Pharmacokinetics of doxepin and desmethyldoxepin: an evaluation with the population approach.
OBJECTIVE
Little information on the population pharmacokinetics of the tricyclic antidepressant doxepine and its pharmacologically active metabolite desmethyldoxepine is available. However, a more individualised drug therapy may be feasible if the influence of various patient characteristics on plasma concentration was known.


METHODS
We retrospectively analysed pharmacokinetic therapeutic drug-monitoring data in 114 psychiatric patients (79 females, 35 males) treated with doxepine for a period of 22-306 days, mostly due to major depression. The data were analysed using the computer program NONMEM. For both, doxepine and its metabolite desmethyldoxepine, a one-compartment model was chosen. Pharmacokinetic parameters clearance (CL/F) and volume of distribution (V/F) of doxepine and desmethyldoxepine were modelled in terms of both random and fixed effects.


RESULTS
The fit of the model to the concentration-time data was significantly improved when V/F was expressed as a function of weight ( P<0.05) and CL/F as a function of age ( P<0.05). Co-medication that inhibits P(450) isoenzymes lowered CL/F of doxepine by 15%.


CONCLUSIONS
The analysis indicates that the factors age and, to some extent, body weight may be a guidance for individual doxepine dose regimens, which however needs confirmation in prospective clinical trials linking pharmacokinetics and therapeutic effect. Co-medication may represent only a minor important covariate.
Abteilung Klinische Pharmakologie, Universität Göttingen, Göttingen, Germany.
M
M
Meyer-Barner
I
I
Meineke
K H
KH
Schreeb
C H
CH
Gleiter
D000328:Adult; D000368:Aged; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004316:Doxepin / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological
D000929:Antidepressive Agents, Tricyclic; D004316:Doxepin; C028701:desmethyldoxepin