Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine.
OBJECTIVE
To determine the multiple dose pharmacokinetics of a new extended release (ER) capsule formulation of tolterodine, compared with the existing immediate release (IR) tablet, in healthy volunteers.


METHODS
Nonblind, randomised, 2-way crossover trial.


METHODS
19 healthy volunteers (7 females, 12 males), mean age 33 years (range 18 to 55 years). Prior to the study, all volunteers were classified as either extensive or poor metabolisers by cytochrome P450 2D6 genotyping.


METHODS
Volunteers received tolterodine ER 4mg once daily or tolterodine IR 2mg twice daily for 6 days (all doses given as the L-tartrate salt). A washout period of 7 days separated the 2 treatments. Serum concentrations of tolterodine, its active 5-hydroxymethyl metabolite (5-HM) and the active moiety (extensive metabolisers: sum of unbound tolterodine + 5-HM; poor metabolisers: unbound tolterodine) were measured for up to 48 hours post-dose on day 6 (steady state). Tolerability was also determined.


RESULTS
17 volunteers (13 extensive metabolisers, 4 poor metabolisers) completed the study and were evaluable for both treatment periods. The 90% confidence interval for the geometric mean ratio of area under the serum concentration-time curve to 24 hours (AUC24) of the active moiety, for all volunteers combined, indicated equivalence for the 2 formulations. Pooled analysis also demonstrated that the peak serum concentration (Cmax) of the active moiety following administration of tolterodine ER was around 75% of that observed for the IR tablet, whereas the trough concentration was around 1.5-fold higher. Overall, the pharmacokinetics of tolterodine (irrespective of genotype) and 5-HM (extensive metabolisers only) were consistent with sustained drug release over 24 hours. Tolterodine ER was well tolerated.


CONCLUSIONS
The new once daily ER formulation of tolterodine 4mg shows pharmacokinetic equivalence (AUC24) to the existing IR tablet given at a dose of 2mg twice daily. Findings of lower Cmax for tolterodine ER may explain the significantly lower rate of dry mouth subsequently observed in patients with overactive bladder.
Olsson
B
B
Experimental Medicine, Biovitrum, Division of Pharmacia, Stockholm, Sweden. Birgitta.Olsson@biovitrum.com
Szamosi
J
J
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003408:Cresols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate
D001559:Benzhydryl Compounds; D003408:Cresols; D003692:Delayed-Action Preparations; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D019389:Cytochrome P-450 CYP2D6