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Subcutaneous Administration of Carbidopa Enhances Oral Levodopa Pharmacokinetics

A Series of Studies Conducted in Pigs, Mice, and Healthy Volunteers

Shaltiel-Karyo, Ronit PhD*; Caraco, Yoseph MD; Zawaznik, Eduardo MSc*; Weinstock, Irena MSc*; Nemas, Mara MSc*; Oren, Sheila MD*; Yacoby-Zeevi, Oron DVM, PhD*; LeWitt, Peter A. MD‡§

doi: 10.1097/WNF.0000000000000345
Original Articles
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Objectives Although commercially available levodopa (LD) formulations include carbidopa (CD) or benserazide for gastrointestinal L-aromatic amino acid decarboxylase inhibition, little is known how manipulating CD delivery affects the pharmacokinetics of LD. Our research systematically evaluated the peripheral and central pharmacokinetics of LD during continuous subcutaneous CD delivery.

Methods We conducted pharmacokinetic experiments in pigs, mice, and humans to characterize effects of continuous subcutaneous CD delivery co-administered with LD as compared with oral LD/CD administration on LD pharmacokinetics. The porcine and human studies compared peripheral LD pharmacokinetic parameters (area under the curves [AUCs], peak plasma concentrations [Cmax], and plasma elimination half-life [t1/2]) and the mouse studies compared brain LD and dopamine concentrations.

Results In the pig, supplementary subcutaneous CD delivery significantly increased the LD t1/2 and AUC versus LD/CD alone and versus additional oral CD administration. In mice, administration of supplementary subcutaneous CD substantially increased mean plasma concentrations of both LD and CD versus oral LD/CD alone at all time points. These increases were mirrored by increased brain dopamine levels for at least the 7 hours of study. In healthy human subjects, continuous subcutaneous CD administration, 3.33 mg/h x24h, increased the plasma LD t1/2, Cmax, and AUC by 17.4%, 40.5%, and 22.3%, respectively (P < 0.003).

Conclusions This series of studies demonstrates that small continuous dosing of subcutaneous CD has an unexpected effect on LD pharmacokinetics greater than the extent of decarboxylase inhibition achieved by additional oral CD administration.

*NeuroDerm Ltd, Rehovot, Israel;

Clinical Pharmacology Unit, Division of Medicine, Hadassah Hebrew-University Medical Center, Jerusalem, Israel; and

Departments of Neurology, Henry Ford Health System, West Bloomfield; and

§Wayne State University School of Medicine, Detroit, MI.

Address correspondence and reprint requests to Peter A. LeWitt, MD, Henry Ford Hospital, 6777 West Maple Rd, West Bloomfield, MI 48322; E-mail: plewitt1@hfhs.org

Y.C. and P.A.L. report consultancy to NeuroDerm and Y.C. was the principal investigator in the human pharmacokinetic study reported herein. R.S.K., E.Z., I.W., and S.O. are employed by NeuroDerm Ltd. M.N. (deceased) and O.Y.Z. were employed by NeuroDerm at the time of the studies and development of this report.

Ms. Nemas died April 30, 2017.

Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare. The study was supported by NeuroDerm Ltd. This series of studies was supported by the Michael J. Fox Foundation for Parkinson's Research (United States) and NeuroDerm Ltd (Israel).

Online date: June 13, 2019

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