-
Movement Disorders : Official Journal... Nov 2022Inhibiting catechol-O-methyltransferase extends the plasma half-life of levodopa, potentially allowing physicians to optimize the levodopa regimen in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Inhibiting catechol-O-methyltransferase extends the plasma half-life of levodopa, potentially allowing physicians to optimize the levodopa regimen in patients with Parkinson's disease (PD) experiencing motor fluctuations.
OBJECTIVES
To evaluate the effects of once-daily opicapone on levodopa plasma pharmacokinetics and motor response when added to two different levodopa dosing regimens.
METHODS
A total of 24 patients with PD and motor fluctuations were enrolled in an exploratory, open-label, modified cross-over trial. Participants first received levodopa/carbidopa 500/125 mg (five intakes) for 2 weeks and were then randomly assigned (1:1) to levodopa/carbidopa 400/100 mg given over either four or five daily intakes plus opicapone 50 mg for an additional 2 weeks. Levodopa 12-hour pharmacokinetics was the primary outcome (ie, excluding the effect of last/evening levodopa/carbidopa intake), with motor complications evaluated as secondary outcomes.
RESULTS
Over 12-hour pharmacokinetics and compared with five-intake levodopa/carbidopa 500/125 mg without opicapone, maximal levodopa concentrations were similar or nonsignificantly higher on both levodopa/carbidopa 400/100 mg regimens plus opicapone. Despite a 100 mg lower total levodopa/carbidopa daily dose, adding opicapone 50 mg at least doubled the levodopa plasma half-life and minimal concentrations, with a significant ≈30% increase in total exposure. The levodopa fluctuation index was only significantly lower for the five intakes plus opicapone regimen (difference of -71.8%; P < 0.0001). Modifications to levodopa pharmacokinetics were associated with decreased off time and increased on time.
CONCLUSIONS
Combining opicapone 50 mg with a 100 mg lower daily dose of levodopa provides higher levodopa bioavailability with avoidance of trough levels. Despite the lower levodopa dose, modifying the levodopa pharmacokinetic profile with opicapone was associated with decreased off time and increased on time. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Levodopa; Parkinson Disease; Cross-Over Studies
PubMed: 36054562
DOI: 10.1002/mds.29193 -
Journal of Parkinson's Disease 2021ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson's disease (PD) experiencing motor... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson's disease (PD) experiencing motor fluctuationsObjective:Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD.
METHODS
This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour 'waking-day' infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). Supplemental oral doses of levodopa were permitted for patients in both groups if required. In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours).
RESULTS
A total of 38 patients were randomized and 33 (87%) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[- 3.3, - 0.7] hours (p = 0.003). ON time with no/mild dyskinesia (no troublesome dyskinesia) was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p < 0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[- 1.8, - 0.5] hours (p≤0.001). Reduction in OFF time was larger in the 24-hour group (- 2.8[- 4.6, - 0.9] hours; p = 0.004) than in the 14-hour group (- 1.3[- 3.1, 0.5] hours; p = 0.16). Complete resolution of OFF time was observed in 42% (n = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event.
CONCLUSION
This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy.
Topics: Aged; Antiparkinson Agents; Carbidopa; Drug Combinations; Dyskinesia, Drug-Induced; Feasibility Studies; Female; Humans; Infusions, Parenteral; Levodopa; Male; Middle Aged; Outcome Assessment, Health Care; Parkinson Disease; Severity of Illness Index; Single-Blind Method
PubMed: 33164945
DOI: 10.3233/JPD-202285 -
Journal of Parkinson's Disease 2021Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson's disease (aPD).
OBJECTIVE
The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients.
METHODS
This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study.
RESULTS
LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups.
CONCLUSION
Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.
Topics: Adult; Antiparkinson Agents; Carbidopa; Dopamine Agonists; Drug Combinations; Female; Humans; Infusions, Subcutaneous; Levodopa; Male; Parkinson Disease; Single-Blind Method
PubMed: 34366380
DOI: 10.3233/JPD-212813 -
Current Medical Research and Opinion Dec 2018Lack of a global consensus on the definition of advanced Parkinson's disease (APD) and considerations for timing of device-aided therapies may result in heterogeneity in...
Developing consensus among movement disorder specialists on clinical indicators for identification and management of advanced Parkinson's disease: a multi-country Delphi-panel approach.
BACKGROUND
Lack of a global consensus on the definition of advanced Parkinson's disease (APD) and considerations for timing of device-aided therapies may result in heterogeneity in care.
OBJECTIVES
To reach consensus among movement disorder specialists regarding key patient characteristics indicating transition to APD and guiding appropriate use of device-aided therapies in the management of PD symptoms.
METHODS
A Delphi-panel approach was utilized to synthesize opinions of movement disorder specialists and build consensus.
RESULTS
A panel was comprised of movement disorder specialists from 10 European countries with extensive experience of treating PD patients (mean =24.8 ± 7.2 years). Consensus on indicators of suspected APD and eligibility for device-aided therapies were based on motor symptoms, non-motor symptoms, and functional impairments. Key indicators of APD included: (i) motor-moderate troublesome motor fluctuations, ≥1 h of troublesome dyskinesia/day, ≥2 h "off" symptoms/day, and ≥5-times oral levodopa doses/day; (ii) non-motor-mild dementia, and non-transitory troublesome hallucinations; (iii) functional impairment-repeated falls despite optimal treatment, and difficulty with activities of daily living. Patients with good levodopa response, good cognition, and <70 years of age were deemed as good candidates for all three device-aided therapies. Patients with troublesome dyskinesia were considered good candidates for both levodopa-carbidopa intestinal gel and Deep Brain Stimulation (DBS). PD patients with levodopa-resistant tremor were considered good candidates for DBS.
CONCLUSION
Identifying patients progressing to APD and suitable for device-aided therapies will enable general neurologists to assess the need for referral to movement disorder specialists and improve the quality of care and patient outcomes.
Topics: Activities of Daily Living; Adolescent; Adult; Aged; Antiparkinson Agents; Carbidopa; Consensus; Drug Combinations; Europe; Female; Gels; Humans; Levodopa; Male; Parkinson Disease; Specialization; Young Adult
PubMed: 30016901
DOI: 10.1080/03007995.2018.1502165 -
American Journal of Obstetrics and... Oct 2020Chronic hypertension is associated with adverse perinatal outcomes, although the optimal treatment is unclear. The aim of this network metaanalysis was to simultaneously... (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVE DATA
Chronic hypertension is associated with adverse perinatal outcomes, although the optimal treatment is unclear. The aim of this network metaanalysis was to simultaneously compare the efficacy and safety of antihypertensive agents in pregnant women with chronic hypertension.
STUDY
Medline, Scopus, CENTRAL, Web of Science, Clinicaltrials.gov, and Google Scholar databases were searched systematically from inception to December 15, 2019. Both randomized controlled trials and cohort studies were held eligible if they reported the effects of antihypertensive agents on perinatal outcomes among women with chronic hypertension.
STUDY APPRAISAL AND SYNTHESIS METHODS
The primary outcomes were preeclampsia and small-for-gestational-age risk. A frequentist network metaanalytic random-effects model was fitted. The main analysis was based on randomized controlled trials. The credibility of evidence was assessed by taking into account within-study bias, across-studies bias, indirectness, imprecision, heterogeneity, and incoherence.
RESULTS
Twenty-two studies (14 randomized controlled trials and 8 cohorts) were included, comprising 4464 women. Pooling of randomized controlled trials indicated that no agent significantly affected the incidence of preeclampsia. Atenolol was associated with significantly higher risk of small-for-gestational age compared with placebo (odds ratio, 26.00; 95% confidence interval, 2.61-259.29) and is ranked as the worst treatment (P-score=.98). The incidence of severe hypertension was significantly lower when nifedipine (odds ratio, 0.27; 95% confidence interval, 0.14-0.55), methyldopa (odds ratio, 0.31; 95% confidence interval, 0.17-0.56), ketanserin (odds ratio, 0.29; 95% confidence interval, 0.09-0.90), and pindolol (odds ratio, 0.17; 95% confidence interval, 0.05-0.55) were administered compared with no drug intake. The highest probability scores were calculated for furosemide (P-score=.86), amlodipine (P-score=.82), and placebo (P-score=.82). The use of nifedipine and methyldopa were associated with significantly lower placental abruption rates (odds ratio, 0.29 [95% confidence interval, 0.15-0.58] and 0.23 [95% confidence interval, 0.11-0.46], respectively). No significant differences were estimated for cesarean delivery, perinatal death, preterm birth, and gestational age at delivery.
CONCLUSION
Atenolol was associated with a significantly increased risk for small-for-gestational-age infants. The incidence of severe hypertension was significantly lower when nifedipine and methyldopa were administered, although preeclampsia risk was similar among antihypertensive agents. Future large-scale trials should provide guidance about the choice of antihypertensive treatment and the goal blood pressure during pregnancy.
Topics: Abruptio Placentae; Amlodipine; Antihypertensive Agents; Atenolol; Cesarean Section; Chronic Disease; Female; Fetal Growth Retardation; Furosemide; Gestational Age; Humans; Hypertension; Incidence; Infant, Small for Gestational Age; Ketanserin; Methyldopa; Network Meta-Analysis; Nifedipine; Perinatal Death; Pindolol; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Premature Birth; Severity of Illness Index
PubMed: 32199925
DOI: 10.1016/j.ajog.2020.03.016 -
The Canadian Journal of Neurological... Jan 2022Levodopa-carbidopa intestinal gel infusion (LCIG) is an established therapy for advanced Parkinson disease (PD), resulting in a significant improvement of quality of... (Review)
Review
Levodopa-carbidopa intestinal gel infusion (LCIG) is an established therapy for advanced Parkinson disease (PD), resulting in a significant improvement of quality of life. With increased LCIG adoption worldwide, potential complications due to abnormal vitamin absorption or metabolism have been reported in these patients. Neurologists are unfamiliar with vitamins physiology and pathophysiological mechanisms in case of their deficiency. Unfortunately, clinical and laboratory guidelines related to vitamin monitoring and supplementation in the context of treatment with LCIG are not available. We herein summarize the current knowledge on three vitamins that are reduced with LCIG therapy reporting on their physiology, laboratory testing, and clinical impact of their deficiency/excess. In addition, we proposed an opinion-based recommendation for clinicians treating LCIG patients. Patients and caregivers should be informed about the risk of vitamin deficiency. Vitamin B12, homocysteine, and methylmalonic acid (MMA) should be tested before starting LCIG, six months after and once/year thereafter. Vitamin B6 and folate testing is not universally available but it should be considered if homocysteine is elevated but MMA and/or total vitamin B12 are normal. Prophylaxis of vitamin deficiency should be started as soon as LCIG is implemented, possibly even before. Dietary recommendations are enough in most patients although a subgroup of patients is at higher risk and should receive Vitamin B12 regularly and cycles of B6. Finally, once diagnosed a vitamin deficiency should be readily treated and accompanied by clinical and laboratory monitoring. Resistant cases should receive non-oral routes of administration and possibly discontinue LCIG, even temporarily.
Topics: Antiparkinson Agents; Carbidopa; Humans; Levodopa; Quality of Life; Vitamins
PubMed: 33875038
DOI: 10.1017/cjn.2021.78 -
Translational Neurodegeneration Oct 2022Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson's disease (PD) to control motor and non-motor fluctuations ('OFF' periods).... (Review)
Review
Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson's disease (PD) to control motor and non-motor fluctuations ('OFF' periods). Transdermal rotigotine is indicated for early fluctuations, while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD. All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD. A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of 'OFF' periods. However, data suggest that despite their efficacy in reducing the number and duration of 'OFF' periods, these strategies still do not prevent 'OFF' periods in the middle to late stages of PD, thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation. Why these emergent 'OFF' periods still occur is unknown. In this review, we analyse the potential reasons for their persistence. The contribution of drug- and device-related involvement, and the problems related to site-specific drug delivery are analysed. We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent 'OFF' periods unresponsive to dopaminergic therapy delivered via CDD.
Topics: Antiparkinson Agents; Apomorphine; Carbidopa; Dopamine; Humans; Levodopa; Parkinson Disease
PubMed: 36229860
DOI: 10.1186/s40035-022-00317-x -
The Medical Letter on Drugs and... Feb 2021
Review
Topics: Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase; Dopaminergic Neurons; Drug Therapy, Combination; Humans; Levodopa; Parkinson Disease
PubMed: 33647001
DOI: No ID Found -
Journal of Parkinson's Disease 2023Oral levodopa is the gold-standard therapy for treating Parkinson's disease (PD) but after a few years of treatment the therapeutic window narrows, and patients often... (Review)
Review
Oral levodopa is the gold-standard therapy for treating Parkinson's disease (PD) but after a few years of treatment the therapeutic window narrows, and patients often experience various treatment-related complications. Patients in this advanced PD stage may benefit from alternative therapy, such as continuous intrajejunal delivery of levodopa-carbidopa intestinal gel (LCIG; or carbidopa-levodopa enteral suspension), continuous intrajejunal delivery of levodopa-carbidopa-entacapone intestinal gel, or continuous subcutaneous apomorphine infusion. Consideration and initiation of infusion therapies in advanced PD are suggested before the onset of major disability. The present review summarizes clinical evidence for infusion therapy in advanced PD management, discusses available screening tools for advanced PD, and provides considerations around optimal use of infusion therapy.
Topics: Humans; Parkinson Disease; Levodopa; Carbidopa; Antiparkinson Agents; Gels; Drug Combinations
PubMed: 37334617
DOI: 10.3233/JPD-225112 -
The Lancet. Neurology May 2024Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson's disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial.
BACKGROUND
Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease.
METHODS
We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete.
FINDINGS
Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury).
INTERPRETATION
Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment.
FUNDING
NeuroDerm.
Topics: Male; Humans; Female; Parkinson Disease; Levodopa; Carbidopa; Antiparkinson Agents; Infusions, Subcutaneous; Dyskinesias; Double-Blind Method; Treatment Outcome
PubMed: 38499015
DOI: 10.1016/S1474-4422(24)00052-8