Steady-State Plasma Concentration Profile of Transdermal Rotigotine: An Integrated Analysis of Three, Open-Label, Randomized, Phase I Multiple Dose Studies

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• 作者：Jan-Peer Elshoff ; PhD¹ ; ^{Jan-Peer.Elshoff@ucb.com} ; Marina Braun ; MD¹ ; Jens-Otto Andreas ; Dipl Math¹ ; Michelle Middle ; MD² ; Willi Cawello ; PhD¹
• 关键词：application site ; bioavailability ; continuous 24-hour drug delivery ; dose proportionality ; rotigotine transdermal patch ; steady-state pharmacokinetic profile
• 刊名：Clinical Therapeutics
• 出版年：2012
• 期刊代码：65_01492918
• 类别：med
• 出版时间：April, 2012
• 卷：34
• 期：4
• 页码：966-978
• 文件大小：447 K

摘要

<h4 class="h4">Backgroundh4>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.<h4 class="h4">Objectiveh4>

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.<h4 class="h4">Methodsh4>

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 cm² patch versus 2 脳 20 cm² patches (SP651) and from a 15 cm² patch versus 1 脳 5 cm² + 1 脳 10 cm² 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.<h4 class="h4">Resultsh4>

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).<h4 class="h4">Conclusionsh4>

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.