title: Sex differences in the pharmacokinetics and bioequivalence of the delayed-release combination of doxylamine succinate-pyridoxine hydrochloride; implications for pharmacotherapy in pregnancy.
abstract: 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 AUC0-t for each analyte. Females had significantly larger AUC0-t 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 Cmax 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.
authors.affiliation: Department of Pediatrics, Division of Clinical Pharmacology/Toxicology, The Motherisk Program, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.forename: Manon
authors.initials: M
authors.lastname: Vranderick
authors.forename: Simerpal K
authors.initials: SK
authors.lastname: Gill
authors.forename: Stuart
authors.initials: S
authors.lastname: Macleod
mesh_terms: D000328:Adult; D000932:Antiemetics / Q000097:blood / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D004025:Dicyclomine / Q000097:blood / Q000493:pharmacokinetics*; D004319:Doxylamine / Q000097:blood / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D011247:Pregnancy; D011736:Pyridoxine / Q000097:blood / Q000493:pharmacokinetics*; D012727:Sex Characteristics; D013810:Therapeutic Equivalency
chemical_list: D000932:Antiemetics; D003692:Delayed-Action Preparations; D004338:Drug Combinations; C004454:dicyclomine, doxylamine, pyridoxine drug combination; D004025:Dicyclomine; D004319:Doxylamine; D011736:Pyridoxine
keywords: Diclegis®; bioequivalence; doxylamine succinate; gender differences; pyridoxal-5′-phosphate; pyridoxine hydrochloride