated AS and UPDRS II + III total score. Recruitment was stopped after an interim futility analysis; therefore, all p values are exploratory. Of 122 patients randomized, 81.1 % completed the study (placebo, n = 32/40 [80.0 %]; low-dose Rotigotine, n = 30/41 [73.2 %]; high-dose Rotigotine, n = 37/41 [90.2 %]). No treatment difference was observed in the change in patient-rated AS (least squares mean [95 % confidence interval (CI)] difference: low-dose, 0.04 [−2.42, 2.50], p =0.977; high-dose, −0.22 [−2.61, 2.18], p = 0.859). Rotigotine improved UPDRS II + III total scores versus placebo (least squares mean [95 % CI] treatment difference: low-dose, −7.29 [−12.30, −2.28], p = 0.005; high-dose, −6.06 [−10.90, −1.21], p = 0.015), and the “mood/apathy” domain of the Non-Motor Symptom Scale as rated by the investigator (secondary outcome). The most frequent adverse events in Rotigotine-treated patients were application site reactions, somnolence, and nausea. Rotigotine did not improve PD-associated apathy as rated by the patient but provided clinically relevant improvement in motor control and activities of daily living. ClinicalTrials.gov identifier NCT01782222 . Trial registration date: January 30, 2013.
Mahnaz Asgharnejad - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics, Tolerability, and Bioequivalence of Two Formulations of Rotigotine in Healthy Chinese Subjects.
Clinical therapeutics, 2018Co-Authors: Yun Liu, Erwin Surmann, Brian Tomlinson, Jiyuan Guo, Mahnaz Asgharnejad, Lars Bauer, Xiaojuan Guo, Jan-peer ElshoffAbstract:Abstract Purpose The pharmacokinetic (PK) profile of the Rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the Rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature–stable (PR2.2.1) formulations of Rotigotine in healthy Chinese men. Methods In treatment period 1 of SP0913, subjects received a single application of Rotigotine 2 mg/24 hours on day 1 followed by a washout period (days 2–6); treatment period 2 (days 6–14) involved multiple doses of Rotigotine 2 mg/24 hours (days 7–9) followed by multiple doses of Rotigotine 4 mg/24 hours (days 10–12), with patches applied for 24 hours each. In PD0011, subjects received a single dose (2 mg/24 hours) of each Rotigotine formulation (PR2.2.1 and PR2.1.1) for 24 hours each in a crossover design. Blood samples were collected at scheduled time points to determine Rotigotine plasma concentrations. Safety and tolerability were evaluated by adverse events monitoring. Results Twenty-four healthy Chinese subjects (12 males, 12 females) were enrolled and completed SP0913. Geometric mean plasma concentrations of unconjugated and total Rotigotine increased to a plateau beginning at ∼8 hours (multiple dose) to 16 hours (single dose) postdose; no characteristic Tmax was observed for unconjugated and total Rotigotine. The respective geometric mean Cmax, Cmax,ss, AUC from zero up to the last analytically quantifiable concentration, and AUC0–24,ss values for unconjugated and total Rotigotine were similar when Rotigotine 2 mg/24 hours was applied as a single dose or multiple-dose regimen. During the multiple-dose period, geometric mean Cmax,ss and AUC0–24,ss of both unconjugated and total Rotigotine were ∼2-fold higher for Rotigotine 4 mg/24 hours than for Rotigotine 2 mg/24 hours. Forty-seven of 50 male Chinese subjects completed PD0011. Primary PK parameters for the room temperature–stable formulation of Rotigotine were highly comparable to the cold-chain formulation. Common adverse events included application site pruritus, nausea, dizziness, and constipation (SP0913 only), with no clinically significant changes in other safety measures. Implications PK profiles and derived PK parameters of unconjugated and total Rotigotine in healthy Chinese subjects were consistent with findings from other ethnic groups receiving single and multiple doses of the Rotigotine transdermal patch. Single and repeated daily doses of the Rotigotine transdermal patch were well tolerated. Room temperature–stable and cold-chain formulations were bioequivalent. ClinicalTrials.gov identifiers: NCT01675024 and NCT02070796.
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Switching from an oral dopamine receptor agonist to Rotigotine transdermal patch: a review of clinical data with a focus on patient perspective
2017Co-Authors: Sun Ju Chung, Mahnaz Asgharnejad, Lars Bauer, Babak Boroojerdi, Arturo Benitez, Tanja Heidbrede, Allison Little, Han Joon KimAbstract:Introduction: Dopamine receptor agonists (DAs) are commonly used to treat Parkinson’s disease (PD) and restless legs syndrome (RLS). In certain situations, switching from oral DAs to Rotigotine transdermal patch may be beneficial for the patient (e.g., optimal symptom control/side effects/perioperative management, preference for once-daily/non-oral administration, RLS augmentation treatment). Areas covered: This narrative review summarizes available data on DA dose equivalency, dose conversions, switching schedules, safety, tolerability, efficacy and patient treatment preferences of switching from oral DAs to Rotigotine (and vice versa) in patients with PD/RLS. The studies were identified in a PubMed search (up to 8 November 2016) using terms (‘dopamine receptor agonist’ OR ‘Rotigotine’) AND ‘switch’. Expert commentary: Randomized controlled studies often do not address the challenges clinicians face in practice, e.g., switching medications within the same class when dosing is not a one-to-one ratio. The authors describe three open-label studies in PD where oral DAs were successfully switched to Rotigotine, and review three studies in RLS where oral DAs/levodopa were switched to Rotigotine. Finally, the authors provide a suggested tool for switching from oral DAs to Rotigotine, which includes dose conversion factors and switching schedules. The authors' view is that low-dose oral DAs (equivalent to ≤8 mg/24 h Rotigotine) may be switched overnight.
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a randomized controlled exploratory pilot study to evaluate the effect of Rotigotine transdermal patch on parkinson s disease associated chronic pain
The Journal of Clinical Pharmacology, 2016Co-Authors: Olivier Rascol, Erwin Surmann, Mahnaz Asgharnejad, Theresa A Zesiewicz, Ray K Chaudhuri, Elisabeth Dohin, Sigrid Nilius, Lars BauerAbstract:Pain is a troublesome nonmotor symptom of Parkinson's disease (PD). This double-blind exploratory pilot study (NCT01744496) was the first to specifically investigate the effect of a dopamine agonist on PD-associated pain as primary outcome. Patients with advanced PD (ie, receiving levodopa) and at least moderate PD-associated chronic pain (≥3 months, ≥4 points on 11-point Likert pain scale) were randomized to Rotigotine (optimal/maximum dose ≤16 mg/24h) or placebo and maintained for 12 weeks. Primary efficacy variable was change in pain severity (Likert pain scale) from baseline to end of maintenance. Secondary variables included percentage of responders (≥2-point Likert pain scale reduction), King's PD Pain Scale (KPPS) domains, and PD Questionnaire (PDQ-8). Statistical analyses were exploratory. Of 68 randomized patients, 60 (Rotigotine, 30; placebo, 30) were evaluable for efficacy. A numerical improvement in pain was observed in favor of Rotigotine (Likert pain scale: least-squares mean [95%CI] treatment difference, -0.76 [-1.87 to 0.34]; P = .172), and proportion of responders was 18/30 (60%) Rotigotine vs 14/30 (47%) placebo. An ∼2-fold numerical improvement in KPPS domain "fluctuation-related pain" was observed with Rotigotine vs placebo. Rotigotine improved PDQ-8 vs placebo (-8.01 [-15.56 to -0.46]; P = .038). These results suggest Rotigotine may improve PD-associated pain; a large-scale confirmatory study is needed.
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Evaluation of Rotigotine transdermal patch for the treatment of apathy and motor symptoms in Parkinson’s disease
BMC neurology, 2016Co-Authors: Robert A. Hauser, Erwin Surmann, Mahnaz Asgharnejad, Elisabeth Dohin, Jarosław Sławek, Paolo Barone, Lars BauerAbstract:This multicenter, double-blind, placebo-controlled study assessed the efficacy of Rotigotine transdermal patch on apathy and motor symptoms in patients with Parkinson’s disease (PD). Patients with PD-associated apathy (Unified Parkinson's Disease Rating Scale [UPDRS] I item 4 [motivation] ≥2 and patient-rated Apathy Scale [AS] ≥14) were randomized 1:1:1 to “low-dose” Rotigotine (≤6 mg/24 h for early PD [those not receiving levodopa] or ≤8 mg/24 h for advanced PD [those receiving levodopa]), “high-dose” Rotigotine (≤8 mg/24 h for early PD or ≤16 mg/24 h for advanced PD), or placebo, and maintained at optimal/maximal dose for 12 weeks. Coprimary efficacy variables were: change from baseline to End of Maintenance in patient-rated AS and UPDRS II + III total score. Recruitment was stopped after an interim futility analysis; therefore, all p values are exploratory. Of 122 patients randomized, 81.1 % completed the study (placebo, n = 32/40 [80.0 %]; low-dose Rotigotine, n = 30/41 [73.2 %]; high-dose Rotigotine, n = 37/41 [90.2 %]). No treatment difference was observed in the change in patient-rated AS (least squares mean [95 % confidence interval (CI)] difference: low-dose, 0.04 [−2.42, 2.50], p =0.977; high-dose, −0.22 [−2.61, 2.18], p = 0.859). Rotigotine improved UPDRS II + III total scores versus placebo (least squares mean [95 % CI] treatment difference: low-dose, −7.29 [−12.30, −2.28], p = 0.005; high-dose, −6.06 [−10.90, −1.21], p = 0.015), and the “mood/apathy” domain of the Non-Motor Symptom Scale as rated by the investigator (secondary outcome). The most frequent adverse events in Rotigotine-treated patients were application site reactions, somnolence, and nausea. Rotigotine did not improve PD-associated apathy as rated by the patient but provided clinically relevant improvement in motor control and activities of daily living. ClinicalTrials.gov identifier NCT01782222 . Trial registration date: January 30, 2013.
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evaluation of Rotigotine transdermal patch for the treatment of apathy and motor symptoms in parkinson s disease
BMC Neurology, 2016Co-Authors: Robert A. Hauser, Erwin Surmann, Mahnaz Asgharnejad, Elisabeth Dohin, Paolo Barone, Jaroslaw Slawek, Lars BauerAbstract:This multicenter, double-blind, placebo-controlled study assessed the efficacy of Rotigotine transdermal patch on apathy and motor symptoms in patients with Parkinson’s disease (PD). Patients with PD-associated apathy (Unified Parkinson's Disease Rating Scale [UPDRS] I item 4 [motivation] ≥2 and patient-rated Apathy Scale [AS] ≥14) were randomized 1:1:1 to “low-dose” Rotigotine (≤6 mg/24 h for early PD [those not receiving levodopa] or ≤8 mg/24 h for advanced PD [those receiving levodopa]), “high-dose” Rotigotine (≤8 mg/24 h for early PD or ≤16 mg/24 h for advanced PD), or placebo, and maintained at optimal/maximal dose for 12 weeks. Coprimary efficacy variables were: change from baseline to End of Maintenance in patient-rated AS and UPDRS II + III total score. Recruitment was stopped after an interim futility analysis; therefore, all p values are exploratory. Of 122 patients randomized, 81.1 % completed the study (placebo, n = 32/40 [80.0 %]; low-dose Rotigotine, n = 30/41 [73.2 %]; high-dose Rotigotine, n = 37/41 [90.2 %]). No treatment difference was observed in the change in patient-rated AS (least squares mean [95 % confidence interval (CI)] difference: low-dose, 0.04 [−2.42, 2.50], p =0.977; high-dose, −0.22 [−2.61, 2.18], p = 0.859). Rotigotine improved UPDRS II + III total scores versus placebo (least squares mean [95 % CI] treatment difference: low-dose, −7.29 [−12.30, −2.28], p = 0.005; high-dose, −6.06 [−10.90, −1.21], p = 0.015), and the “mood/apathy” domain of the Non-Motor Symptom Scale as rated by the investigator (secondary outcome). The most frequent adverse events in Rotigotine-treated patients were application site reactions, somnolence, and nausea. Rotigotine did not improve PD-associated apathy as rated by the patient but provided clinically relevant improvement in motor control and activities of daily living. ClinicalTrials.gov identifier NCT01782222 . Trial registration date: January 30, 2013.
