AN INTEGRATED PHARMACOKINETIC-PHARMACODYNAMIC APPROACH TO OPTIMIZATION OF R-APOMORPHINE DELIVERY IN PARKINSONS-DISEASE

R-apomorphine is a mixed dopamine D-1/D-2 receptor agonist which is po tentially useful in the management of Parkinson's disease. The deliver y of R-apomorphine is complicated however by a number of pharmacokinet ic and pharmacodynamic factors. This review describes the development of a transdermal iontophoretic delivery system for R-apomorphine on th e basis of integrated pharmacokinetic-pharmacodynamic (PK/PD) investig ations in patients with idiopathic Parkinson's disease. The pharmacoki netics and metabolic pathways of R-apomorphine were determined followi ng intravenous infusion of 30 mu g kg(-1) in 15 min in 10 patients. A stepwise infusion protocol was used to determine the therapeutic windo w. A wide interindividual variability in both pharmacokinetics and pha rmacodynamics and a narrow therapeutic concentration range were observ ed. This shows the need for individualized and carefully controlled de livery of R-apomorphine in Parkinson's disease. Transdermal iontophore tic transport was studied both in vitro in human stratum corneum and d ermatomed full skin and in vivo in patients with Parkinson's disease. These studies showed that the delivery of R-apomorphine by transdermal iontophoresis is feasible and furthermore that the rate of delivery c an be carefully controlled by variation of the current density. It is concluded that the delivery of R-apomorphine by transdermal iontophore sis may be an attractive tool in future clinical pharmacological inves tigations in patients with Parkinson's disease aiming at characterizat ion of the influence of chronic treatment and disease progression on t he pharmacokinetics and pharmacodynamics. Ultimately these studies may result in a system which is suitable for clinical application. (C) 19 98 Elsevier Science B.V. All rights reserved.