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.

Objectives: IPX203 is an investigational oral extended-release capsule formulation of carbidopa and levodopa. The pharmacodynamics and efficacy of IPX203 were compared with immediate-release carbidopa-levodopa (IR CD-LD) in this open-label, rater-blinded, multicenter, crossover study in patients with advanced Parkinson disease (PD). Methods: Twenty-eight patients were randomized to 2 weeks of treatment with IR CD-LD followed by IPX203 or IPX203 followed by IR CD-LD. Pharmacokinetic and motor assessments were conducted on days 1 and 15 of each treatment period. Efficacy was assessed using a 3-day PD diary. Pharmacodynamics were assessed by rater-blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III and Investigator Assessment of Subject's Motor State. Results: After a single dose, levodopa concentrations were sustained above 50% of peak concentration for 4.6 hours with IPX203 versus 1.5 hours with IR CD-LD (P < 0.0001). Based on the PD diary, patients experienced significantly less Off time with IPX203 as a percentage of waking hours than IR CD-LD (mean 19.3% vs 33.5%, respectively; P < 0.0001), translating into 2.3 hours less Off time than IR CD-LD with most of this improvement (1.9 hours) being Good On time. There was no significant difference in the amount of On time with troublesome dyskinesia between treatments. Pharmacodynamic assessments demonstrated similar outcomes in favor of IPX203 on day 1 and a significant predose benefit on motor examination after multiple dosing. Conclusions: IPX203 demonstrated a sustained effect to reduce Off time and improve Good On time in patients with PD and motor fluctuations. Both treatments were well tolerated.

Objective IPX203 is an investigational oral extended-release capsule formulation of carbidopa-levodopa (CD-LD). The aim of this study was to characterize the single-dose pharmacodynamics, pharmacokinetics, and safety of IPX203 in subjects with advanced Parkinson disease compared with immediate-release (IR) CD-LD and extended-release CD-LD (Rytary). Methods This was a randomized, open-label, rater-blinded, multicenter, single-dose crossover study. Blinded clinicians assessed subject's motor state and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores for up to 10 hours postdose. Duration of effect was determined using improvement thresholds in the MDS-UPDRS part III. Results Levodopa concentrations increased rapidly and similarly across all 3 treatments and were sustained for a longer duration after IPX203 dosing. All treatments exhibited a rapid onset of pharmacodynamic effect, whereas IPX203 had a significantly longer duration of effect based on MDS-UPDRS part III scores compared with IR CD-LD ( P < 0.0001) and Rytary ( P ≤ 0.0290). IPX203 had a 2.7-hour advantage over IR CD-LD ( P < 0.0001) and a 0.9-hour advantage over Rytary in “off” time ( P = 0.023) and in “good on” time (2.6 hours more than IR CD-LD, P < 0.0001; 0.9 hours more than Rytary, P = 0.0259) as measured by the Investigator Assessment of Subject's Motor State. Subjects were 77% more likely to require rescue following IR CD-LD treatment compared with IPX203 (hazard ratio, 0.23; P < 0.0001). More subjects reported treatment-emergent adverse effects during IR CD-LD (28.0%) and IPX203 (19.2%) than during Rytary (8.0%) treatment. Conclusions Compared with Rytary and IR CD-LD, IPX203 had a longer pharmacodynamic effect consistent with LD pharmacokinetics for the 3 treatments. The safety and tolerability of IPX203 were similar to those of IR CD-LD and Rytary.

We have previously shown that sinusoidal reduced glutathione (GSH) efflux declines during development because of a declining maximum transport rate [Am. J. Physiol. 261 (Gastrointest. Liver Physiol. 24): G648-G656, 1991]. Because rat liver serves as the principal source of plasma GSH, we studied the response of plasma GSH to this declining inflow from liver. In immature (28- to 42-day) and mature (90- to 151-day) rats we injected tracer boluses of [35S]GSH intravenously and collected arterial samples over a 0.75- to 8-min interval while plasma GSH pool remained at steady state. Concentrations and radioactivities of GSH, oxidized glutathione (GSSG), cysteine (CYSH), cystine (CYSS), and cysteine-glutathione disulfides (CYSSG) and the radio-activities of proteins were measured in plasma. Our results show the following changes in plasma concentrations (microM): decreases in unbound (free) GSH (26.0 +/- 2.1 to 12.4 +/- 0.98; P < 0.001), total unbound GSH equivalents GSH + 2GSSG (29.1 +/- 2.1 to 15.3 +/- 1.2; P < 0.001), total reducible (unbound + bound) GSH (39.3 +/- 2.2 to 28.9 +/- 2.6; P < 0.025), and free CYSH (57.6 +/- 8.5 to 29.9 +/- 4.0; P < 0.05); no changes in GSSG (1.57 +/- 0.27 vs. 1.47 +/- 0.41), CYSS (36.7 +/- 12 vs. 43.4 +/- 17), and total unbound CYSH equivalents CYSH + 2CYSS (131 +/- 15 vs. 117 +/- 18); increases in total reducible (unbound + bound) CYSH (158 +/- 8.1 to 203 +/- 24; P < 0.05) and CYSSG (1.80 +/- 0.42 to 4.94 +/- 1.4 in microM GSH equivalents; P < 0.05). A concurrent decline occurred in irreversible disposal rate (IDR) of plasma GSH from 38.5 +/- 4.9 to 16.4 +/- 1.4 nmol.min-1.ml-1 (P < 0.001) as determined by compartmental analysis of tracer data. This 57% decrease in IDR parallels a decrease of 53% in the inflow of GSH estimated by perfused livers (17.0 to 8.0 nmol.min-1.ml plasma-1). However, perfused liver estimates do not match > 44-49% of plasma IDR. Thus perfused liver appears to underestimate the true rate of sinusoidal GSH efflux taking place in vivo. Some earlier arteriovenous data and our present portal vein-to-hepatic vein difference measurements appear to corroborate this view.

Sinusoidal transport of reduced glutathione (GSH) is a carrier-mediated process. Perfused liver and isolated hepatocyte models revealed a low-affinity transporter with sigmoidal kinetics (K(m) approximately 3.2-12 mM), while studies with sinusoidal membrane vesicles (SMV) revealed a high-affinity unit (K(m) approximately 0.34 mM) besides a low-affinity one (K(m) approximately 3.5-7 mM). However, in SMV, both the high- and low-affinity units manifested Michaelis-Menten kinetics of GSH transport. We have now established the sigmoidicity of the low-affinity unit (K(m) approximately 9) in SMV, consistent with other models, while the high-affinity unit has been retained intact with Michaelis-Menten kinetics (K(m) approximately 0.13 mM). We capitalized on the negligible cross-contributions of the two units to total transport at the low and high ends of GSH concentrations and investigated their characteristics separately, using radiation inactivation, as we did in canalicular GSH transport (Am. J. Physiol. 274 (1998) G923-G930). We studied the functional sizes of the proteins that mediate high- and low-affinity GSH transport in SMV by inactivation of transport at low (trace and 0.02 mM) and high (25 and 50 mM) concentrations of GSH. The low-affinity unit in SMV was much less affected by radiation than in canalicular membrane vesicles (CMV). The target size of the low-affinity sinusoidal GSH transporter appeared to be considerably smaller than both the canalicular low- and high-affinity transporters. The high-affinity unit in SMV was markedly inactivated upon irradiation, revealing a single protein structure with a functional size of approximately 70 kDa. This size is indistinguishable from that of the high-affinity GSH transporter in CMV reported earlier.