title: 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.
abstract: 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.
  
  
  METHODS
  This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study.
  
  
  METHODS
  The study was conducted in a phase I clinical unit.
  
  
  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 (AUCt 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 (Cmax) and area under the concentration-time curve from time zero to time t (AUCt ) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean Cmax 61.94 ng/mL, coefficient of variation (CV) 23.2%; mean AUCt 817.33 ng·h/mL, CV 27.4%; and 25 mg: mean Cmax 124.91 ng/mL, CV 18.7%; mean AUCt 1630.85 ng·h/mL, CV 22.8%]. Mean AUCt 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 AUCt 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.
authors: Clinical Investigation, Laboratorios del Dr. Esteve, Barcelona, Spain. svidela@esteve.es
authors: Sebastián
authors: S
authors: Videla
authors: Jesús
authors: J
authors: Cebrecos
authors: Mounia
authors: M
authors: Lahjou
authors: France
authors: F
authors: Wagner
authors: Pascal
authors: P
authors: Guibord
authors: Zhengguo
authors: Z
authors: Xu
authors: Anna
authors: A
authors: Cabot
authors: Mercedes
authors: M
authors: Encabo
authors: Gregorio
authors: G
authors: Encina
authors: Eric
authors: E
authors: Sicard
authors: Artur
authors: A
authors: Sans
mesh_terms: D000328:Adult; D001682:Biological Availability; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004319:Doxylamine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005215:Fasting / Q000097:blood; D005260:Female; D064368:Healthy Volunteers; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D013607:Tablets
chemical_list: D006634:Histamine H1 Antagonists; D013607:Tablets; D004319:Doxylamine; C035385:doxylamine succinate
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