Effect of OROS® controlled-release delivery on the pharmacokinetics and pharmacodynamics of oxybutynin chloride

Abstract

Aims: Dry mouth is a common side-effect seen with immediate-release oxybutynin (IR-Oxy). Ditropan XL® [(Oxy-XL), a controlled-release formulation of oxybutynin chloride, is a once-daily oral dosage form that incorporates the OROS® technology. Dry mouth as the pharmacodynamic measure was compared between Oxy-XL and IR-Oxy administration. The steady state stereospecific pharmacokinetics were also established for the two formulations and the kinetic-dynamic relationship of oxybutynin was examined. Methods: This was a randomized, repeated-dose, double-blind, two-treatment, two-period, crossover study. After a baseline assessment day, volunteers were randomly assigned to one of two treatment sequences and received 4 days of each treatment with a washout period of 7 days between treatments. The treatments were: 1) Oxy-XL 10 mg in the morning and placebo 8 h later, and 2) IR-Oxy 5 mg in the morning and again 8 h later. Volunteers assessed dry mouth severity subjectively using a 100 mm visual analogue scale, VAS (Baseline, treatment days 1 and 4) and objectively by collecting saliva (Baseline and treatment day 4) before dosing and every hour after the morning dose for ∼16 h. Several blood samples were collected during each treatment, with frequent sampling on day 4 to analyse for plasma R- and S-oxybutynin and R- and S-desethyloxybutynin concentrations. Results: Relatively constant plasma concentrations of oxybutynin and its metabolite were seen over 24 h following Oxy-XL administration with the degree of fluctuation being much lower (P=0.001; 66% to 81% reduction for the various analytes) than IR-Oxy. Compared with IR-Oxy, Oxy-XL yielded higher (131% and 158% for the R- and S-isomer, respectively) oxybutynin and lower (62% and 78% for the R- and S-isomer, respectively) desethyloxybutynin bioavailability, suggesting reduced first-pass metabolism. Saliva output (area under the effect curve) was significantly higher [P=0.001; 37% (95% confidence interval: 24, 51%)] with Oxy-XL than with IR-Oxy and, accordingly, dry mouth severity (VAS) integrated over the day was significantly lower with Oxy-XL. The decrease in saliva output and the consequent increase in dry mouth severity correlated with the metabolite R-desethyloxybutynin concentration, and no apparent relationship was observed with the R-oxybutynin concentration. This suggests that the metabolite may contribute to the dry mouth. Therefore, the reduction in metabolite exposure with Oxy-XL may be a possible explanation for the observed decrease in dry mouth severity with OXY-XL compared with IR-Oxy. Conclusions: Oxy-XL maintains relatively constant plasma drug and metabolite concentrations and minimizes first-pass metabolism of oxybutynin. The metabolite appears to contribute to dry mouth associated with oxybutynin, and following Oxy-XL metabolite exposure is reduced compared with IR-Oxy. Consequently less dry mouth was observed with Oxy-XL as compared with IR-Oxy.