The primary objective of this study was to describe the pharmacokinetics of oral pergolide in patients with mild to moderate Parkinson disease using a new high-performance liquid chromatography-tandem mass spectrometry assay. A secondary objective was to investigate the relationship between plasma concentrations and efficacy. Fourteen patients with a diagnosis of Parkinson disease completed this multicenter, open-label, dose-escalating study. Pergolide was administered for 58 days, using increasing daily doses from 0.05 mg daily up to 1 mg three times daily and then tapering the dose. The steady-state pharmacokinetic profile and motor score were determined at dose levels of 0.25, 0.5, and 1 mg three times a day and during elimination after the last dose. Pergolide was absorbed with a median time to maximum concentration of 2 to 3 hours across the dose range. Systemic exposure appeared to increase proportionally with dose over the range of 0.25 to 1 mg three times daily within a patient, but there was a large variability in exposures between patients (interpatient coefficients of variation were 56.4% for the area under the curve). Pergolide was widely distributed (volume of distribution, approximately 14,000 L) and was eliminated with a mean half-life of 21 hours. Motor scores improved as both peak plasma pergolide concentrations and exposure increased. No unexpected safety concerns were identified. Pergolide is absorbed relatively quickly into the systemic circulation, has a large apparent volume of distribution, and has a relatively long half-life (mean, 21 hours). This prolonged half-life is of particular interest, given the current hypothesis that more continuous dopaminergic receptor stimulation may reduce motor complications in patients with Parkinson disease.
From the *Clinical Investigation Center, Department of Clinical Pharmacology, University Hospital, Toulouse, France; †Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, United Kingdom; ‡Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; §Centre de Pharmacologie Clinique, Hôpital de la Timone, Marseille, France; and ¶Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Reprints: Olivier Rascol, MD, Laboratoire de Pharmacologie Clinique, Faculté de Médecine, 37 allées Jules Guesde, 31073 Toulouse Cedex, France (e-mail: email@example.com).
Eli Lilly and Company (Indianapolis, Indiana), supported the publication of this manuscript.