title: Physiologically Based Pharmacokinetic Modeling for Substitutability Analysis of Venlafaxine Hydrochloride Extended-Release Formulations Using Different Release Mechanisms: Osmotic Pump Versus Openable Matrix.
abstract: A Food and Drug Administration-approved generic oral product of venlafaxine hydrochloride (HCl) extended-release (ER) tablets has used a release mechanism based on an openable matrix, which is different from the push-pull osmotic pump system of its reference-listed drug. In an extreme case, a delay in the bursting of the openable matrix may be considered a product failure mode that alters the intended profile of systemic exposure. A physiologically based pharmacokinetic absorption model was established and verified to simulate the pharmacokinetic profiles after a single-dose oral administration of ER venlafaxine HCl tablets based on an osmotic pump or openable matrix design. This model adequately predicted the observed human mean pharmacokinetic metrics with <20% difference between the predicted and observed data. Based on the modeling and simulation results, Cmax and AUCt of the venlafaxine openable matrix tablets were entirely within the bioequivalence acceptance limits (i.e., 80%-125%) when the lag time varied from 0 to 4 h and using drug-release profiles under most dissolution conditions. The results indicated that a bioinequivalence risk is minimal for a delayed onset of drug release from the approved generic venlafaxine HCl ER tablets with an openable matrix design, supporting its substitutability to the reference product.
authors.affiliation: Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Ho-Pi
authors.initials: HP
authors.lastname: Lin
authors.affiliation: Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Dajun
authors.initials: D
authors.lastname: Sun
authors.affiliation: Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993. Electronic address: Xinyuan.Zhang@fda.hhs.gov.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993. Electronic address: Hong.Wen@fda.hhs.gov.
authors.forename: Hong
authors.initials: H
authors.lastname: Wen
mesh_terms: D000284:Administration, Oral; D002214:Capsules; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding / Q000379:methods*; D006801:Humans; D015918:Infusion Pumps, Implantable; D007262:Infusions, Intravenous; D009995:Osmosis / Q000187:drug effects; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D013607:Tablets; D000069470:Venlafaxine Hydrochloride / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D013607:Tablets; D000069470:Venlafaxine Hydrochloride
keywords: bioequivalence; controlled-release; oral drug delivery; osmotic pumps; physiologically based pharmacokinetic modeling