OAB gel may overcome side effects of patch

October 15, 2008

A gel formulation of oxybutynin for overactive bladder is nearing commercial availability, with the potential for a significant improvement in cosmesis and skin-related side effects.

Orlando, FL-A gel formulation of oxybutynin for overactive bladder is nearing commercial availability, with the potential for a significant improvement in cosmesis and skin-related side effects.

A study presented at the 2008 AUA annual meeting showed that once-a-day oxybutynin topical gel exhibited steady-state pharmacokinetics similar to that of the currently marketed oxybutynin patch (Oxytrol). Researchers discussed comparative data between the patch and the investigational 10% w/w ethanolic gel.

"I would expect that, based on the comparative serum levels of oxybutynin and desethyloxybutynin, the gel formulation will preserve many of the advantages associated with the transdermal patch," said study co-author David Staskin, MD, associate professor of urology at Weill-Cornell Medical College, New York, who worked on the study with researchers at Watson Pharmaceuticals.

Dr. Staskin added that while the patch has proven to be clinically effective and systemically tolerable with many adverse events similar to those seen with placebo, skin reactions such as pruritis, erythema, and rash or macules are associated with its use.

A total of 22 male and female volunteers, ages 18 to 44 years, took part in the randomized, open-label, two-way crossover study. Subjects received 18 days of gel therapy (1 gram once daily) or one patch every 3.5 days for 2 weeks, followed by a 4-day application (3.9 mg/day). Participants then received the crossover formulation after a 14-day washout period.

Serum levels of oxybutynin and the active metabolite desethyloxybutynin were obtained during the final 4 days of dosing to measure drug concentrations. Those levels turned out to be very similar between the gel and the patch throughout the 4 days, with mean oxybutynin levels approximately 2.9% higher for the gel than for the patch.

The investigators found no erythema at any gel application site, nor were there any severe or serious adverse events. No patient discontinued use because of an adverse event.

"This study was only a pharmacokinetic study to demonstrate serum equivalence," Dr. Staskin said. "The advantages of transdermal delivery or any delivery that bypasses the gut are based on the theory of controlling the ratio of the oxybutyinin parent compound and the desoxy metabolite.

Transdermal advantages

"Oxybutynin undergoes 'first-pass metabolism' by the cytochrome P450-3A4 system in the proximal intestinal tract and the liver, converting the parent to the less pharmacologically favorable metabolite. The desethyl metabolite has been demonstrated in the laboratory-and has been presumed in clinical studies-to be responsible for increased side effects."

This conversion is avoided with transdermal delivery as opposed to oral oxybutynin, he noted.

"In addition," Dr. Staskin said, "though further investigation is warranted, the decrease in total serum burden of anticholinergic and the change in activity may hopefully provide additional safety advantages, such as a decrease in potential central nervous system events, over oral oxybutynin administration."

Watson Pharmaceuticals announced in late May that its new drug application for oxybutynin chloride topical gel was accepted for filing by the FDA.

Dr. Staskin serves as an adviser to both Watson, which manufactures the gel and the Oxytrol patch, and Antares Pharma, which also has an oybutynin gel in development.