Pharmacokinetic optimisation of dopamine receptor agonist therapy for Parkinson's disease

Dopamine receptor agonists were originally developed as adjunctive therapie s to 'smooth out' motor response fluctuations to levodopa in patients with advanced Parkinson's disease, However, they are now used in the early stage s 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 diseas e include the older ergot derivatives bromocriptine and pergolide and the s econd generation non-ergoline compounds ropinirole and pramipexole. Other d opamine agonists that are used less frequently include cabergoline (a new e rgoline drug, only recently released in some European countries as an antip arkinsonian drug), lisuride (an ergot derivative) and piribedil (an older n on-ergot compound). Data on the pharmacokinetics of oral dopamine agonists, especially the olde r ergot derivatives, are scarce and mostly refer to small groups of healthy young individuals. All these agents, with the exception of pramipexole, ar e subject to extensive enterohepatic first-pass metabolism. Their bioavaila bility is low and shows high intra- and interindividual variability. The pharmacodynamic properties of dopamine agonists relevant to their antip arkinsonian effect have not been clearly defined. As a result, an optimal d osage schedule for the treatment of Parkinson's disease is generally identi fied using highly individualised empirical assessment. This involves consid erable time expenditure and creates difficulty for patients, who have to fo llow complex titration schedules. Dopamine agonists appear to have a low potential for pharmacokinetic intera ction with levodopa. Few data have been reported on the effect of coadminis tration on the pharmacodynamics of levodopa. The available data. indicate t hat 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 significant ly prolongs the motor response to a dose of levodopa in patients experienci ng motor fluctuations, but baseline motor scores are also significantly imp roved, suggesting a long-lasting effect. Subcutaneous apomorphine is currently the only non-oral formulation of a do pamine 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 oth er soluble dopamine agonists by more practical non-oral routes, such as int ranasally or transdermally, have so far been of limited clinical utility or are currently still under investigation.