The role of metabolites in a bioequivalence study II: amoxapine, 7-hydroxyamoxapine, and 8-hydroxyamoxapine.
BACKGROUND
Amoxapine is a dibenzoxazepine type tricyclic antidepressant. The mechanism of clinical action in patients is not well understood. In animals, amoxapine blocks the reuptake of norepinephrine and, to a lesser extent serotonin, into their respective neurons and blocks the response of dopaminergic receptors to dopamine. The major metabolite, 8-hydroxyamoxapine, has similar norepinephrine uptake inhibitory action to the parent drug, but has a more pronounced inhibitory action on serotonin uptake. Another major metabolite, 7-hydroxyamoxapine blocks post-synaptic dopamine receptors.


METHODS
The present study was a traditional two-treatment, two-period, two-sequence crossover design with the primary objective to investigate the average bioequivalence of two formulations of amoxapine. Secondary objectives were to explore the potential roles of metabolites and truncated (partial) areas in bioequivalence studies. Serial plasma samples were harvested from immediately pre dose to 96 hours post dose. The parent drug and the two hydroxy metabolites were monitored by validated HPLC procedures. Geometric mean ratios and 90% confidence intervals (90% CIs) were calculated for Cmax, AUCinfinity, the truncated areas of AUC, AUCinfinity/Cmax, and the truncated areas of AUC/Cmax.


RESULTS
The results indicated that the two formulations were bioequivalent in terms of the conventional parameters Cmax and AUC for all three analytes in the sense that the 90% CIs fitted entirely within preset bioequivalence limits of 80-125%. Moreover, the 90% CIs for the truncated areas AUC2.0hr through AUClast and Cmax/AUC1.0hr through Cmax/AUClast of all three analytes also fell entirely within bioequivalence limits of 80-125%. It was concluded that it was unnecessary to have harvested plasma samples beyond 12 hours, in which case additional plasma samples could have been devoted to the more precise estimation of tmax and Cmax.


CONCLUSIONS
Of the three analytes, test and reference individual plasma concentration versus time curves of 8-hydroxyamoxapine were more closely superimposable than those of the other two analytes. Any decision to use metabolite data in bioequivalence studies, however, must be made a priori to avoid introduction of bias arising from selective post hoc manipulation of the raw data; and to facilitate the design of blood sampling schedules based on prior information about the tmax of the selected analyte.
Midha
K K
KK
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada.
Hubbard
J W
JW
McKay
G
G
Rawson
M J
MJ
Hsia
D
D
D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000097:blood / Q000378:metabolism*; D000328:Adult; D000657:Amoxapine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D006801:Humans; D008875:Middle Aged; D013997:Time Factors
D018759:Adrenergic Uptake Inhibitors; C035234:8-hydroxyamoxapine; C041917:7-hydroxyamoxapine; D000657:Amoxapine