Immediate-release Carbidopa-levodopa Research Articles

IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease

Levodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations. To assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients with Parkinson disease who are experiencing motor fluctuations. RISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial. The study was conducted between November 6, 2018, and June 15, 2021, at 105 academic and clinical centers in the US and Europe. Patients with Parkinson disease taking a total daily dose of 400 mg or more of levodopa and experiencing an average of 2.5 hours or more daily off-time were included in the study. A total of 770 patients were screened, 140 were excluded (those taking controlled-release carbidopa-levodopa apart from a single daily bedtime dose, Rytary (Amneal Pharmaceuticals), additional carbidopa or benserazide, or catechol O-methyl transferase inhibitors or who had a history of psychosis within the past 10 years), and 630 were enrolled in the trial. Following open-label immediate-release carbidopa-levodopa dose adjustment (3 weeks) and conversion to IPX203 (4 weeks), patients were randomized in a 1:1 ratio to double-blind, double-dummy treatment with immediate-release carbidopa-levodopa or IPX203 for 13 weeks. The primary end point was mean change in daily good on-time (ie, on-time without troublesome dyskinesia) from baseline to the end of the double-blind treatment period. A total of 630 patients (mean [SD] age, 66.5 [8.95] years; 396 [62.9%] men) were enrolled, and 506 patients were randomly assigned to receive IPX203 (n = 256) or immediate-release carbidopa-levodopa (n = 250). The study met its primary end point, demonstrating statistically significant improvement in daily good on-time for IPX203 compared to immediate-release carbidopa-levodopa (least squares mean, 0.53 hours; 95% CI, 0.09-0.97; P = .02), with IPX203 dosed a mean 3 times per day vs 5 times per day for immediate-release carbidopa-levodopa. Good on-time per dose increased by 1.55 hours with IPX203 compared to immediate-release carbidopa-levodopa (95% CI, 1.37-1.73; P < .001). IPX203 was well tolerated. The most common adverse events in the double-blind phase (IPX203 vs immediate-release carbidopa-levodopa) were nausea (4.3% vs 0.8%) and anxiety (2.7% vs 0.0%). In this study, IPX203 provided more hours of good on-time per day than immediate-release carbidopa-levodopa, even as IPX203 was dosed less frequently. ClinicalTrials.gov Identifier: NCT03670953.

Long-term Safety and Efficacy of IPX203 in Parkinson’s Disease Patients with Motor Fluctuations: A 9-Month Open-label Extension Trial (S32.006)

Long-term Safety and Efficacy of IPX203 in Parkinson’s Disease Patients with Motor Fluctuations: A 9-Month Open-label Extension Trial (S32.006)

Oral Levodopa Formulation Does Not Affect Progression of Parkinson Disease.

Motor fluctuations develop in most patients treated with carbidopa/levodopa for Parkinson disease. The continuous dopamine stimulation hypothesis suggests that longer-acting forms of levodopa might improve outcomes, but this has been inadequately tested in humans. We undertook to determine if there is any difference in symptom progression rate among patients taking immediate-release carbidopa/levodopa (IR), controlled-release carbidopa/levodopa (CR), or carbidopa/levodopa/entacapone (CLE) using standard outcome measures in a naturalistic study. We evaluated Parkinson disease subjects prospectively followed for up to 48 months in the Parkinson's Disease Biomarker Project. Bayesian linear or generalized linear mixed-effects models were developed to determine if oral levodopa formulation influenced the rate of symptom progression as measured by 8 outcome measures. At baseline, the IR, CR, and CLE groups were similar except that the CR group had milder disease and was represented at only 1 site, and the CLE group had a longer disease duration. In the primary analysis, there was no difference in rate of symptom progression as measured by the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale Part II, Part IV, or total score. In the secondary exploratory analysis, there was no difference in progression rate as measured by change in levodopa equivalent daily dose, Montreal Cognitive Assessment, Parkinson's Disease Questionnaire mobility subscore, Schwab and England Activities of Daily Living Scale, or a global composite outcome. We found no difference in symptom progression rate in patients taking IR, CR, or CLE. This clinical observation supports pharmacokinetic studies demonstrating that none of these oral levodopa formulations achieve continuous dopamine stimulation.

Single-Dose Pharmacokinetics and Pharmacodynamics of IPX203 in Patients With Advanced Parkinson Disease: A Comparison With Immediate-Release Carbidopa-Levodopa and With Extended-Release Carbidopa-Levodopa Capsules.

ObjectiveIPX203 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).MethodsThis 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.ResultsLevodopa 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.ConclusionsCompared 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.

Dosing Patterns during Conversion to IPX066, Extended-Release Carbidopa-Levodopa (ER CD-LD), in Parkinson's Disease with Motor Fluctuations.

Background IPX066 is an extended-release (ER) oral formulation of carbidopa-levodopa (CD-LD). Following an initial peak at about one hour, plasma LD concentrations are maintained for about 4-5 hours. Objective To present dosing factors that may affect the successful conversion to ER CD-LD from other LD formulations. Methods Two-phase 3 studies of ER CD-LD vs. immediate-release (IR) CD-LD (ADVANCE-PD) and vs. CD-LD + entacapone (CLE; ASCEND-PD) in subjects with advanced PD included a 6-week, open-label conversion to ER CD-LD prior to treatment randomization. The “converted” daily LD dose ratio and dose frequency for ER CD-LD were compared to the prior LD treatment regimens at study entry. Results The average daily LD dose ratio at the end of dose conversion to ER CD-LD was approximately 2.1 for IR CD-LD and 2.8 for CLE. The final dose ratios tended to be slightly higher for participants taking lower LD doses at study entry but independent of dose frequency. ER CD-LD dose frequency increased with increasing LD dose and dose frequency at study entry. Participants on higher baseline LD doses ≥800 mg and dose frequencies ≥6 tended to have higher rates of discontinuation during conversion to ER CD-LD. Conclusions Converting participants from other LD formulations to ER CD-LD is based on their current LD regimen. For the most common daily doses (≤1250 mg) and dose frequencies (<7) of LD, final mean dose ratios were within tight ranges of 2.1 to 2.4 for IR CD-LD (ADVANCE-PD) and 2.4 to 2.8 for CLE (ASCEND-PD) and were generally independent of the LD dosing frequency at study entry. These trials are registered with NCT00974974, NCT01130493.

Duration of “on” periods after treatment with extended-release vs. immediate-release carbidopa-levodopa in patients with advanced Parkinson’s disease (P1.020)

Duration of “on” periods after treatment with extended-release vs. immediate-release carbidopa-levodopa in patients with advanced Parkinson’s disease (P1.020)

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

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.

Physicians' experience with RYTARY (carbidopa and levodopa) extended-release capsules in patients who have Parkinson disease.

A discussion between Dr. Dee Silver and Dr. Richard Trosch provides insight and advice for physicians considering a switch from immediate-release carbidopa-levodopa (IR CD-LD) to RYTARY as a treatment for patients with Parkinson disease (PD). The dialogue describes how they identify patients with PD who may and may not be successful switching to RYTARY, how they approach the conversion process and patient compliance, and how they address some side effects that may occur after patients begin taking RYTARY. The clinicians also discuss their experiences with how long it takes to establish a stable regimen as well as provide general advice regarding conversion from treatment with IR CD-LD to RYTARY.

Conversion to IPX066 from Standard Levodopa Formulations in Advanced Parkinson's Disease: Experience in Clinical Trials.

Background:Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours.Objective:To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting.Methods:Patients had ≥2.5 hours/day of “off” time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided.Results:Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily “off” time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE.Conclusions:Among PD patients with substantial “off” time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

New levodopa therapeutic strategies

During its almost half-century of use for treating Parkinson's disease, levodopa therapy has permitted most patients to reverse much of this disorder's symptomatology. However, the full range of its therapeutic properties is not completely understood, as levodopa is showing itself to be more than just a metabolic intermediate for dopamine synthesis. Improving the constancy of drug delivery is the next frontier for enhancing therapeutic options with levodopa. Because conventional immediate-release carbidopa-levodopa tablets yield such variable pharmacokinetic profiles (as do other marketed products attempting to extend levodopa effect), improved formulations are greatly needed by patients experiencing motor fluctuations. Products under development or recently released in the U.S. include intestinal infusion, sustained-release microtablets, gastric-retentive formulations, a levodopa pro-drug, and methods for delivery of the drug by inhalation or subcutaneous infusion.

PND31 - Cost-Effectiveness Analysis of Ipx066 In advanced Parkinson’s Disease

Parkinson’s disease (PD) is a progressive disease associated with substantial economic and societal burden. Immediate-release (IR) carbidopa-levodopa (CD-LD) is the gold standard in treatment for advanced PD patients. However, effectiveness of IR CD-LD diminishes with long-term treatment and is associated with increased “off” time (re-emergence of PD symptoms) and the advent of motor complications. CD-LD plus entacapone (CL+E) has produced some clinical improvement over IR CD-LD alone. IPX066 is an extended-release oral formulation of CD-LD designed to address some of the limitations of IR CD-LD by rapidly attaining and maintaining therapeutic LD concentrations for a prolonged duration. The aim of the study was to evaluate the comparative cost-effectiveness of IPX066 against CL+E. A Markov model was developed comparing IPX066 with branded and generic CL+E in the US market. Health states included ≤ 25% “off” time, > 25% “off” time, and dead. The model simulated a hypothetical patient’s progression over a 5-year period through these health states, with a 6-month Markov cycle length. Outcomes evaluated were total direct costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER). Dosing and efficacy data from a Phase 3 study comparing IPX066 and CL+E, average wholesale acquisition drug costs (RedBook), and published literature were utilized for this evaluation. Non-2014 costs were inflated to reflect the 2014 value using the medical component of the Consumer Price Index. The discount rate employed was 3%. IPX066 was dominant over both branded and generic CL+E therapies, with ICERs of (-$166,044) and (-$75,920), respectively. On average, patients who received IPX066 experienced a 5.1% increase in QALYs (2.90) compared with patients who did not receive IPX066 (2.76). IPX066 dominated the other two therapies throughout multiple sensitivity analyses, driven largely by improved effectiveness of IPX066. IPX066 is likely to be a cost-effective therapy in patients with advanced PD.

PND8 - Patient Self-Assessments in advanced Parkinson’s Disease within updrs and “off” time Subgroups: Comparison of Ipx066 With Immediate-Release Carbidopa-Levodopa

PND8 - Patient Self-Assessments in advanced Parkinson’s Disease within updrs and “off” time Subgroups: Comparison of Ipx066 With Immediate-Release Carbidopa-Levodopa

Double‐blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease

The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279-carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate-release carbidopa-levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high-capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279-carbidopa sustained-release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure. Patients with motor fluctuations who required carbidopa-levodopa four or five times daily were optimized for 2 weeks each on carbidopa-levodopa four or five times daily and XP21279-carbidopa three times daily in a randomized sequence. Next, they received each optimized treatment for 2 weeks in a double-blind/double-dummy, randomized sequence. The primary outcome measure was change from baseline in daily off time at the end of each double-blind treatment period. All patients at 2 sites underwent pharmacokinetic analyses. Twenty-eight of 35 enrolled patients completed both double-blind treatments. The mean total daily off time was reduced from baseline by a mean (± standard error) of 2.7 hours (± 0.48 hours) for immediate-release carbidopa-levodopa and 3.0 hours (± 0.57 hours) for XP21279-carbidopa (P = 0.49). Among 11 patients who completed pharmacokinetic sampling on each optimized treatment, the percentage deviation from the mean levodopa concentration was lower (P < 0.05) for XP21279-carbidopa than carbidopa-levodopa. Both treatments had a similar incidence of new or worsening dyskinesias. XP21279-carbidopa administered three times daily produced a reduction in off time similar to that of carbidopa-levodopa administered four or five times daily, and the difference was not statistically significant. XP21279-carbidopa significantly reduced variability in levodopa concentrations compared with carbidopa-levodopa.

Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial

IPX066 is an oral, extended-release, capsule formulation of carbidopa-levodopa. We aimed to assess this extended-release formulation versus immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations. We did a phase 3, randomised, double-blind, double-dummy study at 68 academic and clinical centres in North America and Europe. Patients with Parkinson's disease who had at least 2·5 h per day of off-time underwent 3 weeks of open-label immediate-release carbidopa-levodopa dose adjustment followed by 6 weeks of open-label extended-release carbidopa-levodopa dose conversion. These patients were then randomly allocated (1:1), by use of an interactive web-response system, to 13 weeks of double-blind treatment with extended-release or immediate-release carbidopa-levodopa plus matched placebos. The primary efficacy measure was off-time as a percentage of waking hours in all patients randomly allocated to treatment groups, adjusted for baseline value. This study is registered with ClinicalTrials.gov, number NCT00974974. Between Sept 29, 2009, and Aug 16, 2010, we enrolled 471 participants, of whom 393 (83%) were randomly allocated in the double-blind maintenance period and were included in the main efficacy analyses. As a percentage of waking hours, 201 patients treated double-blind with extended-release carbidopa-levodopa (mean 3·6 doses per day [SD 0·7]) had greater reductions in off-time than did 192 patients treated double-blind with immediate-release carbidopa-levodopa (mean 5·0 doses per day [1·2]). Covariate-adjusted end-of-study means were 23·82% (SD 14·91) for extended-release carbidopa-levodopa and 29·79% (15·81) for immediate-release carbidopa-levodopa (mean difference -5·97, 95% CI -9·05 to -2·89; p<0·0001). Extended-release carbidopa-levodopa reduced daily off-time by, on average, an extra -1·17 h (95% CI -1·69 to -0·66; p<0·0001) compared with immediate-release carbidopa-levodopa. During dose conversion with extended-release carbidopa-levodopa, 23 (5%) of 450 patients withdrew because of adverse events and 13 (3%) withdrew because of a lack of efficacy. In the maintenance period, the most common adverse events were insomnia (seven [3%] of 201 patients allocated extended-release carbidopa-levodopa vs two [1%] of 192 patients allocated immediate-release carbidopa-levodopa), nausea (six [3%] vs three [2%]), and falls (six [3%] vs four [2%]). Extended-release carbidopa-levodopa might be a useful treatment for patients with Parkinson's disease who have motor fluctuations, with potential benefits including decreased off-time and reduced levodopa dosing frequency. Impax Laboratories.

Population Pharmacodynamics of IPX066: An Oral Extended‐Release Capsule Formulation of Carbidopa–Levodopa, and Immediate‐Release Carbidopa–Levodopa in Patients With Advanced Parkinson's Disease

A pharmacodynamic model is presented to describe the motor effects (tapping rate, Unified Parkinson’s Disease Rating Scale [UPDRS] Part III, and investigator-rating of ON/OFF, including dyskinesia) of levodopa (LD) in patients with advanced idiopathic Parkinson’s disease (PD) treated with immediate-release (IR) carbidopa–levodopa (CD–LD) or an extended-release (ER) formulation of CD–LD (IPX066). Twenty-seven patients participated in this open-label, randomized, single-and multiple-dose, crossover study. The pharmacodynamic models included a biophase effect site with a sigmoid Emax transduction for tapping and UPDRS and an ordered categorical model for dyskinesia. The pharmacodynamics of LD was characterized by a conduction function with a half-life of 0.59 hours for tapping rate, and 0.4 hours for UPDRS Part III and dyskinesia. The LD concentration for half-maximal effect was 1530 ng/mL, 810 ng/mL, and 600 ng/mL for tapping rate, UPDRS Part III, and dyskinesia, respectively. The sigmoidicity of the transduction was 1.53, 2.5, and 2.1 for tapping rate, UPDRS Part III, and dyskinesia, respectively. External validation of the pharmacodynamic model using tapping rate indicated good performance of the model.

Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson's disease

The objective of the study was to compare the pharmacokinetics, motor effects, and safety of IPX066, a novel extended-release formulation of carbidopa-levodopa, with an immediate-release carbidopa-levodopa formulation in advanced Parkinson's disease. We performed an open-label crossover study in 27 subjects with advanced Parkinson's disease experiencing motor fluctuations on levodopa therapy. Subjects were randomized 1:1 to 8 days' treatment with either immediate-release carbidopa-levodopa followed by IPX066 or IPX066 followed by immediate-release carbidopa-levodopa. Pharmacokinetic and motor assessments were undertaken on day 1 for 8 hours (following a single dose) and on day 8 for 12 hours (during multiple-dose administration). Following a single dose of IPX066 or immediate-release carbidopa-levodopa, plasma levodopa concentrations increased at a similarly rapid rate and were sustained above 50% of peak concentration for 4 hours with IPX066 versus 1.4 hours with immediate-release carbidopa-levodopa (P < .0001). Multiple-dose data showed IPX066 substantially reduced variability in plasma levodopa concentrations despite a lower dosing frequency (mean, 3.5 vs 5.4 administrations per day). In addition, total levodopa exposure during IPX066 treatment was approximately 87% higher, whereas the increase in levodopa C(max) was approximately 30% compared with immediate-release carbidopa-levodopa. Both products were well tolerated. IPX066 provided more sustained plasma levodopa concentrations than immediate-release carbidopa-levodopa. Larger, longer-term, well-controlled studies should be conducted to provide rigorous assessment of the clinical effects of IPX066.

Initiating therapy for Parkinson's disease.

Accurate diagnosis and individualized assessment of the risks and benefits of available antiparkinsonian medications should guide initiation of treatment for patients with early Parkinson's disease (PD). In general, the goals of treatment for younger patients (less than age 60 years) are control of impairing symptoms, sparing of levodopa to minimize long-term complications, and consideration of neuroprotection. The primary initial medication choices for patients under age 50 years include selegiline, amantadine, and anticholinergic agents. Patients in their fifties may require a dopamine agonist in addition to or instead of selegiline to achieve adequate symptom control. If the desired response is still not achieved, sustained-release carbidopa-levodopa should be added, followed by adjunctive amantadine or anticholinergic therapy. For older patients (60 years and over), improvement of functional impairment is the primary goal. For these patients, a special concern is to avoid inducing or exacerbating cognitive impairment. Sustained-release carbidopa-levodopa is considered first-line treatment for these patients. Inadequate response can be handled by a trial of immediate-release carbidopa-levodopa and then addition of a dopamine agonist when maximum levodopa doses are reached. Anticholinergic agents, amantadine, and selegiline should be avoided because of their CNS effects.