B Olsson1, J Szamosi. 1. Department of Clinical Pharmacology, Pharmacia AB, Stockholm, Sweden. Birgitta.Olsson@eu.pnu.com
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 8 mg (2 x 4 mg capsules) on an empty stomach or with a standardised high-fat breakfast. Reference therapy comprised tolterodine L-tartrate IR 4 mg (2 x 2 mg 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 (AUCinfinity) of the active moiety, for all volunteers combined, was 0.95 (90% confidence interval 0.88 to 1.03). Equivalence with respect to AUCinfinity (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.
RCT Entities:
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 8 mg (2 x 4 mg capsules) on an empty stomach or with a standardised high-fat breakfast. Reference therapy comprised tolterodine L-tartrate IR 4 mg (2 x 2 mg 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 (AUCinfinity) of the active moiety, for all volunteers combined, was 0.95 (90% confidence interval 0.88 to 1.03). Equivalence with respect to AUCinfinity (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.