Food Does Not Influence the Pharmacokinetics of a New Extended Release Formulation of Tolterodine for Once Daily Treatme
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Clin Pharmacokinet 2001; 40 (2): 135-143 0312-5963/01/0002-0135/$22.00/0 © Adis International Limited. All rights reserved.
Food Does Not Influence the Pharmacokinetics of a New Extended Release Formulation of Tolterodine for Once Daily Treatment of Patients with Overactive Bladder Birgitta Olsson1 and Johan Szamosi2 1 Department of Clinical Pharmacology, Pharmacia AB, Stockholm, Sweden 2 Department of Biostatistics and Data Management, Pharmacia AB, Stockholm, Sweden
Abstract
Objective: To determine whether food intake influences the pharmacokinetics of a new, once daily, extended release (ER) capsule formulation of tolterodine in healthy volunteers, and to compare its bioavailability with that of the existing immediate release (IR) tablet. Design: Open, randomised, 3-way crossover trial. Participants: 17 healthy volunteers (3 females, 14 males) aged between 19 and 50 years. With the exception of 1 male volunteer, all participants were classified as extensive metabolisers by cytochrome P450 2D6 genotyping. Methods: Volunteers received single oral doses of tolterodine L-tartrate ER 8mg (2 × 4mg capsules) on an empty stomach or with a standardised high-fat breakfast. Reference therapy comprised tolterodine L-tartrate IR 4mg (2 × 2mg tablets), administered in the fasting state. Serum concentrations of tolterodine, its active 5-hydroxymethyl metabolite (5-HM) and the active moiety (sum of unbound tolterodine + 5-HM) were measured for up to 72 hours post-dose. Safety endpoints were also determined. Results: No effect of food on the bioavailability of tolterodine ER capsules was apparent and there was no sign of dose-dumping with meals. The geometric mean fed : fasting ratio of area under the serum concentration-time curve to infinity (AUC∞ ) of the active moiety, for all volunteers combined, was 0.95 (90% confidence interval 0.88 to 1.03). Equivalence with respect to AUC∞ (dose-corrected) was also found for the ER capsule compared with the IR tablet, although uncorrected maximum serum concentrations were around 50% lower despite the fact that the capsule dose was twice as high. Seven volunteers reported adverse events, predominantly headache. No volunteer reported dry mouth. Overall, there were no safety concerns. Conclusions: The new ER formulation of tolterodine shows no pharmacokinetic interaction with food. On the basis of these results, patients with overactive bladder may, therefore, be advised to take the drug without regard to the timing of meals, maximising convenience during therapy.
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Tolterodine is the first antimuscarinic agent developed specifically for the treatment of patients with overactive bladder, a common and distressing medical condition characterised by symptoms of increased urinary frequency and urgency, with or without urge incontinence.[1,2] Numerous studies confirm the clinical efficacy and favourable tolerability of tolterodine in the treatment of patients with overactive bladder (for a review see Guay[3]). Moreover, in comparative studies, tolterodine 2mg twice daily has proved ther
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