title: Volume to dissolve applied dose (VDAD) and apparent dissolution rate (ADR): tools to predict in vivo bioavailability from orally applied drug suspensions.
abstract: Low solubility of drug candidates generated in research contributes to their elimination during subsequent development due to insufficient oral bioavailability (BA) of crystalline compound. Therefore, the purpose of the study was to identify critical in vitro solubility and dissolution parameter that would predict critical in vivo dissolution by means of in vitro-in vivo correlation. Thermodynamic solubility and apparent dissolution rate (ADR) were determined using the shake-flask method and mini-flow-through-cell, respectively. Oral BA studies in rats and humans were conducted from drug solution and suspension/tablets. Relative BA was calculated using F(rel) [%]=AUC(suspension)/AUC(solution)*100, representing a measure of in vivo dissolution. Roughly, F(rel) rat >50% translates into F(rel) human of >90%. Both, ADR and log volume to dissolve applied dose (VDAD), when plotted against F(rel) rat, revealed certain threshold levels, (ADR, ∼150-200 μg of compound dissolved under respective assay conditions; VDAD, ∼100-500 ml/kg) which translate into F(rel) in rats of >50%. Thus, assuming that F(rel)>50% in rats is indicative of sufficient in vivo dissolution in humans after oral application, drugs should exhibit a VDAD of ∼100-500 ml/kg or less in aqueous media to avoid insufficient or varying drug absorption.
authors.affiliation: Bayer Healthcare, Global Drug Discovery, Germany. uwe.muenster@bayer.com
authors.forename: Uwe
authors.initials: U
authors.lastname: Muenster
authors.forename: Christian
authors.initials: C
authors.lastname: Pelzetter
authors.forename: Thomas
authors.initials: T
authors.lastname: Backensfeld
authors.forename: Andreas
authors.initials: A
authors.lastname: Ohm
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuhlmann
authors.forename: Hartwig
authors.initials: H
authors.lastname: Mueller
authors.forename: Klemens
authors.initials: K
authors.lastname: Lustig
authors.forename: Jörg
authors.initials: J
authors.lastname: Keldenich
authors.forename: Susanne
authors.initials: S
authors.lastname: Greschat
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Göller
authors.forename: Mark Jean
authors.initials: MJ
authors.lastname: Gnoth
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000328:Adult; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D055598:Chemical Phenomena; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D009055:Mouth; D010316:Particle Size; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013535:Suspensions; D055815:Young Adult
chemical_list: D004364:Pharmaceutical Preparations; D013535:Suspensions