Food Does Not Influence the Pharmacokinetics of a New Extended Release Formulation of Tolterodine for Once Daily Treatment of Patients with Overactive Bladder
- 103 Downloads
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.
Open, randomised, 3-way crossover trial.
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.
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 end-points were also determined.
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.
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.
KeywordsOveractive Bladder Oxybutynin Extended Release Tolterodine Poor Metabolisers
This study was sponsored by Pharmacia Corporation. The authors wish to thank Nkechi Azie, Joy Wisser and Sharyn Cugnetti at the Pharmacia Clinical Research Unit, Kalamazoo, Michigan, USA, for the clinical conduct of the study.
- 2.Wein AJ, Rovner ES. The overactive bladder: an overview for primary care health providers. Int J Fertil 1999; 44: 56–66Google Scholar
- 7.Nilvebrant L. The mechanism of action of tolterodine. Rev Contemp Pharmacother 2000; 11: 13–27Google Scholar
- 8.Physicians’ desk reference®. 54th ed. Montvale (NJ): Medical Economics Co. Inc., 2000: 2439–41Google Scholar
- 19.Olsson B, Brynne N, Johansson C, et al. Food increases the bioavailability of tolterodine but not effective exposure. J Clin Pharmacol 2001; 41: 1–7Google Scholar
- 20.Chow S-C, Liu J-P. Design and analysis of bioavailability and bioequivalence studies. New York (NY): Marcel Dekker, 1992Google Scholar
- 21.Pharmacia Corporation. Influence of tolterodine on the pharmacokinetics of Neovletta®, an oral contraceptive. An open, randomized, multiple-dose cross-over study in healthy volunteers [Document no. 9600483]. Stockholm: Pharmacia Corp. (Data on file)Google Scholar
- 24.Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. 3rd ed. Philadelphia (PA): Williams & Wilkins, 1995Google Scholar
- 25.Pharmacia Corporation. Dose proportionality of tolterodine. An open, randomized, single-dose cross-over study in healthy volunteers [Document no. 9600247]. Stockholm: Pharmacia Corp. (Data on file)Google Scholar
- 28.Byrne AJ, NcNeil JJ, Harrison PM, et al. Stable oral availability of sustained release Propranolol when co-administered with hydralazine or food: evidence implicating substrate delivery rate as a determinant of presystemic drug interactions. Br J Clin Pharmacol 1984; 17 Suppl. 1: 45S–50SPubMedCrossRefGoogle Scholar
- 30.Van Kerrebroeck P, Kreder K, Jonas U, et al. Tolterodine oncedaily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. In pressGoogle Scholar
- 31.Olsson B, Szamosi J. Multiple dose pharmacokinetics of a new once daily, extended-release tolterodine formulation versus immediate release tolterodine. Clin Pharmacokinet. In pressGoogle Scholar