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Pharmacokinetics, safety, and tolerability of rotigotine transdermal system in healthy Japanese and Caucasian subjects following multiple-dose administration

Abstract

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.

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Acknowledgments

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.

Author information

Correspondence to Willi Cawello.

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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

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Keywords

  • Dopamine agonist
  • Ethnic groups
  • Japanese/Caucasian comparison
  • Multiple doses
  • Pharmacokinetics
  • Rotigotine
  • Transdermal delivery