title: Utility of PBPK Absorption Modeling to Guide Modified Release Formulation Development of Gaboxadol, a Highly Soluble Compound With Region-Dependent Absorption.
abstract: Given the complexity of controlled release (CR) formulations, selecting the right preclinical tools is important to enable decision making on the in vivo performance of these formulations during development. In recent years, with the advancements of absorption/physiologically based pharmacokinetic (PBPK) modeling, such computational approaches play an increasing role in guiding formulation development. Development of PBPK models for CR formulations requires additional information compared with immediate release (IR) products. Perhaps the most important aspect is the need to simulate absorption in the lower intestine. Relatively few publications have investigated the use of PBPK models for compounds with region-dependent absorption. In this manuscript, we use gaboxadol as a model compound with region-dependent absorption. We first explored gaboxadol regional absorption in dogs to develop a PBPK model for absorption in the large intestine. Two matrix-based CR formulations were subsequently developed and tested in minipigs and demonstrated distinctly different pharmacokinetic profiles from the IR formulation. A minipig absorption PBPK model successfully predicted the observed plasma concentration data, with the predictions based on the in vitro dissolution being within the observed experimental variability. Finally, we demonstrate the development of an in vitro-in vivo correlation for the preclinical data using the same PBPK model.
authors.affiliation: Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck & Company, Inc., West Point, Pennsylvania 19486. Electronic address: filippos_kesisoglou@merck.com.
authors.forename: Filippos
authors.initials: F
authors.lastname: Kesisoglou
authors.affiliation: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Wallingford, Connecticut 06492.
authors.forename: Anand
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck & Company, Inc., West Point, Pennsylvania 19486.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Manser
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003692:Delayed-Action Preparations / Q000378:metabolism / Q000494:pharmacology; D004285:Dogs; D065546:Drug Liberation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007555:Isoxazoles / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D010599:Pharmacokinetics; D012995:Solubility; D013552:Swine; D013556:Swine, Miniature
chemical_list: D003692:Delayed-Action Preparations; D007555:Isoxazoles; C015542:gaboxadol
keywords: bioavailability; controlled release; intestinal absorption; in vitro/in vivo correlations (IVIVC); physiologically based pharmacokinetic modeling; preclinical pharmacokinetics; site-specific absorption