Rotigotine is a dopamine receptor agonist indicated for the treatment of Parkinson’s disease and moderate-to-severe restless legs syndrome. Continuous transdermal delivery of rotigotine via a silicon-based patch maintains stable plasma concentrations over 24 h. The objective of the study was to evaluate the pharmacokinetics, safety, and tolerability of a multiple-dose schedule of rotigotine transdermal patch in Japanese and Caucasian subjects. In this open-label, repeated-dose, parallel-group study (ClinicalTrials.gov: NCT01854216), healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by gender, body mass index, and age. Subjects underwent a 9-day patch application period. 12 Japanese and 12 Caucasian subjects were included in the pharmacokinetic analyses. Mean apparent doses (actual amount of drug delivered) increased proportionally with rotigotine nominal dosages (1, 2, and 4 mg/24 h) and were similar for both ethnic groups, with large inter-individual variability. Mean plasma concentration-time profiles for unconjugated rotigotine were similar in both ethnic groups at day 3 for each dosage. Peak concentrations (C max,ss) and area under the concentration-time curves from pre-dose to the concentration measured 24 h after administration of patch (AUC(0–24,ss)) showed similar exposure in both groups; higher values in Japanese subjects were explained by differences in body weight. For total rotigotine, C max,ss and AUC(0–24,ss) values were higher in Caucasian subjects and could be explained by small differences in apparent dose. Rotigotine was generally well tolerated following multiple applications up to 4 mg/24 h. These findings suggest similar dosage requirements for rotigotine transdermal system in Japanese and Caucasian populations.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Braun M, Cawello W, Boekens H, Horstmann R (2009) Influence of domperidone on pharmacokinetics, safety and tolerability of the dopamine agonist rotigotine. Br J Clin Pharmacol 67:209–215
Cawello W, Wolff HM, Meuling WJ, Horstmann R, Braun M (2007) Transdermal administration of radiolabelled [14C]rotigotine by a patch formulation: a mass balance trial. Clin Pharmacokinet 46:851–857
Cawello W, Braun M, Boekens H (2009) Absorption, disposition, metabolic fate, and elimination of the dopamine agonist rotigotine in man: administration by intravenous infusion or transdermal delivery. Drug Metab Dispos 37:2055–2060
Cawello W, Ahrweiler S, Sulowicz W, Szymczakiewicz-Multanowska A, Braun M (2012) Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function. Br J Clin Pharmacol 73:46–54
Cawello W, Kim SR, Braun M, Elshoff JP, Ikeda J, Funaki T (2014) Pharmacokinetics, safety and tolerability of rotigotine transdermal patch in healthy Japanese and Caucasian subjects. Clin Drug Investig 34:95–105
Elshoff JP, Braun M, Andreas JO, Middle M, Cawello W (2012) Steady-state plasma concentration profile of transdermal rotigotine: an integrated analysis of three, open-label, randomized, phase I multiple dose studies. Clin Ther 34:966–978
Garcia-Borreguero D, Ferini-Strambi L, Kohnen R et al (2012) European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society. Eur J Neurol 19:1385–1396
Giladi N, Boroojerdi B, Korczyn AD, Burn DJ, Clarke CE, Schapira AH (2007) Rotigotine transdermal patch in early Parkinson’s disease: a randomized, double-blind, controlled study versus placebo and ropinirole. Mov Disord 22:2398–2404
Gough K, Hutchison M, Keene O et al (1995) Assessment of dose proportionality: report from the Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Party. Drug Inf J 29:1039–1048
Hattori N (2003) Appropriate dosing of pergolide in monotherapy and adjunctive therapy in Parkinson’s disease. Curr Opin Neurol 16(Suppl 1):S21–S25
Hening WA, Allen RP, Ondo WG et al (2010) Rotigotine improves restless legs syndrome: a 6-month randomized, double-blind, placebo-controlled trial in the United States. Mov Disord 25:1675–1683
International Conference on Harmonisation; guidance on ethnic factors in the acceptability of foreign clinical data; availability–FDA (1998). Notice. Fed Regist 63:31790–31796
Jankovic J (2005) Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations. Mov Disord 20(Suppl 11):S11–S16
Jankovic J, Aguilar LG (2008) Current approaches to the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat 4:743–757
LeWitt PA, Lyons KE, Pahwa R (2007) Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study. Neurology 68:1262–1267
Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR (2011) The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Mov Disord 26:399–406
Muangpaisan W, Hori H, Brayne C (2009) Systematic review of the prevalence and incidence of Parkinson’s disease in Asia. J Epidemiol 19:281–293
Oertel WH, Benes H, Garcia-Borreguero D et al (2010) Rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome: a randomized, placebo-controlled polysomnographic study. Sleep Med 11:848–856
Parkinson Study Group (2003) A controlled trial of rotigotine monotherapy in early Parkinson’s disease. Arch Neurol 60:1721–1728
Poewe WH, Rascol O, Quinn N et al (2007) Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease: a double-blind, double-dummy, randomised controlled trial. Lancet Neurol 6:513–520
Scheller D, Ullmer C, Berkels R, Gwarek M, Lubbert H (2009) The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson’s disease. Naunyn Schmiedebergs Arch Pharmacol 379:73–86
Trenkwalder C, Benes H, Poewe W et al (2008) Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 7:595–604
Van Den Eeden SK, Tanner CM, Bernstein AL et al (2003) Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 157:1015–1022
Watts RL, Jankovic J, Waters C, Rajput A, Boroojerdi B, Rao J (2007) Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology 68:272–276
The authors acknowledge the participation of FOCUS Clinical Drug Development GmbH (Neuss, Germany) which conducted the study. AAI Deutschland GmbH & Co. KG (now NUVISAN GmbH; Neu-Ulm, Germany) performed all bioanalytical work to quantify rotigotine and metabolites in plasma and urine samples. The authors acknowledge Steve Dobson (Evidence Scientific Solutions, Horsham, UK) for editorial support, which was funded by UCB Pharma, Brussels, Belgium, and Ging-Ging Li, CMPP (UCB Pharma, Brussels, Belgium) for publication coordination. All costs associated with the development and the publishing of the present manuscript were met by the sponsor.
Conflict of interest
This study was funded by UCB Pharma, Monheim am Rhein, Germany. WC, MB, and J-PE are employees of UCB Pharma, Monheim am Rhein, Germany. SRK, JI, and TF are employees of Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan. TM has served as a paid consultant to Taiho, Hisamitsu, and GSK.
About this article
Cite this article
Cawello, W., Kim, S.R., Braun, M. et al. Pharmacokinetics, safety, and tolerability of rotigotine transdermal system in healthy Japanese and Caucasian subjects following multiple-dose administration. Eur J Drug Metab Pharmacokinet 41, 353–362 (2016). https://doi.org/10.1007/s13318-015-0273-6
- Dopamine agonist
- Ethnic groups
- Japanese/Caucasian comparison
- Multiple doses
- Transdermal delivery