title: Systemic in vitro and in vivo evaluation for determining the feasibility of making an amorphous solid dispersion of a B-Raf (rapidly accelerated fibrosarcoma) inhibitor.
abstract: It is well acknowledged that oral bioavailability of a drug candidate is often influenced by factors such as the permeability, physico-chemical properties, and metabolism of the drug. Among the physico-chemical properties, solubility and dissolution rate are considered the most critical factors affecting the oral bioavailability of a compound G-F is a potent and selective B-Raf inhibitor with poor solubility and adsorption is limited by solubility at high doses. In order to overcome this issue using a spray-dried amorphous dispersion (SDD) formulation was evaluated. A combination of theoretical solubility prediction and in vitro dissolution, were used to predict the in vivo exposure of G-F. The predicted value was found to have good agreement with the in vivo exposure from dosing the crystalline and amorphous form of G-F. In general, this combined approach demonstrated that the amorphous form of G-F offers an advantage over the crystalline form of G-F in terms of solubility; in vitro dissolution and in vivo absorption were predictable and consistent with the literature. This systemic approach provides a great value for compound development.
authors.affiliation: Department of Small Molecule Pharmaceutics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cui
authors.forename: Po-Chang
authors.initials: PC
authors.lastname: Chiang
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
authors.forename: Steve
authors.initials: S
authors.lastname: Wenglowsky
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Ran
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D005240:Feasibility Studies; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D008956:Models, Chemical; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf
keywords: AUC; B-Raf; Bioavailability; C(max); C(p); CL; DSC; Dissolution; F; HPLC; HPMC-E4; HPMCAS-MF; High Performance Liquid Chromatography; K; K(a); K12; K21; MP; Prediction; Raf; SDD; SEM; Solubility; T(g); XRPD; absorption constant; area under the concentration-timer profile; bioavailability; clearance; differential scanning calorimetry; first-order terminal elimination rate constant; glass transition temperature; hydroxypropyl methylcellulose (grade E4); hydroxypropyl methylcellulose acetate succinate (grade-MF); intercompartment rate constant from central to peripheral compartment; intercompartment rate constant from peripheral to central compartment; isobaric heat capacity; maximum concentration; melting point; powder X-ray diffraction; rapid accelerated fibrosarcoma; scanning electron microscopy; spray-dried amorphous dispersion