Dose-ranging Pharmacokinetic Study of ANTUROL&#8482 Transdermal Oxybutynin Gel for Overactive Bladder

Objectives

The study was an open-label, randomized, parallel, three-treatment, dose-ranging pharmacokinetic study.

The endpoint of this study was to evaluate single-dose and multiple-dose pharmacokinetics and safety profiles of trans-dermal ANTUROL™ Gel 3%, in doses of 42 mg, 60 mg, and 84 mg oxybutynin (OXY) per day after 20 days of consecutive topical application.

Methods

This study was performed in 49 healthy volunteers (Caucasians and Negroid), aged 19 to 53 (mean 35) years. The ANTUROL™ gel formulation contained 3% w/w of OXY base in a hydroalcoholic non-occlusive matrix including a patented combination of penetration enhancers. Three different doses of the gel were administered topically once a day during 20 consecutive days:

-Treatment A: 1.4 g gel = 42 mg OXY -Treatment B: 2.0 g gel = 60 mg OXY
-Treatment C: 2.8 g gel = 84 mg OXY  

The gel was applied on to the lower abdominal region over an area of, respectively, 350 cm2 for treatment A, 500 cm2 for B, and 700 cm2 for C. Venous blood samples for analysis of plasma OXY and DEO (N-desethyloxybutynin, active metabolite) levels were collected before gel application once daily up to day 26 (decay), and intensively on days 2 (8 samplings for single dose PK) and 21 (8 samplings for steady state PK).

Results

Approximately linear pharmacokinetics appears to apply within the investigated dose range for OXY, since 1.4-fold dose increase results in 1.4-fold Cavg increase for treatment A (3.0±1.0 ng/mL) versus B (4.3±2.4 ng/mL), and in 1.4-fold Cavg increase for treatment B (4.3±2.4 ng/mL) versus C (5.4±1.6 ng/mL). It is to note that for treatment B (60 mg), the Cavg (4.3 ng/mL) is similar to what reported in the literature for OXYTROL™ Patch delivering 3.9 mg/day (4.2 ng/mL). The average DEO levels are 0.9 to 1.3 times that of the parent compound. These levels appear to be lower compared to what reported in the literature for OXYTROL™ Patch, which were about 1.4 times higher than that of the parent drug. Adverse effects monitoring during all dose regimens showed that the treatment was well tolerated, since incidence of local skin erythema was 3 to 4 times less than in OXYTROL™ Patch, and dry mouth prevalence was very limited.

Conclusions

Topical daily administration of ANTUROL™ Gel can deliver sufficient OXY amounts leading for the 60 mg dose to comparable plasma levels with respect to the marketed OXYTROL™ patch. A low incidence of anticholinergic side effects is expected during clinical use because of the avoidance of presystemic metabolism and low DEO plasma concentrations. Local skin erythema is reduced by application of the non-occlusive gel. Transdermal gel administration of OXY represents an interesting alternative to the patch, since it cumulates the advantages of the latter (lower DEO levels than the tablets, and even much lower for the gel) without irritating the skin, as well as to offer high dose regimen flexibility.

Keywords

Overactive bladder, Oxybutynin, Desethyloxybutynin, Transdermal gel, Pharmacokinetics

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