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Levodopa-Carbidopa Intestinal Gel Pharmacokinetics: Lower Variability than Oral Levodopa-Carbidopa

Published on May 16, 2017in Journal of Parkinson's disease3.698
· DOI :10.3233/JPD-161042
Ahmed A. Othman19
Estimated H-index: 19
,
Matthew R. Rosebraugh1
Estimated H-index: 1
+ 2 AuthorsSandeep Dutta18
Estimated H-index: 18
Abstract
: In a double-blind, double-dummy, double-titration Phase 3 trial in advanced Parkinson's disease (PD) patients, the efficacy and safety of Levodopa-carbidopa intestinal gel (LCIG) infusion were characterized relative to immediate-release oral levodopa-carbidopa (LC-oral) treatment. We present in this report the comparative pharmacokinetic profiles of LCIG and LC-oral from this pivotal study. The results presented in this report clearly demonstrate that LCIG results in lower variability and fluctuations in levodopa and carbidopa plasma concentrations compared to LC-oral. The superior pharmacokinetic profiles with LCIG were consistent with its improved efficacy compared to LC-oral as demonstrated in this study.
  • References (17)
  • Citations (4)
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References17
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#1Yasaman Kianirad (NU: Northwestern University)H-Index: 3
#2Tatyana Simuni (NU: Northwestern University)H-Index: 22
Levodopa (LD) is the most effective medication to treat Parkinson’s disease (PD). However, motor fluctuations and drug-induced dyskinesia compromise the long-term success of levodopa therapy in PD. These response complications are due, at least in part, to fluctuating LD plasma levels (as a result of erratic gastric emptying, variable jejunal absorption, and most importantly, the short half-life of LD) with standard levodopa formulations. Keeping levodopa concentrations as constant as possible i...
9 CitationsSource
#1Ahmed A. Othman (Cairo University)H-Index: 19
#2Krai Chatamra (AbbVie)H-Index: 10
Last. Masahiro Nagai (Ehime University)H-Index: 15
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26 CitationsSource
#1C. Warren Olanow (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 80
#2Karl Kieburtz (URMC: University of Rochester Medical Center)H-Index: 64
Last. Angelo AntoniniH-Index: 70
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Summary Background Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. Me...
285 CitationsSource
#1Dag Nyholm (Uppsala University)H-Index: 28
#2Per OdinH-Index: 43
Last. Ahmed A. Othman (Cairo University)H-Index: 19
view all 7 authors...
Motor complications of Parkinson’s disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral levodopa therapy. Levodopa–carbidopa intestinal gel (LCIG) is infused continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of levodopa, carbidopa, and levodopa metabolite, 3-O-methyldopa (3-OMD) with 16-h LCIG infusion. Nineteen advanced PD patients (mean age, 65 years) who were on...
39 CitationsSource
#1Peter A. LeWitt (WSU: Wayne State University)H-Index: 48
#2Danna JenningsH-Index: 34
Last. Harold Murck (Novartis)H-Index: 1
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Controlled-release carbidopa and levodopa (CL-CR) and the combination of carbidopa, levodopa, and entacapone (CLE) are used for extending levodopa (L-dopa) effects. In a randomized, open-label crossover study of 17 PD subjects with wearing-off responses, we compared 8-hour L-dopa pharmacokinetics (PK) and clinical effects after two doses of CL-CR (50 and 200 mg, respectively) and CLE (37.7, 150, 200 mg, respectively). PK analysis revealed the anticipated near-equivalent mean L-dopa area-under-th...
31 CitationsSource
#1Dag NyholmH-Index: 28
#2Håkan AskmarkH-Index: 21
Last. Sten-Magnus AquiloniusH-Index: 44
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Pharmacotherapy for Parkinson’s disease (PD) is based on levodopa, the most effective dopaminergic drug. The development of motor complications constitutes the major challenge for new or refined therapies.To evaluate the impact of levodopa pharmacokinetics on motor function, an observational study in the patients’ home environment was carried out. A high variability in plasma levodopa levels was found in all patients, irrespective of treatment regimen. The impact of levodopa pharmacokinetics was...
162 CitationsSource
#1Dag NyholmH-Index: 28
#2Hans LennernäsH-Index: 9
Last. Sten-Magnus AquiloniusH-Index: 44
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Pharmacotherapy for Parkinson’s disease (PD) is based on levodopa, the most effective dopaminergic drug. The development of motor complications constitutes the major challenge for new or refined therapies.To evaluate the impact of levodopa pharmacokinetics on motor function, an observational study in the patients’ home environment was carried out. A high variability in plasma levodopa levels was found in all patients, irrespective of treatment regimen. The impact of levodopa pharmacokinetics was...
63 CitationsSource
#1Kamal A. Sagar (DCU: Dublin City University)H-Index: 10
#2Malcolm R. Smyth (DCU: Dublin City University)H-Index: 55
A reliable multi-dimensional column chromatographic method employing amperometric detection using a carbon fibre microelectrode procedure was used for monitoring the plasma profiles and to evaluate the pharmacokinetics and bioavailability of levodopa (L-dopa) and carbidopa (C-dopa), after ingestion of oral formulations containing these drugs. The peak currents obtained for the different analytes were directly proportional to the analyte over the concentration range 0.02–4 μg ml−1. Using this met...
20 CitationsSource
#1C. Warren OlanowH-Index: 80
#2Ray L. WattsH-Index: 56
Last. William C. KollerH-Index: 40
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Parkinson’s disease (PD) is named in honor of James Parkinson, whose classic monograph, “An Essay on the Shaking Palsy,” written in 1817, has provided an enduring description of the clinical features of this disorder.1 PD is an age-related neurodegenerative disorder with an average age at onset of 60 years. An estimated 1 million persons in the United States suffer from PD,2 and there are approximately 60,000 new cases each year. United States Census Bureau projections indicate that there will b...
598 CitationsSource
Cited By4
Newest
#1Bendix Labeit (WWU: University of Münster)H-Index: 1
#2Inga ClausH-Index: 3
Last. Tobias WarneckeH-Index: 24
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Background. Pharyngeal dysphagia is a common symptom of Parkinson’s disease (PD) leading to severe complications. PD-related pharyngeal dysphagia (PDrPD) may significantly improve in up to half of patients following acute oral levodopa challenge. Objective. The aim of this study was to investigate the effects of levodopa-carbidopa intestinal gel (LCIG) on PDrPD. Methods. Forty-five PD patients under LCIG treatment were available for retrospective analysis. In all patients with PDrPD who underwen...
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#1Cindy Zadikoff (AbbVie)H-Index: 1
#2Werner Poewe (Innsbruck Medical University)H-Index: 113
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Background. Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa administration and clinical benefits to patients with advanced Parkinson’s disease (PD). This report evaluates long-term safety and efficacy of high-dose LCIG in PD patients. Methods. Data were collected from several prospective, phase III clinical studies and an observational registry. The phase III program (N = 412) included four multicenter studies: a 12-week, randomized, double-blind study and three open-label ...
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#1Sheridan M. Hoy (Springer Science+Business Media)H-Index: 9
An enteral suspension (ES)/intestinal gel formulation of levodopa/carbidopa (hereafter referred to as levodopa/carbidopa ES) [Duodopa® (EU); Duopa™ (USA)] has been developed to overcome the fluctuating plasma levodopa concentrations associated with oral levodopa/carbidopa formulations. In various countries, including those of the EU (under the Mutual Recognition Procedure), it is approved for the treatment of advanced levodopa-responsive Parkinson’s disease (PD) with severe motor fluctuations an...
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#1Fahd Amjad (Georgetown University)H-Index: 1
#2Danish Bhatti (UNMC: University of Nebraska Medical Center)H-Index: 3
Last. Leonard Verhagen Metman (Rush University Medical Center)H-Index: 5
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Results from recent studies have shown that continuous infusion of levodopa-carbidopa intestinal gel (LCIG) into the jejunum (a part of the small intestine) effectively manages the motor and nonmotor complications (e.g., tremor, extreme stiffness in arms and legs, difficulty walking, and impaired balance) experienced by patients with advanced Parkinson’s disease (PD). LCIG is administered by a portable pump directly into the patient’s jejunum by a permanent tube that is inserted surgically. LCIG...
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#1Matthew R. Rosebraugh (AbbVie)H-Index: 1
#2Hari V. Kalluri (AbbVie)
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A new levodopa‐carbidopa intestinal gel (LCIG) system featuring a higher levodopa/carbidopa (LD/CD) concentration and viscosity, LCIG‐HV, is being developed to reduce the intrajejunal volume of LD/CD that is administered as compared to the current commercial formulation, LCIG‐LV. This study characterizes the LCIG‐HV formulation and compares it to the LCIG‐LV formulation via dissolution testing and a clinical pharmacokinetic bioequivalence study. In vitro release profiles of LD/CD were determined...
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#1Libo Wang (JLU: Jilin University)H-Index: 2
#2Jia Li (JLU: Jilin University)H-Index: 1
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#1Hubert H. FernandezH-Index: 54
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Levodopa-carbidopa intestinal gel (designated as carbidopa-levodopa enteral suspension in the United States) provides stable plasma levodopa concentrations and reduces motor fluctuations in advanced Parkinson's disease patients through continuous delivery of levodopa via percutaneous endoscopic gastrojejunostomy. We report long-term safety and efficacy outcomes from an open-label phase 3 treatment program.PD patients (n = 262) who completed a 12-week double-blind study and its 52-week open-label...
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