Pharmacokinetic Dose Proportionality Between Two Strengths (12.5 mg and 25 mg) of Doxylamine Hydrogen Succinate Film-Coated Tablets in Fasting State: A Single-Dose, Randomized, Two-Period Crossover Study in Healthy Volunteers

BACKGROUND: Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years. OBJECTIVE: The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects. STUDY DESIGN: This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study. SETTING: The study was conducted in a phase I clinical unit. SUBJECTS AND METHODS: A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration–time curve (AUC(t normalized)). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG). RESULTS: In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (C (max)) and area under the concentration–time curve from time zero to time t (AUC(t)) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean C (max) 61.94 ng/mL, coefficient of variation (CV) 23.2 %; mean AUC(t) 817.33 ng·h/mL, CV 27.4 %; and 25 mg: mean C (max) 124.91 ng/mL, CV 18.7 %; mean AUC(t) 1630.85 ng·h/mL, CV 22.8 %]. Mean AUC(t normalized) was 815.43 ng·h/mL, CV 22.8 % for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUC(t) was 98.92 (90 % CI: 92.46, 105.83). The most common adverse event was somnolence. CONCLUSIONS: Exposure to doxylamine was proportional over the therapeutic dose range of 12.5–25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated.