title: Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept.
abstract: The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery.
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany. Electronic address: uwe.muenster@bayer.com.
authors.forename: Uwe
authors.initials: U
authors.lastname: Muenster
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueck
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Dorina
authors.initials: D
authors.lastname: van der Mey
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Schlemmer
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Greschat-Schade
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Haerter
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Pelzetter
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Pruemper
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Verlage
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Göller
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ohm
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry; D001682:Biological Availability; D001702:Biopharmaceutics / Q000379:methods; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D006801:Humans; D054709:Lecithins / Q000737:chemistry; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D012995:Solubility; D013607:Tablets / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D001647:Bile Acids and Salts; D054709:Lecithins; D004364:Pharmaceutical Preparations; D013607:Tablets
keywords: Bioavailability; Biopharmaceutics classification system; Developability classification system; Development; Dissolution; Frel; Solubility; Tablet vs. solution; VDAD; pH-dependent volume to dissolve applied dose