Evaluation of the Relationship Between Sumanirole Exposure and Orthostatic Hypotension

Authors: Passarell JA, Owen JS, Liolios K, D’Souza GA, Carel BJ
Conference: AAPS
Keywords: blood pressure, bp, central nervous system agents, CrCL, creatinine clearance, d2 receptor, dopamine, gender, levodopa, logistic regression, neurology, orthostatic hypotension, Parkinson's disease, pharmacodynamic, pharmacokinetic, PK, PK/PD, safety
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

PURPOSE: Sumanirole is a selective D2 receptor agonist in development for treatment of Parkinson’s disease (PD). This agent is expected to have a better safety profile compared to other dopaminergic agents due to receptor selectivity. Using a previously developed population pharmacokinetic (PPK) model, PK/PD analyses were performed on Phase II data to evaluate the relationship between sumanirole exposure and the occurrence of orthostatic hypotension (OH).

METHODS: Data were obtained from two double-blind, placebo-controlled trials of sumanirole: alone in early PD, or with levodopa for advanced PD. Patients received twice-daily extended-release oral sumanirole doses (2–48 mg/d). Subject-specific Bayesian estimates of area under the concentration-time curve (AUC) were generated based on the PPK model, with creatinine clearance and gender as significant covariates of sumanirole clearance. OH occurrence (systolic blood pressure (SBP) change of ≥20 mm Hg with supine-to-standing position change) was recorded for 11 weeks. Longitudinal logistic regression analyses were performed to evaluate AUC, study, and dose duration as predictors of OH occurrence.

RESULTS: A total of 1980 SBP observations from 214 patients on placebo and 3974 from 378 patients on sumanirole were available. The overall proportion of OH occurrences was significantly higher (P=0.01) in patients treated with placebo (18% of observations) compared with patients treated with sumanirole (15% of observations). However, within the sumanirole-treated patient group, logistic regression identified sumanirole AUC as a significant predictor of OH occurrence, where OH was more likely to occur with higher AUCs. The predicted probabilities of OH ranged from 0.14 at a sumanirole AUC of 0 ng•h/mL to 0.35 at an AUC of 2300 ng•h/mL. Study and dose duration were not significant predictors.

CONCLUSIONS: These results suggest that OH occurrence in patients receiving placebo was significantly higher than in patients receiving sumanirole, although a relationship between sumanirole AUC and OH was detected in the sumanirole treatment group.

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

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