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Clinical Pharmacokinetics

, Volume 40, Issue 2, pp 135–143 | Cite as

Food Does Not Influence the Pharmacokinetics of a New Extended Release Formulation of Tolterodine for Once Daily Treatment of Patients with Overactive Bladder

  • Birgitta Olsson
  • Johan Szamosi
Original Research Article

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 end-points 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.

Keywords

Overactive Bladder Oxybutynin Extended Release Tolterodine Poor Metabolisers 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

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.

References

  1. 1.
    Jackson S. The patient with overactive bladder: symptoms and quality of life issues. Urology 1997; 50(6A Suppl.): 18–22PubMedCrossRefGoogle Scholar
  2. 2.
    Wein AJ, Rovner ES. The overactive bladder: an overview for primary care health providers. Int J Fertil 1999; 44: 56–66Google Scholar
  3. 3.
    Guay DRP. Tolterodine, a new antimuscarinic drug for treatment of bladder overactivity. Pharmacotherapy 1999; 19: 267–80PubMedCrossRefGoogle Scholar
  4. 4.
    Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology 1997; 50(6A Suppl.): 90–6PubMedCrossRefGoogle Scholar
  5. 5.
    Abrams P, Freeman R, Anderström C, et al. Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol 1998; 81: 801–10PubMedCrossRefGoogle Scholar
  6. 6.
    Drutz H, Appell RA, Gleason D, et al. Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder. Int Urogynecol J Pelvic Floor Dysfunct 1999; 10: 283–9PubMedCrossRefGoogle Scholar
  7. 7.
    Nilvebrant L. The mechanism of action of tolterodine. Rev Contemp Pharmacother 2000; 11: 13–27Google Scholar
  8. 8.
    Physicians’ desk reference®. 54th ed. Montvale (NJ): Medical Economics Co. Inc., 2000: 2439–41Google Scholar
  9. 9.
    Brynne N, Stahl MMS, Hallén B, et al. Pharmacokinetics and pharmacodynamics of tolterodine in man: a new drug for the treatment of urinary bladder overactivity. Int J Clin Pharmacol Ther 1997; 35: 287–95PubMedGoogle Scholar
  10. 10.
    Brynne N, Dalén P, Alván G, et al. Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of tolterodine. Clin Pharmacol Ther 1998; 63: 529–39PubMedCrossRefGoogle Scholar
  11. 11.
    Postlind H, Danielson A, Lindgren A, et al. Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes. Drug Metab Dispos 1998; 26: 289–93PubMedGoogle Scholar
  12. 12.
    Nilvebrant L, Gillberg P-G, Sparf B. Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine. Pharmacol Toxicol 1997; 81: 169–72PubMedCrossRefGoogle Scholar
  13. 13.
    Mahgoub A, Idle JR, Dring LG, et al. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; II: 584–6CrossRefGoogle Scholar
  14. 14.
    Alván G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990; 39: 533–7PubMedCrossRefGoogle Scholar
  15. 15.
    Brynne N, Forslund C, Hallén B, et al. Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity. Br J Clin Pharmacol 1999; 48: 564–72PubMedCrossRefGoogle Scholar
  16. 16.
    Påhlman I, Gozzi P. Serum protein binding of tolterodine and its major metabolites in humans and several animal species. Biopharm Drug Dispos 1999; 20: 91–9PubMedCrossRefGoogle Scholar
  17. 17.
    Larsson G, Hallén B, Nilvebrant L. Tolterodine in the treatment of overactive bladder: analysis of the pooled phase II efficacy and safety data. Urology 1999; 53: 990–8PubMedCrossRefGoogle Scholar
  18. 18.
    Welling PG. Interactions affecting drug absorption. Clin Pharmacokinet 1984; 9: 404–34PubMedCrossRefGoogle Scholar
  19. 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. 20.
    Chow S-C, Liu J-P. Design and analysis of bioavailability and bioequivalence studies. New York (NY): Marcel Dekker, 1992Google Scholar
  21. 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
  22. 22.
    Dahl ML, Johansson I, Palmertz MP, et al. Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population. Clin Pharmacol Ther 1992; 51: 12–7PubMedCrossRefGoogle Scholar
  23. 23.
    Palmér L, Andersson L, Andersson T, et al. Determination of tolterodine and the 5-hydroxymethyl metabolite in plasma, serum and urine using gas chromatography-mass spectrometry. J Pharm Biomed Analysis 1997; 16: 155–65CrossRefGoogle Scholar
  24. 24.
    Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. 3rd ed. Philadelphia (PA): Williams & Wilkins, 1995Google Scholar
  25. 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
  26. 26.
    Tam YK. Individual variation in first-pass metabolism. Clin Pharmacokinet 1993; 25: 300–28PubMedCrossRefGoogle Scholar
  27. 27.
    Semple HA, Tam YK, Coutts RT. A computer simulation of the food effect: transient changes in hepatic blood flow and Michaelis-Menten parameters as mediators of hepatic first pass metabolism and bioavailability of Propranolol. Biopharm Drug Dispos 1990; 11: 61–76PubMedCrossRefGoogle Scholar
  28. 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
  29. 29.
    McLean AJ, Isbister C, Bobik A, et al. Reduction of first-pass hepatic clearance of Propranolol by food. Clin Pharmacol Ther 1981; 30: 31–4PubMedCrossRefGoogle Scholar
  30. 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. 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

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Department of Clinical PharmacologyPharmacia ABStockholmSweden
  2. 2.Department of Biostatistics and Data ManagementPharmacia ABSweden

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