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

• Published in: British journal of clinical pharmacology 2001-10, Vol.52 (4), p.409-417
• Main Authors: Sathyan, Gayatri, Chancellor, Michael B., Gupta, Suneel K.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; anticholinergic; Biological and medical sciences; Biological Availability; Cholinergic Antagonists - blood; Cholinergic Antagonists - pharmacokinetics; Cholinergic Antagonists - pharmacology; controlled‐release; Cross-Over Studies; Delayed-Action Preparations; Ditropan XL; Double-Blind Method; dry mouth; Female; General pharmacology; Half-Life; Humans; Male; Mandelic Acids - blood; Mandelic Acids - pharmacokinetics; Mandelic Acids - pharmacology; Medical sciences; Metabolic Clearance Rate; OROS® systems; oxybutynin; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics/Pharmacodynamics; Pharmacology. Drug treatments; urinary incontinence; Urinary system
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.0306-5251.2001.01463.x

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 exp