title: Steady-state plasma concentration profile of transdermal rotigotine: an integrated analysis of three, open-label, randomized, phase I multiple dose studies.
abstract: BACKGROUND
  The dopamine agonist rotigotine is formulated in a transdermal delivery system (patch) for once-daily application. It has been reported as efficacious in the treatment of idiopathic Parkinson's disease (PD) and restless legs syndrome.
  
  
  OBJECTIVE
  This article summarizes the results of 3 clinical studies conducted to characterize the 24-hour pharmacokinetic profile of rotigotine in steady state and the effect of different patch application sites on this profile. In addition, the relative bioavailability of a single, large patch versus 2 smaller patches was assessed.
  
  
  METHODS
  One Phase I study (SP871) assessed the steady-state pharmacokinetic properties at different application sites at a rotigotine maintenance dose of 3 mg/24 hours in healthy participants. Due to tolerability issues, the steady-state pharmacokinetic properties of rotigotine at higher doses (8 mg/24 hours) was assessed in 2 Phase I studies (SP630, SP651) in early-stage PD patients. Relative rotigotine bioavailability from a 40 cm(2) patch versus 2 × 20 cm(2) patches (SP651) and from a 15 cm(2) patch versus 1 × 5 cm(2) + 1 × 10 cm(2) patches (SP871) was also evaluated. Rotigotine concentrations in plasma were analyzed using a validated LC-MS/MS method. The pharmacokinetic variables were calculated using standard noncompartmental analysis.
  
  
  RESULTS
  Release of rotigotine to the skin was 31% to 62% of total drug content in the patch. Variability of rotigotine exposure was low within participants (15%) compared with the variability observed between participants (54%). Rotigotine exposure increased proportionally in the therapeutic dose range of 2 mg/24 hours to 8 mg/24 hours. Plasma concentrations at steady state were stable over the 24-hour patch-on period. Delivery via a single, large patch compared with a combination of smaller patches did not appear to influence exposure to rotigotine. Bioavailability showed some variability depending on patch application site (hip, shoulder, abdomen, flank, thigh, upper arm); the respective mean ratios for AUC ranged between 0.87 (abdomen vs flank) and 1.46 (shoulder vs thigh).
  
  
  CONCLUSIONS
  Continuous rotigotine delivery via a once-daily transdermal patch generated stable mean steady-state 24-hour plasma concentrations in healthy participants as well as patients with early-stage PD. Doses were achieved either by application of 1 large patch or a combination of smaller patches, resulting in the same total surface area.
authors.affiliation: UCB Pharma, UCB BiosciencesGmbH, Alfred-Nobel-Str. 10, Monheim am Rhein, Germany. Jan-Peer.Elshoff@ucb.com
authors.forename: Jan-Peer
authors.initials: JP
authors.lastname: Elshoff
authors.forename: Marina
authors.initials: M
authors.lastname: Braun
authors.forename: Jens-Otto
authors.initials: JO
authors.lastname: Andreas
authors.forename: Michelle
authors.initials: M
authors.lastname: Middle
authors.forename: Willi
authors.initials: W
authors.lastname: Cawello
mesh_terms: D000279:Administration, Cutaneous; D001682:Biological Availability; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D018491:Dopamine Agonists; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine