Single-dose pharmacokinetics of terodiline, including a stable isotope technique for improvement of statistical evaluations

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Abstract
A bioequivalence study with terodiline (Mictrol®) was performed in 8 healthy volunteers given a 25 mg oral dose of either of two solid dosage forms together with a water solution of the deuterated drug. The solid dosage forms were found to be bioequivalent. Moreover, their pharmacokinetic profiles were the same as for the water solution. The basic pharmacokinetic parameters (means ± SE) of terodiline were calculated to: biological half‐life in serum 60 ± 4 h, maximum serum concentration 79 ± 4 μg 1−1 and the corresponding time 4 ± 1 h, oral serum clearance 75 ± 7 ml min−1, urinary excretion 15.3 ± 1.5 per cent of dose, and renal serum clearance 10.9 ± 2.2 ml min−1. The within‐subject variability (serum‐derived parameters) was about 8 per cent (CV per cent) and the between‐subject variation 2–4 times higher. A single parameter estimate in subjects of a comparative population can be expected to show a 3‐fold variation (95 per cent confidence). The deuterated drug could be used as a covariate to increase the power/precision in the statistical evaluation of the bioequivalence. In that way the 95 per cent confidence interval for the difference between the formulations, as well as the difference that could be detected with 80 per cent power, was reduced 2‐ to 5‐fold. The covariate method was thus in this respect extremely efficient. In bioequivalence studies with drugs where a large number of subjects would be needed using conventional statistical analyses, this method also offers a possibility to considerably reduce the size of the panel, while retaining sufficient power and precision in the estimates.

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