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Development and Pharmacokinetic Characterization of New Delayed Pulsatile-Release Ondansetron Formulation
N. Rebecca Barwick , J. Corey Fowler, Tong H Lee, Steven T Szabo, Ashwin Patkar, Wayne F Beyer, Lan-Yan Yang, Shein-Chung Chow, Bruce K Burnett, Brett Froeliger, O. Barry Mangum Abstract
Purpose: Several monotherapy agents have failed to show consistent clinical efficacy against methamphetamine dependence. Preclinical studies have demonstrated that combining a dopamine agonist with the 5-HT3 antagonist, ondansetron, reverses behavioral and neurobiological alterations in animal models of psychostimulant abuse. The main purpose of this study is to assess the PK profiles of the novel single oral dose delayed, pulsatile release ondansetron formulation (Ond-PR1), which will allow temporally-dependent double-dosing combination treatments under a single-dosing regimen.
Methods: Two formulations of ondansetron (Ond-PR1 and Ond-PR2), which, when administered simultaneously with a dopamine agonist, result in the requisite drug peak separation. Six subjects received one 8mg tablet of the new formulation of ondansetron after 10 hours of fasting, then twelve blood draws were taken over a period of ten hours for PK analyses. The primary PK parameter of interest was the tmax. Therefore, tmax with in vitro dissolution time of 3 - 4 h is expected to be 5 - 6 h.
Results: Ond-PR2 provided optimal pharmacokinetic delivery to achieve maximum dosing at 3.5 hours post peak MPh administration. Tmax: Ond-1 (6.8), Ond-2 (5.9); AUC: Ond-1 (136.1), Ond-2 (191.2); Cmax: Ond-1 (31.2), Ond-2 (36.5); Half-life: Ond-1 (9.7), Ond-2 (8.2). The results from this single dose pharmacokinetic study provide some insight into the necessary release pattern of ondansetron. Ond-PR2 provided optimal pharmacokinetic delivery to achieve the desired pharmacokinetic profile.
Conclusions: The results from this single dose pharmacokinetic study provided insight into the release pattern of ondansetron alone and in combination with methylphenidate to pursue further study in a phase II clinical research program.