title: Differences in Food Effects for 2 Weak Bases With Similar BCS Drug-Related Properties: What Is Happening in the Intestinal Lumen?
abstract: Ketoconazole and posaconazole are both Biopharmaceutics Classification System class 2 drugs (highly permeable, poorly soluble), are structurally similar, and are administered at the same doses. Nevertheless, the duodenal concentration profile and the magnitude of the positive food effect observed for these 2 drugs are markedly different. The aim of this study was to investigate, by means of in silico models, the likely mechanism(s) behind such differences. On the basis of the simulations presented here, it seems highly likely that the balance between the degree of supersaturation in the intestinal lumen and the drug flux across enterocyte membrane can explain the massive difference in the relevance of in vivo precipitation for these 2 drugs, when administered in the fasted state. In the fed state, it appears that the slower gastric emptying together with the higher solubility combines to effect better absorption in the case of posaconazole.
authors.affiliation: Division of Therapeutic Equivalence, Brazilian Health Surveillance Agency (Anvisa), Brasilia, Brazil; Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Cristofoletti
authors.affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, UK.
authors.forename: Nikunjkumar
authors.initials: N
authors.lastname: Patel
authors.affiliation: Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. Electronic address: dressman@em.uni-frankfurt.de.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Dressman
mesh_terms: D000293:Adolescent; D000328:Adult; D001702:Biopharmaceutics; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D005215:Fasting; D005260:Female; D018565:Food-Drug Interactions; D005746:Gastric Emptying; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007654:Ketoconazole / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D014230:Triazoles / Q000737:chemistry / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D014230:Triazoles; C101425:posaconazole; D007654:Ketoconazole
keywords: PBPK model; biopharmaceutics; food effect; ketoconazole; posaconazole; supersaturation