Pharmacokinetics of oxybutynin chloride topical gel: effects of application site, baths, sunscreen and person-to-person transference.

BACKGROUND

Oxybutynin chloride topical gel (OTG; Gelnique®) is an approved formulation for the transdermal administration of oxybutynin, an established antimuscarinic therapy for overactive bladder (OAB). Transdermal administration of oxybutynin minimizes plasma concentrations of the active metabolite N-desethyloxybutynin (N-DEO), which can have anticholinergic adverse effects.

OBJECTIVES

In four phase I studies, we separately assessed the effects of OTG application site selection on oxybutynin bioavailability (site-to-site study); the effects of post-application showering on oxybutynin steady-state pharmacokinetics (showering study); the effects of sunscreen application on oxybutynin absorption (sunscreen study); and the person-to-person transfer of oxybutynin through skin-to-skin contact at the application site (transference study).

METHODS

All four studies were open-label, randomized, phase I studies. The site-to-site and showering studies involved repeated administration of OTG to establish steady-state plasma concentrations of oxybutynin and N-DEO; the other two studies involved single doses. Clinical visits were required for pharmacokinetic sampling, supervision of OTG self-application on pharmacokinetic sampling days, showering, sunscreen application and transference experiments. The study included healthy subjects aged 18-45 years. Subjects with conditions requiring medical therapy or interfering with the application of OTG or the interpretation of pharmacokinetic results were excluded. Participants applied OTG (1 g containing oxybutynin chloride 10%, 1.14 mL/dose) once daily to the abdomen, upper arm/shoulder or thigh. Showering occurred 1-6 hours after dosing. Sunscreen was applied 30 minutes before or after OTG application. Abdomen-to-abdomen contact with movement for 15 minutes between treated and untreated participants was conducted 1 hour after dosing. Time points of serial blood sampling for pharmacokinetic analyses varied among studies. Plasma concentrations of oxybutynin and N-DEO (except transference study) were measured. Bioequivalence was tested with ANOVA models for log(e)-transformed plasma exposure (area under the plasma concentration-time curve [AUC]) and maximum plasma concentration (C(max)) to generate 90% confidence intervals (CIs).

RESULTS

Oxybutynin and N-DEO exposures (AUCs) from time zero to 24 hours (AUC(24)) were similar for the three application sites, with N-DEO/oxybutynin mean AUC(24) ratios of approximately 0.9. The 90% CIs for thigh-to-abdomen ratios of oxybutynin AUC(24) (0.93, 1.23) and C(max) (0.85, 1.16) were within the interval required for bioequivalence (0.8, 1.25); the other application site ratios for oxybutynin had boundaries slightly outside this interval. Showering 1-6 hours and sunscreen application 30 minutes before or after OTG application had minor effects on oxybutynin concentrations. After vigorous skin contact between treated and untreated participants at the application site, the mean ± SD AUC from time zero to 48 hours (AUC(48)) of oxybutynin in 12 untreated participants was 29.8 ± 24.5 ng · h/mL, approximately one-quarter of the exposures generally seen in subjects treated with a single dose of OTG. Oxybutynin AUC(48) after clothing-to-skin contact was undetectable in 12 of 14 untreated participants and very low (mean ± SD 0.4 ± 0.8 ng · h/mL) in two untreated female participants.

CONCLUSION

The bioavailability of oxybutynin and its pharmacokinetic profile are not greatly affected by application site selection, post-application showering or sunscreen use shortly before or after dosing with OTG. Oxybutynin transference to untreated persons is essentially prevented by avoiding direct skin-to-skin contact with the application site.