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The role of metabolites in a bioequivalence study 1: loxapine, 7-hydroxyloxapine and 8-hydroxyloxapine.

Author(s): Midha KK, Hubbard JW, McKay G, Hawes EM, Hsia D

Affiliation(s): College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.

Publication date & source: 1993-04, Int J Clin Pharmacol Ther Toxicol., 31(4):177-83.

Publication type: Clinical Trial; Randomized Controlled Trial; Research Support, Non-U.S. Gov't

Loxapine is a drug which is used in the treatment of psychotic disorders. The drug is extensively biotransformed in humans to produce a variety of metabolites, some of which have pharmacological activity. Seven-hydroxyloxapine is 4-5 times more active than the parent drug, although its concentrations in plasma are relatively low. Eight-hydroxyloxapine, on the other hand, is inactive, but is present in higher concentrations in plasma than the parent drug. In the present randomized crossover study to evaluate the bioequivalence of two dosage forms containing loxapine, the parent drug and its 7-hydroxy and 8-hydroxy metabolites were monitored for up to 96 hours after the administration of the test or reference formulations. Estimates of average bioavailability (AUC- infinity, AUC0t and Cmax) were obtained by the difference of the least squares means of log test and log reference. A 90% confidence interval for the log difference was derived from the within-subject error. The test of bioequivalence requires the 90% confidence band so calculated to fall entirely within an imposed regulatory interval of 80-125%. The results showed the two formulations to be bioequivalent in terms of the log mean differences and 90% confidence bands calculated for all three analytes. In fact, the within-subject variabilities of the metabolites were relatively low, so that the 90% confidence intervals for ln AUC0 infinity, ln AUC0t and ln Cmax calculated for the metabolites, were narrower that those for the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)

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