Dataset Information

Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease.

ABSTRACT: Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double-blind, parallel-group, dose-ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn-Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED50 was 450 mg levodopa. Equilibration half-life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half-life. The quantitative model allowed description of the entire time course of response to clinical trial intervention.

SUBMITTER: Mao ZL

PROVIDER: S-EPMC5066683 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease.

Mao Zhongping Lily ZL Modi Nishit B NB

Journal of clinical pharmacology 20160118 8

Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) pa ...[more]

PMID: 26632091

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Project description:BackgroundThe introduction of carbidopa-levodopa extended-release (CD-LD ER) capsules (Rytary®) did not go as smoothly as expected, largely due to difficulty around dose conversion from available immediate-release (IR) levodopa (LD) formulations. The dose conversion table in the CD-LD ER prescribing information was similar to the table used in the pivotal clinical trial and is considered by many prescribing HCPs to be less than optimal. By the end of the dose conversion period in that trial, dosing in 76% of subjects was adjusted for symptom control; roughly 60% of patients required a higher dose and about half required more frequent administration than the recommended TID dosing.ObjectiveThe primary objective of our nationwide (US) survey was to determine the dose conversion strategy most commonly employed by CD-LD ER frequent prescribers. The survey also aimed to explore additional features regarding CD-LD ER use in clinical practice.MethodsA survey consisting of 21 multiple-choice questions was developed and administered to experts in the use of CD-LD ER, based on prescription volume.ResultsOf the 394 HCPs who were invited to participate, 90 (23%) HCPs completed the survey. All respondents were aware of the dose conversion table; the largest group did not find the table to be helpful and did not use it to convert patients to CD-LD ER. The most common strategy in calculating the CD-LD ER dose was based on the total daily LD IR dose, with the majority of that group initiating dose conversion by doubling the total daily LD dose from CD-LD IR and administering CD-LD ER one less time per day.ConclusionOverall, most survey respondents agreed that a good starting point for CD-LD ER conversion could be doubling the daily LD IR dose and administering it one time less frequently. Moreover, rapid patient follow-up after initial dose conversion to allow for further dose adjustments plays a critical role in achieving success. Gaining experience over time is important for satisfactory conversion.

Project description:ImportanceMedical treatment of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) is an unmet need.ObjectiveTo evaluate the efficacy and safety of ADS-5102 (amantadine) extended-release 274-mg capsules for treatment of LID in patients with PD.Design, setting, and participantsA randomized, double-blind, placebo-controlled clinical trial was conducted between May 7, 2014, and July 22, 2015, at 44 North American sites among patients with PD treated with levodopa who experienced at least 1 hour of troublesome dyskinesia per day with at least mild functional impact.InterventionsPatients were randomized to receive placebo or 274 mg of ADS-5102 administered orally at bedtime for up to 25 weeks.Main outcomes and measuresThe primary efficacy analysis was the change from baseline to week 12 in the Unified Dyskinesia Rating Scale total score for ADS-5102 vs placebo in the modified intent-to-treat population. OFF time (amount of time the PD medication is not controlling motor symptoms) was a key secondary end point. Safety analyses included all patients who received the study drug (ADS-5102 or placebo).ResultsA total of 189 patients were screened, and 126 were randomized; the modified intent-to-treat population included 121 patients (51 women and 70 men; mean [SD] age, 64.7 [9.1] years). At week 12, the least-squares mean (SE) change in the Unified Dyskinesia Rating Scale score was -15.9 (1.6) for ADS-5102 (n = 63) and -8.0 (1.6) for placebo (n = 58) (treatment difference, -7.9; 95% CI, -12.5 to -3.3; P < .001). OFF time decreased by a mean (SE) of 0.6 (0.3) hours for ADS-5102 and increased by 0.3 (0.3) hours for placebo (treatment difference, -0.9 hours; 95% CI, -1.6 to -0.2; P = .02). Common adverse events for ADS-5102 vs placebo included visual hallucinations (15 [23.8%] vs 1 [1.7%]), peripheral edema (15 [23.8%] vs 0), and dizziness (14 [22.2%] vs 0). Adverse events led to treatment discontinuation for 13 patients receiving ADS-5102 (20.6%) vs 4 patients receiving placebo (6.9%).Conclusions and relevanceADS-5102, 274 mg at bedtime, may be an effective treatment for LID. An additional benefit is reduced OFF time. To our knowledge, this is the first demonstration of an oral treatment reducing both LID and OFF time in patients with PD with dyskinesia.Trial registrationclinicaltrials.gov Identifier: NCT02136914.

Project description:Background and objectiveIPX066 is a multiparticulate extended-release formulation of carbidopa-levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson's disease (PD).MethodsParticipants were enrolled from two phase III IPX066 studies and one open-label phase II study. Early PD patients were titrated to an appropriate dosing regimen while advanced patients started with regimens established in the antecedent studies. Adjustment was allowed throughout the extension. Clinical utility measures included the Unified Parkinson's Disease Rating Scale (UPDRS) and Patient Global Impression (PGI) ratings.ResultsAmong 268 early PD patients, 53.4 % reported adverse events (AEs) and 1.1 % (three patients) discontinued due to AEs; the most frequent AEs were nausea (5.6 %) and insomnia (5.6 %). Among 349 advanced patients, 60.2 % reported AEs and 3.7 % (13 patients) discontinued due to AEs; the most frequent AEs were dyskinesia (6.9 %) and fall (6.6 %). At month 9 (or early termination), 78.3 % of early patients were taking IPX066 three times daily (median: 720 mg/day) and 87.7 % of advanced patients were taking IPX066 three or four times daily (median: 1450 mg/day). Adjusting for 70 % bioavailability relative to immediate-release (IR) carbidopa-levodopa, the median dosages correspond to ~500 and ~1015 mg/day of IR levodopa in early and advanced PD, respectively. Based on the plasma profiles previously observed in PD patients, the IPX066 regimens in the extension can be estimated to provide a levodopa Cmax (maximum plasma drug concentration) similar to or lower than that provided by IR regimens during the antecedent trials. UPDRS and PGI findings showed sustained treatment effects throughout the extension.ConclusionDuring 9 months of extended use, IPX066 exhibited a safety/tolerability profile consistent with dopaminergic PD therapy.

Dataset Information

Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease.

Publications

Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease.

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