Irregular gastrointestinal drug absorption in Parkinson's disease

ArticleinExpert Opinion on Drug Metabolism & Toxicology 4(2):193-203 · March 2008with40 Reads
DOI: 10.1517/17425255.4.2.193 · Source: PubMed
Abstract
Symptomatic treatment of Parkinson's disease (PD) is based on the dopamine precursor levodopa. Levodopa is only absorbed in the small intestine, where transit time is approximately 3 h and the plasma elimination half-life is short. Therefore, gastric emptying is a major determining factor for onset of symptom relief. Gastric emptying is delayed in PD, thereby causing motor fluctuations such as 'delayed on'. Factors that further slow gastric emptying should be recognised and eliminated if possible. A literature search was performed with the aim to cover the area of irregular gastrointestinal drug absorption in PD. Methods for facilitation of pyloric passage or increase of bioavailability are discussed. Development of new drug formulations and alternative routes of administration is ongoing. Transdermal patches and pumps for subcutaneous or intraduodenal infusions are available for patients with severe fluctuations due to erratic gastric emptying.
    • "Alternatively, CD-LD may be administered as a controlled-release (CR) formulation . However, CR CD-LD has shown slow, sometimes unpredictable absorption [8][9][10][11], perhaps contributing to patient reports of delayed onset and decreased predictability of response [8, 9, 12, 13]. IPX066 (marketed as Rytary ® [carbidopa and levodopa] extended release capsules) is an oral extended-release CD-LD formulation designed to rapidly achieve therapeutic LD plasma concentrations and maintain them for a prolonged duration [14], allowing dosing at 6-hour intervals in both early and advanced PD patients. "
    [Show abstract] [Hide abstract] ABSTRACT: 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.
    Full-text · Article · Oct 2015
    • "Parkinson's disease is a degenerative disorder of the central nervous system, causing various movement related and psychiatric symptoms. Levodopa and dopamine agonists are effective in alleviating the motor symptoms of the disease, but a high variability in levodopa absorption from the gastrointestinal tract after oral administration causes fluctuations in the plasma concentration of the drug [1] . In more advanced Parkinson's patients, this often results in fluctuations between 'on periods', in which the Parkinson's disease symptoms are well controlled, and 'off periods', in which the Parkinson's disease symptoms are poorly controlled [2]. "
    Article · Sep 2015
    • "Parkinson's disease is a degenerative disorder of the central nervous system, causing various movement related and psychiatric symptoms. Levodopa and dopamine agonists are effective in alleviating the motor symptoms of the disease, but a high variability in levodopa absorption from the gastrointestinal tract after oral administration causes fluctuations in the plasma concentration of the drug [1] . In more advanced Parkinson's patients, this often results in fluctuations between 'on periods', in which the Parkinson's disease symptoms are well controlled, and 'off periods', in which the Parkinson's disease symptoms are poorly controlled [2]. "
    [Show abstract] [Hide abstract] ABSTRACT: Because of its rapid onset of action, pulmonary administration of levodopa is an interesting alternative to oral administration for the rescue treatment of Parkinson's disease patients in an off period. We studied the ability of Parkinson's disease patients to operate a dry powder inhaler (DPI) correctly during an off period. We used an instrumented test inhaler with three different resistances to air flow to record flow curves and computed various inhalation parameters. We observed that all (13) patients were able to generate pressure drops > 2 kPa over the highest resistance and 10 out of 13 patients achieved at least 4 kPa. Inhaled volumes (all resistances) varied from 1.2 L to 3.5 L. Total inhalation time and the time to peak inspiratory flow rate both decreased with decreasing inhaler resistance. Twelve out of thirteen patients could hold their breath for at least five seconds after inhalation and nine could extend this time to ten seconds. The data from this study indicate that patients with Parkinson's disease will indeed be able to use a dry powder inhaler during an off period and they provide an adequate starting point for the development of a levodopa powder inhaler to treat this particular patient group.
    Full-text · Article · Jul 2015
Show more