title: Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm.
abstract: Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.
authors.affiliation: Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck & Co. Inc., WP75B-210, 770 Sumneytown Pike, West Point, Pennsylvania, 19486-0004, USA, filippos_kesisoglou@merck.com.
authors.forename: Filippos
authors.initials: F
authors.lastname: Kesisoglou
authors.forename: Amitava
authors.initials: A
authors.lastname: Mitra
mesh_terms: D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D015195:Drug Design; D065546:Drug Liberation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D010316:Particle Size; D010599:Pharmacokinetics; D012995:Solubility; D013607:Tablets
chemical_list: D003692:Delayed-Action Preparations; D013607:Tablets