CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. Oxybutynin chloride exhibits only one-fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions characterized by involuntary bladder contractions, cystometric studies have demonstrated that oxybutynin increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void. Oxybutynin thus decreases urgency and the frequency of both incontinent episodes and voluntary urination.
Antimuscarinic activity resides predominantly in the R-isomer. A metabolite, desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in vitro studies.
Pharmacokinetics
Absorption
Following the first dose of DITROPAN XL® (oxybutynin chloride), oxybutynin plasma concentrations rise for 4 to 6 hours; thereafter steady concentrations are maintained for up to 24 hours, minimizing fluctuations between peak and trough concentrations associated with oxybutynin.
The relative bioavailabilities of R- and S-oxybutynin from DITROPAN XL are 156% and 187%, respectively, compared with oxybutynin. The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar in shape; Figure 1 shows the profile for R-oxybutynin.
Table 1 Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following a Single Dose of DITROPAN XL 10 mg (n=43) | Parameters (units) | R-Oxybutynin | S-Oxybutynin |
|---|
| Cmax (ng/mL) | 1.0 | (0.6) | 1.8 | (1.0) |
| Tmax (h) | 12.7 | (5.4) | 11.8 | (5.3) |
| t1/2 (h) | 13.2 | (6.2) | 12.4 | (6.1) |
| AUC(0-48) (ng∙h/mL) | 18.4 | (10.3) | 34.2 | (16.9) |
| AUCinf (ng∙h/mL) | 21.3 | (12.2) | 39.5 | (21.2) |
 Figure 1. Mean R-oxybutynin plasma concentrations following a single dose of DITROPAN XL 10 mg and oxybutynin 5 mg administered every 8 hours (n=23 for each treatment).
Steady-state oxybutynin plasma concentrations are achieved by Day 3 of repeated DITROPAN XL dosing, with no observed drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters.
DITROPAN XL steady-state pharmacokinetics were studied in 19 children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g. spina bifida). The children were on DITROPAN XL total daily dose ranging from 5 to 20 mg (0.10 to 0.77 mg/kg). Sparse sampling technique was used to obtain serum samples. When all available data are normalized to an equivalent of 5 mg per day DITROPAN XL, the mean pharmacokinetic parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in Table 2. The plasma-time concentration profiles for R- and S-oxybutynin are similar in shape; Figure 2 shows the profile for R-oxybutynin when all available data are normalized to an equivalent of 5 mg per day.
Table 2 Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters in Children Aged 5-15 Following Administration of 5 to 20mg DITROPAN XL Once Daily (n=19) All Available Data Normalized to an Equivalent of DITROPAN XL 5 mg Once Daily | R-Oxybutynin | S-Oxybutynin | R- Desethyloxybutynin | S- Desethyloxybutynin |
|---|
| Cmax (ng/mL) | 0.7 ± 0.4 | 1.3 ± 0.8 | 7.8 ± 3.7 | 4.2 ± 2.3 |
| Tmax (hr) | 5.0 | 5.0 | 5.0 | 5.0 |
| AUC (ng∙hr/mL) | 12.8 ± 7.0 | 23.7 ± 14.4 | 125.1 ± 66.7 | 73.6 ± 47.7 |
 Figure 2. Mean steady state (±SD) R-oxybutynin plasma concentrations following administration of 5 to 20 mg DITROPAN XL once daily in children aged 5-15. Plot represents all available data normalized to an equivalent of DITROPAN XL 5 mg once daily.
Food Effects
The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions.
Distribution
Plasma concentrations of oxybutynin decline biexponentially following intravenous or oral administration. The volume of distribution is 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. Its metabolic products include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which is pharmacologically active. Following DITROPAN XL administration, plasma concentrations of R- and S-desethyloxybutynin are 73% and 92%, respectively, of concentrations observed with oxybutynin.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered dose excreted unchanged in the urine. Also, less than 0.1% of the administered dose is excreted as the metabolite desethyloxybutynin.
Dose Proportionality
Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (Cmax and AUC) following administration of 5-20 mg of DITROPAN XL are dose proportional.
Special Populations
Geriatric:
The pharmacokinetics of DITROPAN XL were similar in all patients studied (up to 78 years of age).
Pediatric:
The pharmacokinetics of DITROPAN XL were evaluated in 19 children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The pharmacokinetics of DITROPAN XL in these pediatric patients were consistent with those reported for adults (see Tables 1 and 2, and Figures 1 and 2 above).
Gender:
There are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of DITROPAN XL.
Race:
Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of DITROPAN XL.
Renal Insufficiency:
There is no experience with the use of DITROPAN XL in patients with renal insufficiency.
Hepatic Insufficiency:
There is no experience with the use of DITROPAN XL in patients with hepatic insufficiency.
Drug-Drug Interactions:
See PRECAUTIONS: Drug Interactions.
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