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.

The Delayed-Release Combination of Doxylamine and Pyridoxine (Diclegis®/Diclectin®) for the Treatment of Nausea and Vomiting of Pregnancy

“…Females have significantly larger systemic exposure to both components of Diclectin ® than males[64]Matok et al, 2013Comparing the pharmacokinetics of Diclectin ® in non-pregnant females and in the first trimester of pregnancy50 females in first trimester of pregnancy compared with 18 non-pregnant femalesIn the first trimester of pregnancy, the pharmacokinetics of Diclectin ® are similar to those of non-pregnant females[65]Rowland et al, 1989Pharmacokinetics of doxylamine in pregnant primatesPrimatesNo pregnancy-induced changes in pharmacokinetics[66] C max peak plasma concentration…”

“…A recent study determined the effect of sex on the pharmacokinetics and bioequivalence (BE) of Diclectin ® [ 64 ]. This single-center, reference-replicate study calculated the pharmacokinetic parameters from 1 h pre-dose until 72 h post-dose in healthy males ( n = 12) and non-pregnant females ( n = 12) after oral administration of two tablets.…”

“…BE testing did not show BE between males and females. The authors concluded that these results may have implications for future BE studies using doxylamine/pyridoxine, and that this drug, for use exclusively in women, should be studied in women and not in men [ 64 ].…”

The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs

“…While most of the studies described were small in size and short in duration, there are findings supportive that for certain anticholinergic medications in certain settings This review on the role of sex, age, and CYP polymorphism on anticholinergic medications confirmed that lower doses are preferable for some individuals. First, women often experience increased drug exposure 49,122 which likely contributes to their experience of more adverse drug reactions than men. 95,97,115,116,118 Women can have other modifying factors such as increased age or CYP polymorphisms which can further potentiate their increased exposure to anticholinergic medications.…”

Evaluation of sex‐by‐formulation interaction in bioequivalence studies of efavirenz tablets

“…Other authors have suggested the need for recruiting male and females in bioequivalence studies simply because they exhibit different exposures when the reference product is administered . Although obvious, it seems necessary to highlight the fact that the existence of sex‐related differences in pharmacokinetics of many drugs is not indicative of a sex‐by‐formulation interaction because if a drug exhibits different pharmacokinetic parameters between males and females, the same is expected for the test and for the reference product.…”