Predictions of in vivo plasma concentrations from in vitro release kinetics: application to doxepin parenteral (i.m.) suspensions in lipophilic vehicles in dogs.
A flow through dissolution system was applied to obtain biorelevant dissolution rates from controlled release systems for parenteral administration using the antidepressant doxepin as a model compound. Plasma concentrations were simulated using the disposition function of doxepin obtained from administration of an aqueous doxepin solution (AponalR) to beagle dogs. Input functions were obtained from in vitro dissolution experiments with three parenteral controlled release suspensions of doxepin hydrochloride (DHCl), doxepin pamoate (DP-1), and microspheres of doxepin hydrochloride in poly D,L-lactid-co-glycolid (MC-1) in isopropyl myristate. The predicted plasma concentrations were compared with experimentally obtained concentrations in vivo. Good correlations (r > 0.88) between observed and predicted data were obtained for all formulations investigated. Similarly, in vivo release kinetics calculated by the Loo-Riegelman method were compard with release kinetics measured in vitro and showed good correlations (r > 0.89). It is anticipated that the in vitro dissolution system permits assessment of the clinical relevance of observed variations in dissolution rates e.g. between batches of one formulation.
Gido
C
C
Department of Pharmacology, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
Langguth
P
P
Mutschler
E
E
D000042:Absorption; D000818:Animals; D003692:Delayed-Action Preparations; D004285:Dogs; D004316:Doxepin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D007273:Injections, Intramuscular; D008297:Male; D008863:Microspheres; D014677:Pharmaceutical Vehicles; D012995:Solubility; D013535:Suspensions
D003692:Delayed-Action Preparations; D014677:Pharmaceutical Vehicles; D013535:Suspensions; D004316:Doxepin