Lack of Significant Drug Interactions for Sumanirole in Phase II Studies Using Population Pharmacokinetic (PPK) Methods

Authors: Owen JS, Liolios K, D’Souza GA, Carel BJ
Conference: AAPS
Keywords: case report form, central nervous system agents, CrCL, creatinine clearance, dopamine, drug interaction, levodopa, neurology, NONMEM, Parkinson's disease, PK, selegiline, sumanirole
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Purpose: Sumanirole is a highly D2-selective dopamine receptor agonist that is in development for the treatment of Parkinson’s disease (PD). Metabolism of sumanirole and in vitro data indicate that clinically significant pharmacokinetic (PK) drug-drug interactions are unlikely. This was further investigated using population pharmacokinetic (PPK) methodology.

Methods: Data were obtained from 2 double-blind, placebocontrolled trials of sumanirole alone in early PD and sumanirole with levodopa in advanced PD. Patients received twicedaily extended-release oral sumanirole doses ranging from 2 to 48 mg/d. A one-compartment PPK model, with creatinine clearance (CrCL) and gender as covariates of clearance (CL/F), was used in NONMEM® to characterize the influence of concomitantly administered drugs on sumanirole PK. Use of a specialized case report form (CRF) page streamlined construction of the drug-interaction analysis dataset. Various single agents and classes of compounds were evaluated as a linear shift to the CL/F model. Univariate forward selection (α=0.05) was followed by backward elimination (α=0.001).

Results: PPK data included 378 patients and 20 healthy subjects. Levodopa coadministration occurred in 111 subjects (200 sumanirole concentrations) and was absent for 287 subjects (2394 concentrations in early PD patients). Levodopa did not significantly (P=0.281) influence sumanirole PPK (<5% increase in mean CL/F). Selegiline was coadministered in 85 subjects and had an effect, but this did notreach statistical significance (P<0.001). The magnitude of the effect was small accounting for only a 10% decrease in CL/F for a patient with average CrCL. Other compounds and classes investigated, such as amantadine, aspirin, β-blockers, hypotensive agents, organic anion and cation transport substrates and inhibitors, renal anions, renal cations, and trihexyphenidyl, did not significantly alter sumanirole PK.

Conclusion: Sumanirole is not susceptible to drug interactions based on these PPK data. No single agent, including levodopa, or class of compounds studied, significantly altered sumanirole PK.

American Association of Pharmaceutical Scientists (AAPS); Toronto, Ontario, Canada; November 2002

By Joel S. Owen, Kathryn Liolios, Gwyn A. D’Souza, Barbara J. Carel