title: Mitigation of Adverse Clinical Events of a Narrow Target Therapeutic Index Compound through Modified Release Formulation Design: An in Vitro, in Vivo, in Silico, and Clinical Pharmacokinetic Analysis.
abstract: BMS-914392 is a tricyclic pyranoquinoline BCS class 2 weak base that demonstrates high solubility in low pH environments. Initial clinical studies indicated that rapid release of high dose BMS-914392 led to transient adverse events associated with peak plasma concentrations. A modified release (MR) formulation strategy was proposed to suppress the peak blood concentration and maintain total exposure to overcome the adverse effects. Three modified release prototype formulations were developed and tested via a USP 3 dissolution method to verify that each formulation can effectively slow the release of BMS-914392. A pharmacokinetic (PK) absorption model was employed to guide the formulation development and selection. Simulations showed good agreement with plasma levels measured after oral dosing in dogs. Identification of key formulation factors to achieve release rates suitable for blunting peak blood levels without diminishing exposure were achieved through combined preclinical data and use of GastroPlus simulations. PK absorption model refinements based on phase 1 data, dog pharmacokinetic results, and in vitro data provided reliable predictions of human absorption profiles and variability in patients. All three prototype formulations demonstrated lower maximum plasma concentrations of BMS-914392 and maintained satisfactory relative bioavailability. Both the PK absorption model and subsequent clinical data indicated that an acidified hydrophilic matrix MR formulation had the greatest potential to reduce the incidence of adverse events and showed the best exposure profile in fasted state healthy subjects with and without famotidine coadministration. The risk based development process achieved successful screening and selection of a suitable modified release formulation to enable clinical efficacy trials.
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb , New Brunswick, New Jersey 08903, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Good
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb , New Brunswick, New Jersey 08903, United States.
authors.forename: Ruiling
authors.initials: R
authors.lastname: Hartley
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb , New Brunswick, New Jersey 08903, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Mathias
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb , New Brunswick, New Jersey 08903, United States.
authors.forename: John
authors.initials: J
authors.lastname: Crison
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Giridhar
authors.initials: G
authors.lastname: Tirucherai
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb , Moreton, U.K.
authors.forename: Peter
authors.initials: P
authors.lastname: Timmins
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb , New Brunswick, New Jersey 08903, United States.
authors.forename: Munir
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb , New Brunswick, New Jersey 08903, United States.
authors.forename: Raja
authors.initials: R
authors.lastname: Haddadin
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb , New Brunswick, New Jersey 08903, United States.
authors.forename: Otilia
authors.initials: O
authors.lastname: Koo
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb , New Brunswick, New Jersey 08903, United States.
authors.forename: Faranak
authors.initials: F
authors.lastname: Nikfar
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
authors.forename: Nga Kit Eliza
authors.initials: NK
authors.lastname: Fung
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D018592:Cross-Over Studies; D004285:Dogs; D015738:Famotidine / Q000008:administration & dosage; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008954:Models, Biological; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012995:Solubility
chemical_list: D011804:Quinolines; D015738:Famotidine; C037219:quinoline
keywords: BCS 2 weak base; enteric coating; hydrophilic matrix tablets; in vitro dissolution; in vivo site of absorption; modified release formulation; pH effect mitigation; pharmacokinetic absorption model