Pharmacokinetics of Rytary®, An Extended-Release Capsule Formulation of Carbidopa-Levodopa

Abstract

Parkinson's disease (PD) is a chronic progressive neurological disorder characterized by resting tremor, rigidity, bradykinesia, gait disturbance, and postural instability. Levodopa, the precursor to dopamine, coadministered with carbidopa or benserazide, aromatic amino acid decarboxylase inhibitors, is the most effective and widely used therapeutic agent in the treatment of PD. With continued levodopa treatment, a majority of patients develop motor complications such as dyskinesia and motor 'on-off' fluctuations, which are, in part, related to the fluctuations in plasma concentrations of levodopa. A new extended-release (ER) carbidopa-levodopa capsule product (also referred to as IPX066) was developed and approved in the US as Rytary^® and in the EU as Numient^®. The capsule formulation is designed to provide an initial rapid absorption of levodopa comparable to immediate-release (IR) carbidopa-levodopa, and to subsequently provide stable levodopa concentrations with reduced peak-to-trough excursions in plasma concentrations in order to reduce motor fluctuations associated with pulsatile stimulation of dopamine receptors and to minimize dyskinesia. Phase III studies of this ER carbidopa-levodopa capsule formulation in patients with PD have shown a significant reduction in 'off' time compared with IR carbidopa-levodopa and carbidopa-levodopa-entacapone. We present a review of the clinical pharmacokinetics and pharmacodynamics of this ER product of carbidopa-levodopa in healthy subjects and in patients with PD.

Keywords: Carbidopa; Entacapone; Levodopa; Levodopa Dose; Sinemet.

Fig. 1

Pharmacokinetic profile for immediate-release CD-LD, individual extended-release components and intact capsules of Rytary^®. Data presented are LD concentrations from different studies that evaluated the performance of individual components and the pharmacokinetics of extended-release CD-LD capsules. CD carbidopa, LD levodopa

Fig. 2

Single-dose pharmacokinetics of IR and ER CD-LD in patients with Parkinson’s disease. ER extended-release, IR immediate-release, CD carbidopa, LD levodopa

Fig. 3

Multiple-dose pharmacokinetics of IR and ER CD-LD in patients with Parkinson’s disease. Arrows represent oral dose administrations every 3 or 6 h. ER extended-release, IR immediate-release, CD carbidopa, LD levodopa, Qxh every x hours

Fig. 4

Relationship between LD dose and LD pharmacokinetics in patients with Parkinson’s disease. C _max maximum observed plasma concentration, AUC _∞ area under the concentration–time curve extrapolated to infinity, LD levodopa