Onset and duration of effect of extended-release carbidopa-levodopa in advanced Parkinson’s disease

Abstract

Background

In patients with Parkinson’s disease (PD), oral dosing of extended-release carbidopa-levodopa (Rytary, IPX066 [ER CD-LD]) achieves peak levodopa plasma concentrations within 1 hour and maintains them for 4–6 hours.

Aims

To compare the onset and duration of ER CD-LD benefit with those of immediate-release carbidopa-levodopa (IR CD-LD) in PD patients with motor fluctuations, using crossover data, and to evaluate which threshold values of improvement in finger-tapping and Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores yield results most similar to those for trained raters’ “on”/“off” assessments.

Methods

Patients underwent serial “on”/“off” rating and provided serial finger-tapping and UPDRS motor scores after receiving, in an “off” state, their usual morning IR dose or an ER dose designed to produce a similar levodopa peak concentration. Predefined improvement thresholds for analysis were 10%, 15%, and 20% increases in finger-tapping score and 2.5, 5, 7, and 11-point decreases in UPDRS motor score. Serial plasma samples were assayed for levodopa.

Results

Among 27 patients, mean time to onset of an “on” state was similar for ER compared with IR CD-LD (0.83 vs 0.81 hour), but mean duration was significantly longer for ER CD-LD than for IR CD-LD (5.56 vs 2.69 hours; P<0.0001). Duration was best matched by a $20% improvement in finger-tapping, a $11-point improvement in UPDRS motor score, and a levodopa plasma concentration $1,000 ng/mL.

Conclusion

For ER CD-LD, observer assessments of “on” state were corroborated by sustained treatment effects. Correlations among “on”-state duration, finger-tapping score, and UPDRS motor score may suggest clinically relevant thresholds for acute assessment of treatment benefit.

Keywords:

• Rytary
• carbidopa-levodopa
• Parkinson’s disease
• treatment
• duration of effect
• motor fluctuations

Acknowledgments

This study was supported by Impax Laboratories, Inc. Under the direction of the authors, editorial assistance was provided by Michael Feirtag of The Curry Rockefeller Group, LLC, which was funded by Impax Laboratories, Inc.

Author contributions

RAH: design and execution of the clinical study, conduct of data analyses, writing of the first draft, and review and critique of the manuscript; AE: design and execution of the clinical study, conduct of data analyses, and review and critique of the manuscript; SK: design of the clinical study, conduct of statistical and data analyses, and review and critique of the manuscript; SG: design and execution of the clinical study, conduct of data analyses, and review and critique of the manuscript; NBM: design and execution of the clinical study, conduct of data analyses, and review and critique of the manuscript. All authors contributed toward data analysis and drafting and revising the paper, and agree to be accountable for all aspects of the work.

Disclosure

Robert A Hauser has received honoraria or payments for consulting, advisory services, or speaking services over the past 12 months from AbbVie, Allergan, AstraZeneca, Biotie Therapeutics, Ceregene, Chelsea Therapeutics, Cleveland Clinic, Eli Lilly, GE Healthcare, Impax Laboratories, Inc., Neurocrine, Indus, Ipsen Biopharmaceuticals, Lundbeck, Merck/MSD, Noven Pharmaceuticals, Pfizer, Straken Pharmaceuticals, Targacept, Teva Pharmaceutical Industries, Ltd., Teva Neuroscience, Upsher-Smith Laboratories, UCB, UCB Pharma SA, University of Houston, US WorldMeds, XenoPort, and Zambon Company SpA. Dr Hauser’s institution has received research support over the past 12 months from Abbott Laboratories, Addex Therapeutics, Allergan, AstraZeneca, Biotie Therapeutics, Chelsea Therapeutics, Civitas, GE Healthcare, Impax Laboratories, Inc., Ipsen Biopharmaceuticals, Merck/MSD, Merz, the Michael J. Fox Foundation for Parkinson’s Research, NINDS, the Parkinson Study Group, Schering-Plough, Teva Neuroscience, UCB, and Vita-Pharm. Dr Hauser has received royalties in the past 12 months from the University of South Florida. Aaron Ellenbogen has participated in a speaker bureau for Teva Pharmaceuticals and has been a study investigator and consultant for Impax Laboratories, Inc., clinical studies. Sarita Khanna, Suneel Gupta, and Nishit B Modi are employees and stockholders of Impax Laboratories, Inc. The authors report no other conflicts of interest in this work.