Development and Benefits of Intestinal Gel LECIG for Patients with Parkinson's Disease
Patients with advanced Parkinson's disease, for whom the current regimen of orally and transdermally administered medications is insufficient for symptom relief, now have a new treatment option. It involves the continuous administration of an intestinal gel that combines three effective antiparkinsonian drugs.
Metabolism of Levodopa and Development of Related Therapies
In the 1960s, levodopa was first used in patients with Parkinson's disease (PD) and remains the gold standard of treatment today. In the central nervous system (CNS), levodopa is converted to the missing dopamine by DOPA decarboxylase (DDC).
Levodopa is also metabolized in peripheral tissue by DDC to dopamine and by catechol-O-methyltransferase (COMT) to 3-O-methyldopa (3-OMD) and S-adenosyl-homocysteine. These peripheral conversions lead to some side effects and decrease the bioavailability of levodopa in the CNS. Inhibitors of DDC and COMT address these complications by increasing the amount of levodopa that crosses the blood-brain barrier. Clinical studies have confirmed that adding a DDC inhibitor (carbidopa, benserazide) to orally administered levodopa reduces side effects and improves PD symptom control. The levodopa + carbidopa or levodopa + benserazide combinations developed in the 1970s were complemented in the 1990s by the COMT inhibitor entacapone.
Intestinal Gels as a Favorable Dosage Form
In the 1990s, a new dosage form for administering levodopa and carbidopa was developed in Sweden—an intestinal gel LCIG delivered via an infusion pump through a percutaneous endoscopic gastrostomy extending into the jejunum. This unique delivery method helped achieve more stable plasma concentrations of levodopa, approximating continuous dopaminergic stimulation in the CNS. The European Medicines Agency (EMA) registered the product in 2005.
Subsequent clinical studies showed that combining LCIG with orally administered COMT inhibitors allows a 20% reduction in the LCIG dose while maintaining stable plasma concentrations of levodopa and motor function. This finding led to the development of the LECIG intestinal gel, which combines levodopa, carbidopa, and entacapone. The product was registered in Sweden in 2018 and in the Czech Republic three years later.
In the Czech Republic, LECIG is covered by health insurance for patients with advanced PD, responsive to levodopa treatment but with severe motor fluctuations and dyskinesias when existing antiparkinsonian drug combinations are unsatisfactory, for patients with significant swallowing difficulties preventing oral medication administration, or when other treatments are contraindicated.
The disadvantages of this modality compared to standard oral therapy include the initial need for an invasive procedure and potential technical issues with the pump. Otherwise, the safety profile of the medications matches that of oral treatment.
Reducing the Risk of Peripheral Neuropathy
Long-term use of levodopa is associated with the development of peripheral neuropathy in PD patients, characterized by dysfunction of sensory, motor, and sometimes autonomic nerves. Current findings suggest that the elevated risk of this complication is related to the duration of therapy, high doses of levodopa, and sustained high plasma concentrations of homocysteine and other levodopa metabolites.
Inhibition of COMT reduces the number of metabolites generated by the methylation pathway. A pharmacokinetic clinical study found that transitioning patients from LCIG to LECIG, by introducing entacapone into the therapy, reduces 3-OMD concentration by 35%. Subsequent clinical studies confirmed that COMT inhibitors indeed reduce the risk of peripheral neuropathy. We examined the neuroprotective effect of entacapone in more detail in one of our previous articles.
Conclusion
The LECIG intestinal gel is an effective therapy for patients with advanced Parkinson's disease. Carbidopa and entacapone increase levodopa's bioavailability in the CNS while preventing undesirable peripheral metabolism of the drug. This allows for a reduction in the required dose of levodopa. Continuous administration of the intestinal gel via pump leads to more sustained dopaminergic stimulation, reducing the risk of significant motor fluctuations typical of intermittent drug administration.
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Source: Nyholm D., Jost W. H. Levodopa-entacapone-carbidopa intestinal gel infusion in advanced Parkinson's disease: real-world experience and practical guidance. Ther Adv Neurol Disord 2022 Jun 26; 15: 17562864221108018, doi: 10.1177/17562864221108018.
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