Comparison of the bioavailability and adhesiveness of different rotigotine transdermal patch formulations

Abstract

Objective:

Rotigotine transdermal patch is approved for the treatment of early and advanced idiopathic Parkinson’s disease (PD) and moderate-to-severe idiopathic restless legs syndrome (RLS). A cold chain manufacturing and distribution process was temporarily implemented in 2008, as this reduced the crystal formation reported within patches stored at room temperature. In order to overcome the crystallization issue and meet EMA and FDA requirements, a new room temperature stable formulation was developed. The three studies reported here were conducted to determine whether the new room temperature stable patch demonstrated similar bioavailability and adhesiveness to the original and intermediate patches.

Methods:

Data are reported from three cross-over studies that compared the original, cold chain and room temperature stable patch. Two open-label bioequivalence studies investigated the 2 mg/24 h dosage in healthy individuals (SP951, n = 52 [Clinicaltrials.gov: NCT00881894]; SP0987, n = 50 [NCT01059903]) and a double-blind patch adhesiveness study investigated the 8 mg/24 h dosage in patients with PD (SP1066, n = 56 [NCT01338896]).

Results:

Plasma concentration–time curves and geometric means for pharmacokinetic parameters were similar for the cold chain vs. original patch in SP951 (AUC_(0–tz): 2.68 vs. 2.71 ng/mL*h; point estimate: 0.99 [90% confidence interval (CI): 0.91, 1.07]) (C_max: 0.131 vs. 0.136 ng/mL; 0.96 [0.89, 1.04]) and for the room temperature stable vs. cold chain patch in SP0987 (AUC_(0–tz): 4.51 vs. 4.87 ng/mL*h; 0.90 [0.84, 0.97]) (C_max: 0.23 vs. 0.23 ng/mL; 0.95 [0.88, 1.02]). In both studies, 90% CIs for ratios of AUC_(0–tz) and C_max were within the bioequivalence acceptance range (0.8–1.25). In SP1066, overall median adhesiveness scores were similar for cold chain (0.5 [range: 0–4]) and room temperature stable (0 [0–4]) formulations.

Conclusion:

These results demonstrated bioequivalence and indicated similar adhesiveness of the approved room temperature stable rotigotine patch with the original and cold chain patches. Potential limitations include the enrolment of healthy volunteers in the bioequivalence studies, as these individuals were likely to be younger than the general PD or RLS population.

Keywords::

• Adhesion
• Bioequivalence
• Dopamine receptor agonist
• Rotigotine
• Transdermal

Transparency

Declaration of funding

The SP951, SP0987 and SP1066 studies were supported by UCB Pharma.

Declaration of financial/other relationships

J.-P.E. is a salaried employee of UCB Pharma, Monheim am Rhein, Germany. L.T. was the principal investigator of the SP1066 study. He has received payments for consultancy from UCB Pharma, Medtronic Inc., Boston Scientific, Bayer Healthcare, and Archimedes Pharma; and honoraria for speaking at symposia sponsored by UCB Pharma, Teva Pharma, Lundbeck Pharma, Bracco, Gianni PR, Medas Pharma, Desitin Pharma, Boehringer Ingelheim, GlaxoSmithKline, Eumecom, Orion Pharma, Medtronic, Boston Scientific, Cephalon, Abbott, GE Medical, Archimedes, and Bayer. L.T. did not receive any financial support or any other form of reimbursement for working as a co-author on this manuscript. L.T.’s institution has received funding by the German Research Foundation, the German Ministry of Education and Research, Manfred und Ursula Müller Stiftung, Klüh Stiftung, Hoffnungsbaum e.V., NBIA Disorders Society USA, Köln Fortune, Medtronic, Deutsche Parkinson Vereinigung, Archimedes Pharma, Abbott, Bayer, UCB Pharma, zur Rose Pharma, and Teva. M.S., C.A. and M.B. are salaried employees of UCB Pharma, Monheim am Rhein, Germany. M.K. is a former employee of UCB Pharma, Monheim am Rhein, Germany and is currently employed by LTS Lohmann Therapie-Systeme AG, Andernach, Germany. L.B. is a salaried employee of UCB Pharma, Monheim am Rhein, Germany and receives stock options from his employment.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

The authors acknowledge Hannah Carney PhD (Evidence Scientific Solutions, Horsham, UK), for writing assistance which was funded by UCB Pharma, and Azita Tofighy PhD (UCB Pharma, Brussels, Belgium) for publication coordination. The SP951 study was conducted by FOCUS Clinical Drug Development GmbH, Neuss, Germany and the SP0987 study was conducted by CRS Clinical Research Services Mönchengladbach GmbH, Mönchengladbach, Germany. The authors acknowledge the SP1066 study investigators: Nin Bajaj MD, Simon Bittkau MD, Bernard R. Boothman MD, David J Burn MD, Christoph Engelmann MD, Wolfgang Molt MD, Christian Oehlwein MD, Werner Poewe MD, Ali Safavi MD, Erich Scholz MD, Malcolm J Steiger MD, Dieter Volc MD and Paul Worth MD.