title: Integrating In Vitro, Modeling, and In Vivo Approaches to Investigate Warfarin Bioequivalence.
abstract: We demonstrate the use of modeling and simulation to investigate bioequivalence (BE) concerns raised about generic warfarin products. To test the hypothesis that the loss of isopropyl alcohol and slow dissolution in acidic pH has significant impact on the pharmacokinetics of warfarin sodium tablets, we conducted physiologically based pharmacokinetic absorption modeling and simulation using formulation factors or in vitro dissolution profiles as input parameters. Sensitivity analyses indicated that warfarin pharmacokinetics was not sensitive to solubility, particle size, density, or dissolution rate in pH 4.5, but was affected by dissolution rate in pH 6.8 and potency. Virtual BE studies suggested that stressed warfarin sodium tablets with slow dissolution rate in pH 4.5 but having similar dissolution rate in pH 6.8 would be bioequivalent to the unstressed warfarin sodium tablets. A four-way, crossover, single-dose BE study in healthy subjects was conducted to test the same hypothesis and confirmed the simulation conclusion.
authors.affiliation: Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wen
authors.affiliation: Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fan
authors.affiliation: Vince and Associates Clinical Research Inc, Overland Park, Kansas, USA.
authors.forename: B
authors.initials: B
authors.lastname: Vince
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, USA.
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, USA.
authors.forename: W
authors.initials: W
authors.lastname: Gao
authors.affiliation: Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kinjo
authors.affiliation: Office of Translational Sciences, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Brown
authors.affiliation: Office of Translational Sciences, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: W
authors.initials: W
authors.lastname: Sun
authors.affiliation: Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: W
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lionberger
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D016568:Drugs, Generic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D011897:Random Allocation; D013607:Tablets; D013810:Therapeutic Equivalency; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D016568:Drugs, Generic; D013607:Tablets; D014859:Warfarin