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.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0511-y) contains supplementary material, which is available to authorized users.

Study on the Role of the Inclusion Complexes with 2-Hydroxypropyl-β-cyclodextrin for Oral Administration of Amiodarone

“…A new modified-release formulation not only alters the release of a drug but also influence the release and dissolution rate in the different digestive sites because of different rates of absorption, leading to multiple peaking phenomena [73][74][75].…”

Extended-release oral capsule of carbidopa–levodopa in Parkinson disease

“…The addition of carbidopa to levodopa partially suppresses the peripheral metabolism of levodopa, reducing side effects such as nausea (Sinemet = Sine-Emesis = Without Vomiting), and maximizing levodopa transport into the central nervous system where its therapeutic potential can be realized. 23 Active amino acid transporters mediate the small bowel intestinal absorption and blood brain barrier (BBB) penetration of levodopa into the central nervous system. Iterations of CD/LD, including CR CD/LD and CD/LD/E, involved modifications with a goal towards increased duration of effect and minimizing the potentiation of motor fluctuations by providing more stable levodopa concentrations.…”

“…Each capsule contains four components: IR, ER component 1, and ER component 2 (all of which contain both LD and CD as active ingredients), plus a functional excipient component, which contains tartaric acid as an acidifying agent designed to facilitate the absorption of LD. 23 The combination of components creates an initial increase in plasma concentration (with the IR component) and provides a more sustained concentration (with the two ER components). 23 Theoretically, the acidifying agent facilitates the maximal utilization of LD through more rapid absorption of LD prior to the drug travelling beyond the proximal expanse of the small intestine (where the bulk of LD absorption takes place) and by improving the absorption of LD beyond the duodenum and jejunum.…”

“… 23 The combination of components creates an initial increase in plasma concentration (with the IR component) and provides a more sustained concentration (with the two ER components). 23 Theoretically, the acidifying agent facilitates the maximal utilization of LD through more rapid absorption of LD prior to the drug travelling beyond the proximal expanse of the small intestine (where the bulk of LD absorption takes place) and by improving the absorption of LD beyond the duodenum and jejunum. The plasma concentration of LD over 12 h after ingesting the IR and both ER components individually as well as after ingesting a complete ER CD/LD capsule is shown in Figure 1 .…”

“…The plasma concentration of LD over 12 h after ingesting the IR and both ER components individually as well as after ingesting a complete ER CD/LD capsule is shown in Figure 1 . 23 The pharmacokinetic profiles of each individual component and of a complete ER CD/LD capsule seen in the figure correspond to a single dose of 390 mg (two 195 mg capsules).…”