Continuous Subcutaneous Administration Of Carbidopa Enhances Levodopa Pharmacokinetics: A Series Of Studies Conducted In The Pig, Mouse And Healthy Volunteers

OBJECTIVE: To systematically evaluate the peripheral and central pharmacokinetics of levodopa during continuous subcutaneous carbidopa delivery.BACKGROUND: Although commercially available levodopa formulations include carbidopa or benserazide for dopa-decarboxylase inhibition, little is known how carbidopa delivery affects the pharmacokinetics of oral levodopa.METHODS: We conducted a series of pharmacokinetic studies in pigs, mice, and humans to characterize effects of continuous subcutaneous carbidopa delivery co-administered with oral levodopa/carbidopa (IR-LD/CD) compared to oral IR-LD/CD on levodopa pharmacokinetics. The porcine and human studies compared peripheral levodopa pharmacokinetic parameters (area under the curves [AUC], peak plasma concentrations [Cmax] and plasma elimination half-life [t½]) and the mouse studies compared brain levodopa and dopamine levels.RESULTS: In pigs receiving oral IR-LD/CD (125/25mg, TID), additional continuous subcutaneous carbidopa delivery (60mg/24h) significantly increased the levodopa t1/2 and AUC versus IR-LD/CD alone, and versus IR-LD/CD plus oral carbidopa at doses equivalent to those administered subcutaneously. In mice, continuous administration of carbidopa (0.5mg/24h) in addition to oral IR-LD/CD (1.2/0.3 mg BID) improved peripheral levodopa pharmacokinetics as well as brain dopamine concentrations, with no significant effect on brain levodopa levels. We also confirmed that carbidopa given at relatively high and constant rates of delivery does not inhibit levodopa decarboxylation to dopamine in the brain. In healthy human volunteers receiving oral IR-LD/CD (200/50mg BID), subcutaneous continuous administration of carbidopa (80mg/24h) increased the plasma levodopa t½, Cmax and AUC by 17.4[percnt], 40.5[percnt] and 22.3[percnt], respectively, and reduced the Tmax by 22.0[percnt], (all pu003c0.003 versus IR-LD/CD plus saline infusion).CONCLUSIONS: This series of studies demonstrates that maintaining basal plasma concentrations of carbidopa are essential for attaining maximum plasma concentrations of levodopa and that small continuous dosing of subcutaneous carbidopa has a positive effect on levodopa pharmacokinetics.Studies supported by Neuroderm. Disclosure: Dr. Yacobi-Zeevi has received personal compensation for activities with NeuroDerm as an employee. Dr. Zawoznik has received personal compensation for activities with Neuroderm as an employee. Dr. Weinstock has received personal compensation for activities with Neuroderm as an employee. Dr. Nemas has received personal compensation for activities with Neuroderm. Dr. Yossi Caraco has received research support from BioBlast Pharma and Ultragenyx Pharmaceutical. Dr. LeWitt has received personal compensation for activities with Acorda Pharmaceuticals. Dr. Oren has received personal compensation for activities with NeuroDerm as an employee. Dr. Shaltiel-Karyo holds stock and/or stock options in Neuroderm.