Oxybutynin chloride: alterations in drug delivery and improved therapeutic index

Oxybutynin chloride (Ditropan, Alza) is widely regarded as the most efficient antimuscarinic agent for the treatment of bladder detrusor dysfunction resulting in urinary urgency, frequency and urge incontinence. Oxybutynin metabolism occurs primarily in the proximal gastrointestinal tract and the hepatic circulation and is mediated by the cytochrome P450 3A4 isozyme. The major degradation products are desethyloxybutynin, which possesses pharmacological activity, and phenylcyclohexylglycolic acid, which is metabolically inert. A major limitation to long-term compliance with immediate-release oxybutynin remains the necessity for twice- or thrice-daily dosing regimens to provide sustained pharmacological efficacy. Side effects induced by cytochrome P450 metabolism of oxybutynin into the primary metabolite desethyloxybutynin within the gut wall substantially affect the tolerability of the compound within the individual. The oral osmotic delivery system provides unique advantages for drug delivery and substantially alters the tolerability profile of the oxybutynin chloride compound. This extended-release formulation consists of a two component core encapsulated by a semi-permeable membrane. The osmotic gradient between the surrounding environment and the inner core of the delivery system remains constant and water absorption within the capsule is controlled by the semipermeable membrane causing a controlled release of drug, which is sustained over 24 h. Herein are reviewed the various pre- and post-approval trials which have documented the overall therapeutic index of the oral osmotic oxybutynin (Ortho-McNeil Pharmaceuticals). Subsequent post-market surveillance issues are reviewed as are new developments in oxybutynin delivery.