Pharmacokinetic Optimisation of Dopamine Receptor Agonist Therapy for Parkinson??s Disease

Abstract

Dopamine receptor agonists were originally developed as adjunctive therapies to ‘smooth out’ motor response fluctuations to levodopa in patients with advanced Parkinson’s disease. However, they are now used in the early stages of the disease, in monotherapy or combination with low doses of levodopa, to delay the onset of levodopa therapy and its complications. Oral dopamine agonists currently available worldwide for Parkinson’s disease include the older ergot derivatives bromocriptine and pergolide and the second generation non-ergoline compounds ropinirole and pramipexole. Other dopamine agonists that are used less frequently include cabergoline (a new ergoline drug, only recently released in some European countries as an antiparkinsonian drug), lisuride (an ergot derivative) and piribedil (an older non-ergot compound). Data on the pharmacokinetics of oral dopamine agonists, especially the older ergot derivatives, are scarce and mostly refer to small groups of healthy young individuals. All these agents, with the exception of pramipexole, are subject to extensive enterohepatic first-pass metabolism. Their bioavailability is low and shows high intra- and interindividual variability. The pharmacodynamic properties of dopamine agonists relevant to their antiparkinsonian effect have not been clearly defined. As a result, an optimal dosage schedule for the treatment of Parkinson’s disease is generally identified using highly individualised empirical assessment. This involves considerable time expenditure and creates difficulty for patients, who have to follow complex titration schedules. Dopamine agonists appear to have a low potential for pharmacokinetic interaction with levodopa. Few data have been reported on the effect of coadministration on the pharmacodynamics of levodopa. The available data indicate that pergolide and bromocriptine significantly increase the duration of the motor response to levodopa, while baseline motor effects and the magnitude of motor response are substantially unchanged. Cabergoline also significantly prolongs the motor response to a dose of levodopa in patients experiencing motor fluctuations, but baseline motor scores are also significantly improved, suggesting a long-lasting effect. Subcutaneous apomorphine is currently the only non-oral formulation of a dopamine agonist available; it is used as add-on rescue therapy for patients who have advanced Parkinson’s disease and a wide spectrum of complex motor, sensory, autonomic and cognitive ‘wearing-off ’ phenomena not controlled by optimal oral dopaminergic therapy. Attempts to deliver apomorphine and other soluble dopamine agonists by more practical non-oral routes, such as intranasally or transdermally, have so far been of limited clinical utility or are currently still under investigation.