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Drug Delivery and Transport into the Central Circulation: An Example of Zero-Order In vivo Absorption of Rotigotine from a Transdermal Patch Formulation

  • Willi Cawello
  • Marina Braun
  • Jens-Otto Andreas
Short Communication
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Abstract

Background and Objective

Pharmacokinetic studies using deconvolution methods and non-compartmental analysis to model clinical absorption of drugs are not well represented in the literature. The purpose of this research was (1) to define the system of equations for description of rotigotine (a dopamine receptor agonist delivered via a transdermal patch) absorption based on a pharmacokinetic model and (2) to describe the kinetics of rotigotine disposition after single and multiple dosing.

Methods

The kinetics of drug disposition was evaluated based on rotigotine plasma concentration data from three phase 1 trials. In two trials, rotigotine was administered via a single patch over 24 h in healthy subjects. In a third trial, rotigotine was administered once daily over 1 month in subjects with early-stage Parkinson’s disease (PD). A pharmacokinetic model utilizing deconvolution methods was developed to describe the relationship between drug release from the patch and plasma concentrations. Plasma–concentration over time profiles were modeled based on a one-compartment model with a time lag, a zero-order input (describing a constant absorption via skin into central circulation) and first-order elimination. Corresponding mathematical models for single- and multiple-dose administration were developed.

Results

After single-dose administration of rotigotine patches (using 2, 4 or 8 mg/day) in healthy subjects, a constant in vivo absorption was present after a minor time lag (2–3 h). On days 27 and 30 of the multiple-dose study in patients with PD, absorption was constant during patch-on periods and resembled zero-order kinetics.

Conclusion

Deconvolution based on rotigotine pharmacokinetic profiles after single- or multiple-dose administration of the once-daily patch demonstrated that in vivo absorption of rotigotine showed constant input through the skin into the central circulation (resembling zero-order kinetics). Continuous absorption through the skin is a basis for stable drug exposure.

Notes

Acknowledgements

The authors thank the participants of all three studies. Medical writing and editorial assistance were provided by Alex Loeb, PhD, CMPP (Evidence Scientific Solutions, Philadelphia, PA) and Nicole Meinel, PhD, CMPP (Evidence Scientific Solutions, London, UK), funded by UCB Pharma (Brussels, Belgium), and publication coordination was provided by Cédric Laloyaux, PhD (Strategic Publication Lead Neurology, UCB Pharma, Brussels, Belgium).

Compliance with Ethical Standards

Funding

These studies were funded by Schwarz Pharma (since acquired by UCB Pharma).

Conflict of interest

The authors are salaried employees of UCB Pharma (all have received stock options from their employment).

Ethical approval

These studies were carried out in accordance with Good Clinical Practice and the Declaration of Helsinki. The study protocols were approved by local ethics committees in accordance with all required local regulations. Written informed consent was obtained from all participants prior to enrollment.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Willi Cawello
    • 1
  • Marina Braun
    • 1
  • Jens-Otto Andreas
    • 1
  1. 1.UCB PharmaMonheim am RheinGermany

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