title: An integrated pharmacokinetic-pharmacodynamic approach to optimization of R-apomorphine delivery in Parkinson's disease.
abstract: R-apomorphine is a mixed dopamine D(1)/D(2) receptor agonist which is potentially useful in the management of Parkinson's disease. The delivery of R-apomorphine is complicated however by a number of pharmacokinetic and pharmacodynamic factors. This review describes the development of a transdermal iontophoretic delivery system for R-apomorphine on the basis of integrated pharmacokinetic-pharmacodynamic (PK/PD) investigations in patients with idiopathic Parkinson's disease. The pharmacokinetics and metabolic pathways of R-apomorphine were determined following intravenous infusion of 30 µg kg(-1) in 15 min in 10 patients. A stepwise infusion protocol was used to determine the therapeutic window. A wide interindividual variability in both pharmacokinetics and pharmacodynamics and a narrow therapeutic concentration range were observed. This shows the need for individualized and carefully controlled delivery of R-apomorphine in Parkinson's disease. Transdermal iontophoretic transport was studied both in vitro in human stratum corneum and dermatomed 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 can be carefully controlled by variation of the current density. It is concluded that the delivery of R-apomorphine by transdermal iontophoresis may be an attractive tool in future clinical pharmacological investigations in patients with Parkinson's disease aiming at characterization of the influence of chronic treatment and disease progression on the pharmacokinetics and pharmacodynamics. Ultimately these studies may result in a system which is suitable for clinical application.
authors.affiliation: Leiden-Amsterdam Center for Drug Research, Divisions of Pharmacology and Pharmaceutical Technology, Sylvius Laboratory, P.O. Box 9503, 2300 RA Leiden, The Netherlands
authors.initials: HE
authors.lastname: Boddé
authors.lastname: Van Laar T
authors.lastname: Van der Geest R
authors.initials: M
authors.lastname: Danhof