Sex-by-formulation interaction assessed through a bioequivalence study of efavirenz tablets
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Abstract
bioavailability and bioequivalence (product discrimination) is often ignored. On this work results from an
average bioequivalence study between tablets containing 600 mg of the antiretroviral efavirenz (EFV), carried
out with 14 healthy subjects (8 female and 6 men) in a randomized 2-period, 2-treatment crossover design,
are analyzed from a sex-based approach. Sequences were balanced within each sex group. Considering all
subjects, no differences were observed on EFV absorbed amount, as shown by the estimated 90CI of the AUC96
Test/Reference bioequivalence ratio (T/R): 0.950–1.05. However, results were not conclusive due to the 90CI
for CMAX T/R was 0.743–1.07. Over this parameter, a significant sex-by-formulation interaction was detected:
90CI CMAX T/R was 0.838–1.36 in women and 0.540–0.920 in men; with a 52% relative difference between
point estimates. Formulation differences were therefore evidenced only by male subjects. In vitro dissolution
and disintegration tests for both products were carried out in two aqueous media: A) SLS 0.25% and B) HCl/KCl
pH 1.2. T/R results for dissolution efficiency and tablet disintegration times of formulations in both A and B
media were highly correlated with CMAX T/R bioequivalence results observed in women and men respectively,
showing that a dissimilar gastrointestinal environment between sexes affected EFV oral absorption. This work
shows how sex-by-formulation interaction can affect bioequivalence conclusions. Sex effect on product discrimination
should be specially disclosed in bioequivalence studies, mainly for drugs aimed to be given to both sexes.
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