COMT inhibition with entacapone for patients with Parkinson’s disease and motor complications: the novelty of continuous infusion

Enhancing levodopa efficacy through peripheral COMT inhibition and using continuous infusion are both established strategies for managing motor fluctuations. Both approaches aim to improve the pharmacokinetics of levodopa in order to maintain a steady delivery of levodopa to the brain, avoid the deep troughs in levodopa plasma concentrations associated with oral levodopa delivery, and thereby reduce OFF time. In this review, we describe the pharmacologic rationale for combining COMT inhibition with entacapone and continuous dopaminergic delivery that led to the development of levodopa/entacapone/carbidopa intestinal gel (LECIG). Entacapone is a peripheral COMT inhibitor, that effectively reduces the metabolism of levodopa to 3-O-methyldopa and increases the amount of levodopa that can be transported into the brain. However, entacapone has a short half-life and poor oral bioavailability that necessitates frequent dosing for optimal efficacy. Continuous infusion of entacapone allows for improved bioavailability from direct delivery to the duodenum/jejunum. As such, lower overall levodopa doses can be given to achieve therapeutically effective concentrations. Accumulating real-world evidence with LECIG supports its use in managing motor fluctuations in patients whose control is becoming suboptimal with oral approaches. We provide an overview of the growing evidence base for its risk-benefit profile in patients with motor fluctuations.