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Retrospective analyses were carried out on 22 analytes involved in nine bioequivalence studies on conventional release products, in which 90% confidence intervals were calculated for partial areas under the plasma concentration versus time curves (AUCs) from the first sampling time to AUC last , The use of partial areas up to 2× the maximum t max among all subjects in any given study gave the same bioequivalence decisions as AUC last .

A bioequivalence study was carried out to compare the bioavailabilities of two formulations containing racemic hydroxychloroquine. The study was based on a single phase parallel design because the enantiomers of hydroxychloroquine have very long terminal phase half lives. A group of n = 72 healthy young men were randomly assigned to receive a single dose of either test ( n = 36 subjects) or the reference ( n = 36 subjects) formulation after which serial blood samples were harvested over 77 days. The two products were found to be bioequivalent in that 90% confidence intervals fell entirely within bioequivalence limits of 80–125% for the log transformed parameters C max and AUC 4 whether calculated from non-chiral or enantioselective blood concentrations. Similarly, 90% confidence intervals for the partial areas from AUC 4 through AUC Inst all fell within 80–125%. These data suggest that enantioselective assays were not required and that blood samples need only have been harvested up to 12 h.

There are few archival data on the impact of stereoisomerism on bioequivalence studies. A bioequivalence study was carried out on two formulations of doxepin containing 15% of the active cis isomer and 85% of the less active trans isomer. Plasma concentrations of cis N-desmethyldoxepin remained at approximately 15% of total in only 2 of 30 healthy volunteers who completed the study. In the remaining 28 subjects, however, the proportion of cis N-desmethyldoxepin steadily increased with time such that by 72 h post dose, cis N-desmethyldoxepin comprised approximately 90% of the metabolite present in plasma. Nevertheless, the 90% confidence intervals (In AUClast, In Cmax and In Cmax/AUClast) for N-desmethyldoxepin fell entirely within bioequivalence li whether stereoselective or non-stereoselective data were analyzed. Thus the results of this study did not support arguments in favor of the use of stereoselective methods in bioequivalence studies.

Sprague Dawley rats (n = 16) were injected intramuscularly with fluphenazine decanoate (78 mg/kg) in sesame oil. Groups of four rats were surgically prepared on days 1, 7, 15 and 32 post-injection and samples of lymph obtained from the thoracic duct. Fluphenazine was found in similar concentrations in lymph and plasma, although the decanoate was not detected in either body fluid. These data suggest that the lymphatic system plays a role in the presystemic absorption of fluphenazine after i.m. administration of fluphenazine decanoate in the rat. In vitro experiments showed that fluphenazine decanoate was very rapidly hydrolyzed when incubated with rat plasma ( t 1 2 0.6 h ) or muscle homogenates ( t 1 2 1.0 h ). Rates of hydrolysis of fluphenazine decanoate were lower in dog muscle homogenates ( t 1 2 4.3 h ), and very much lower when incubated with plasma from dog 42.9 h) or humans ( t 1 2 50.9 h).

A bioequivalence study on perphenazine/amitriptyline combination compared three formulations (TST-1, TST-2 and REF) containing the same nominal dose of perphenazine, while TST-2 contained 20% less amitriptyline than the other two formulations. ANOVA-SNK on log-transformed partial areas AUC024 through AUC0∞ showed the intra-subject variabilities of perphenazine to be consistently higher than those of amitriptyline or nortriptyline. There was also a marked increase in intra-subject variability for perphenazine on extrapolating AUC0last to infinity. Thus, whhile the 1–2α confidence intervals (90% CIs) and ratios of geometric means for perphenazine fell within preset limits of 80–125% in all pairwise comparisons, the CIs for AUC0∞ violated the upper limit in comparisons of TST-2 and REF (or TST-2 and TST-1). This outcome could be attributed to high intra-subject variability on AUC0∞. ANOVA-SNK of amitriptyline identified a significant difference in extent of amitriptyline absorbed from TST-2 compared with TST-1 and REF. Thus, in pairwise comparisons between TST-1 and REF, all 90% CIs for amitriptyline partial areas AUC04 through AUC0∞ fell within 80–125% limits. In corresponding comparisons between TST-2 and REF (or TST-2 and TST-1), however, the lower limit of the 90% CIs for AUC01 through AUC0last consistently fell below the 80% cut off. By contrast, 90% CIs associated with the ratios Cmax/AUC04 through Cmax/AUC0∞ all fell within preset limits indicating no differences in absorption rate of amitriptyline, consistent with the theoretical argument that Cmax/AUC is influenced by rate but not extent of absorption. Thus the partial area method is applicable to the evaluation of both relative rate and extent of absorption from conventional release products. Similarly, analyses of nortriptyline data showed that the partial area method is also effective in the evaluation of rate and extent of formation of a metabolite in a bioequivalence study. The partial area method permits a greater number of plasma samples to be devoted to accurate estimation of tmax and Cmax since the necessity to estimate AUC0∞ is obviated.