Sex differences in the pharmacokinetics and bioequivalence of the delayed-release combination of doxylamine succinate-pyridoxine hydrochloride; Implications for pharmacotherapy in pregnancy

Most bioequivalence (BE) studies are conducted in males with the assumption that variability in pharmacokinetics is similar between the sexes. The purpose of this single]center, reference replicate study was to determine the effect of sex on the pharmacokinetics and BE of doxylamine.pyridoxine 10 mg.10 mg delayed-release tablets. Healthy males (n.12) and non-pregnant females (n.12) were administered two tablets, and blood sampling was conducted from 1 hour pre-dose until 72 hours post-dose. After 21 days, dose administration and blood sampling were re-conducted. All analytes were measured using liquid chromatography-tandem mass-spectrometry. Pharmacokinetic parameters were calculated for each study period using standard, non-compartmental methods, and differences were assessed using ANOVA. BE testing was conducted using the relative 90% confidence interval for the AUC0t for each analyte. Females had significantly larger AUC0t for doxylamine, 1,550 ng h/mL (coefficient of variance [CV=19%]) versus 1,272 ng h/ mL (CV=21%; P≤.05), and pyridoxine, 35 ng h/mL, (CV=43%) versus 25 ng h/mL (CV=31%; P≤.05) compared to males. A higher C_max for doxylamine was observed in females, 107 ng/mL (CV=16%), compared to males, 86 ng/mL (CV=15%) (P≤.05). BE testing did not demonstrate bioequivalence between males and females. Pharmacokinetic differences observed between the sexes have implications for future BE studies using doxylamine.pyridoxine.