Pharmacokinetic-pharmacodynamic relationships of apomorphine in patients with Parkinson's disease

In the treatment of patients with Parkinson's disease, apomorphine has an e stablished place as a back-up therapy if other antiparkinsonian drugs, such as levodopa and oral dopamine agonists, have not controlled the existing r esponse fluctuations, Apomorphine is a synthetic derivative of morphine, wi th a totally distinct pharmacological profile, It is a very lipophilic comp ound which is easily (auto)oxidised, This (auto)oxidation is the main metab olic route besides glucuronidation and sulphation, which are both responsib le for about 10% of the metabolic transformation, Apomorphine quickly passes the nasal and intestinal mucosa as well as the b lood-brain barrier (depending on the administration route), Many routes of administration have been explored, but subcutaneous, sublingual, nasal and rectal administration are used in clinical practice, The volume of distribu tion varies between 1 and 2 times bodyweight, The elimination half-life is very short (30 to 90 min) depending on the type of parenteral administratio n, Apomorphine is a high clearance drug (3 to 5 L/kg/h) and is mainly excre ted and metabolised by the liver. Only 3 to 4% is excreted unchanged in the urine. The clinical effect of apomorphine can be linked directly to its concentrat ion in the cerebrospinal fluid. Consequently, a 2-compartment model can be used to predict the clinical effects of apomorphine. The pharmacokinetic-ph armacodynamic data reflect the clinical observations of steep dose-effect c urves if apomorphine is used in patients with random 'on-off' fluctuations. These dose-effect curves an less steep in stable or 'wearing-off' (end-of- dose deterioration) patients. Intravenous infusions of apomorphine in combination with timed motor assess ments can be used clinically to characterise the therapeutic window of a pa rticular patient if dyskinesia persists after single injections of apomorph ine. If more population data become available, the population pharmacokinet ics-pharmacodynamics of apomorphine could be helpful in predicting the clin ical effects of apomorphine in the several subgroups of patients with Parki nson's disease.