Bioavailability investigation of two different oral formulations of doxepin.
Two different oral doxepin (CAS 1668-195) formulations (Doxepin-ratiopharm 25 mg film-coated tablets as test preparation and 25 mg dragées of the reference preparation) were investigated in 30 healthy male and female volunteers in order to prove bioequivalence between these preparations. A single 75 mg oral dose (3 units of test or reference preparation) was given according to a randomised two-way cross-over design in the fasted state. Blood samples for determination of plasma concentration of doxepin and its metabolite N-desmethyldoxepin were collected at pre-defined time points up to 168 h following drug administration. A wash-out period of three weeks separated both treatment periods. Doxepin and N-desmethyldoxepin plasma concentrations were determined by means of a validated LC-MS/MS method. Values of 193,463 pgh/ml (test preparation) and 197,988 pg h/ml (reference preparation) for doxepin as well as values of 313,298 pg h/ml (test preparation) and 306,663 pgh/ml (reference preparation) for N-desmethyldoxepin for the parameter AUC0-infinity demonstrate a nearly identical extent of drug absorption. Maximum concentrations (Cmax) for doxepin/N-desmethyldoxepin of 15,960.06/6,883.69 pg/ml and 18,614.73/6,846.62 pg/ml were achieved for test and reference preparation. Time to reach doxepin maximum plasma concentration (tmax) was 1.98 h for both preparations and for N-desmethyldoxepin tmax was 4.52 h (test preparation) and 4.15 h (reference preparation). Cmax and AUC0-infinity values were tested for statistically significant differences by means of the Two One-Sided T-Tests procedure following ln-transformation of data. Bioequivalence was assumed if the 90% confidence intervals of the T/R-ratios were in the range of 80%-125% for ln-transformed AUC0-infinity and 70%-143% for ln-transformed Cmax. Based on the results obtained in this study, bioequivalence between the test and the reference preparation was demonstrated.
Geister
U
U
Pharmakin GmbH, Gesellschaft für Pharmakokinetik, Ulm, Germany. ursugeis@pharmakin.de
Gaupp
M
M
Arnold
P
P
Schaarschmidt
D
D
Doser
K
K
Renner
J
J
D000284:Administration, Oral; D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001711:Biotransformation; D002138:Calibration; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004316:Doxepin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D011786:Quality Control
D000929:Antidepressive Agents, Tricyclic; D004316:Doxepin