Effect of controlled‐release delivery on the pharmacokinetics of oxybutynin at different dosages: severity‐dependent treatment of the overactive bladder

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Abstract
OBJECTIVE: To assess the pharmacokinetics of a controlled‐release formulation of oxybutynin (OROS®‐O, ALZA Corp., Mountain View, CA) at different dosages, compared with immediate‐release oxybutynin (IR‐O), and to determine the pharmacodynamic properties in the severity‐dependent reduction of urge urinary incontinence (UUI).PATIENTS AND METHODS: In all, 105 patients were enrolled in this multicentre, randomized, double‐blind study. Individual dose titration was used to assess the minimum effective, maximum tolerated or maximum allowed dose of either OROS‐O or IR‐O. Blood samples were collected during maintenance therapy with frequent sampling to analyse for R‐oxybutynin and R‐desethyloxybutynin concentrations. Pre‐dose plasma levels before dosing were obtained as the minimum concentrations achieved at steady state during the dosing regimen. In parallel, UUI episodes were assessed at baseline and during maintenance therapy at the final dose level.RESULTS: For both IR‐O and OROS‐O, initial R‐oxybutynin plasma concentrations increased in a dose‐dependent fashion. For comparable dosages pre‐dose plasma levels were higher for OROS‐O than IR‐O. After one dose of IR‐O plasma concentrations peaked at ≈ 27‐fold after 1 h and decreased to baseline levels within 4–8 h. In contrast, plasma concentrations of R‐oxybutynin remained constant for up to 24 h after taking OROS‐O at all doses. The overall percentage reduction in weekly UUI episodes was 84% (to 4.8 episodes) and 88% (to 3.1 episodes) for OROS‐O and IR‐O, respectively (P < 0.05). Patients who titrated to final dose levels of 10, 15 and 20 mg OROS‐O differed in their weekly UUI episodes at baseline (14.5, 30.3 and 42.0). Because of individual dose titration, UUI episodes/week were profoundly reduced at all applied doses (1.9–2.0, respectively). Fewer patients reported moderate to severe dry mouth with OROS‐O than with IR‐O (25% vs 46%, P < 0.05).CONCLUSION: The pharmacokinetics of OROS‐O are proportional to dose, with minimal fluctuations between peak and trough concentrations, as associated with IR‐O. In clinical practice OROS‐O may thus facilitate the highly effective severity‐dependent treatment of UUI with flexible dose adaptations based on the patients’ needs.