12.3  Pharmacokinetics
Absorption

Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. Steady-state concentrations are achieved within 7 days of continuous dosing. Absorption of oxybutynin is similar when GELNIQUE is applied to the abdomen, upper arm/shoulders or thighs. Mean plasma concentrations during a randomized, crossover study of the three recommended application sites in 39 healthy men and women are shown in Figure 1.

Average steady-state plasma oxybutynin concentrations were 4.7, 5.2, and 5.5 ng/mL for the abdomen, upper arm/shoulder and thigh application sites, respectively (Table 2).

Table 2: Mean (SD) steady-state pharmacokinetic parameters for oxybutynin following GELNIQUE application to the abdomen, upper arm/shoulder and thigh (N = 39).  
Application Site  AUC0-24
(ng•hr/mL)  Cmax
(ng/mL)  Cavg
(ng/mL)
 Abdomen  112.7 (58.00)  6.8 (3.93)  4.7 (2.39)
 Upper Arm/Shoulder  133.8 (81.58)  8.3 (5.97)  5.5 (3.37)
 Thigh  125.1 (84.67)  7.0 (4.95)  5.2 (3.50)

Distribution

Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution was estimated to be 193 L after intravenous administration of 5 mg oxybutynin chloride.

Metabolism

Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly CYP3A4, found mostly in the liver and gut wall. Metabolites include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and N-desethyloxybutynin (DEO), which is pharmacologically active.

Transdermal administration of oxybutynin bypasses the first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyloxybutynin metabolite. Only small amounts of CYP3A4 are found in skin, limiting pre-systemic metabolism during transdermal absorption. The AUC ratio of N-desethyloxybutynin metabolite to parent compound following multiple transdermal applications is approximately 1:1 for GELNIQUE.

Following intravenous administration, the elimination half-life of oxybutynin is approximately 2 hours. After the final steady-state dose of GELNIQUE, oxybutynin and N-desethyloxybutynin demonstrated biphasic elimination with plasma concentrations beginning to decrease 24 hours after dosing. Elimination was more rapid between 24 and 48 hours after dosing, during which time plasma concentrations of oxybutynin and N-desethyloxybutynin declined by about one-half. This rapid elimination phase was followed by a more prolonged terminal elimination phase. The apparent elimination half-lives including the terminal elimination phase were 64 hours and 82 hours for oxybutynin and DEO, respectively.

Excretion

Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered dose excreted unchanged in the urine. Less than 0.1% of the administered dose is excreted as the metabolite N-desethyloxybutynin.

Person-to