Effect of Antacid on the Pharmacokinetics of Extended-Release Formulations of Tolterodine and Oxybutynin
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In general, extended-release (ER) formulations are designed to prolong the duration of efficacy and reduce the adverse effects of a drug. These formulations often contain the entire daily dose in a single tablet. Therefore, failure of the ER mechanism not only diminishes the desired benefits, but may temporarily expose the patient to drug concentrations higher than those released from a conventional tablet. In this study we determined whether pH has an effect on drug release from the ER formulations of oxybutynin (OROS® technology) and tolterodine (membrane coated beads) in vitro and in vivo.
In vitro studies were based on standardised dissolution experiments for each drug in media of different pH (artificial gastric fluid at pH 1.2, artificial intestinal fluid at pH 7.5, and water). In the two separate, identically designed in vivo studies, single doses of each drug were administered alone and with an antacid to male and female healthy volunteers aged 18–45 years. The randomised, crossover, open-label in vivo studies employed a validated assay to determine plasma concentrations of tolterodine and its metabolite 5-hydrox-ymethyl tolterodine (5-HM), or oxybutynin and its metabolite N-desethyloxybutynin.
The in vitro study showed similar slow and steady drug release from ER-oxybutynin in each pH medium, with 64–71% released after 12 hours. Drug release from ER-tolterodine was steady and slow in artificial gastric fluid, with 72.5% of drug released after 12 hours. However, drug release was much faster in artificial intestinal fluid and water, where 69.8% and 69.1%, respectively, of the drug was released within 4 hours. These in vitro results were consistent with the findings of the in vivo studies. In vivo, the pharmacokinetic profile (peak plasma concentration [Cmax] and area under the concentration-time curve) of ER-oxybutynin was similar after administration with or without antacid, whereas Cmax values of both tolterodine and 5-HM increased significantly when ER-tolterodine was administered with antacid (p ≤ 0.017 vs ER-tolterodine alone).
Changes in pH affected the release of tolterodine from ER-tolterodine, while they had no effect on the release of oxybutynin from the proprietary ER technology used in ER-oxybutynin. The technology employed in ER formulations thus determines sensitivity of drug release to external factors.
KeywordsDrug Release Oxybutynin Tolterodine Poor Metaboliser Active Moiety
These studies were funded by Ortho-McNeil/ALZA. Dr Sathyan, Ms Guo and Dr Gupta are employees of ALZA Corporation. Dr Dmochowski and Dr Appell are consultants to Ortho-McNeil and study investigators in clinical trials sponsored by Ortho-McNeil/ALZA and Pharmacia-Upjohn.
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