title: Effect of Common Excipients on the Oral Drug Absorption of Biopharmaceutics Classification System Class 3 Drugs Cimetidine and Acyclovir.
abstract: The objective was to assess the impact of larger than conventional amounts of 14 commonly used excipients on Biopharmaceutics Classification System (BCS) class 3 drug absorption in humans. Cimetidine and acyclovir were used as model class 3 drugs across three separate four-way crossover bioequivalence (BE) studies (n = 24 each) in healthy human volunteers, denoted as study 1A, 1B, and 2. In study 1A and 1B, three capsule formulations of each drug were manufactured, collectively involving 14 common excipients. Capsule formulations that incorporated hydroxypropyl methylcellulose (HPMC) or magnesium stearate exhibited lower absorption. The cimetidine commercial solution contained sorbitol and also resulted in lower absorption. Hence, in study 2, two capsule formulations with lower amounts of HPMC and magnesium stearate, the sorbitol-containing commercial solution, and a sorbitol-free solution were assessed for BE. Overall, 12 common excipients were found in large amounts to not impact BCS class 3 drug absorption in humans, such that these excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather simply be not more than the quantities studied here. Meanwhile, for each HPMC and microcrystalline cellulose, BCS class 3 biowaivers require these two excipients to be qualitatively the same and quantitatively very similar to the reference.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Soundarya
authors.initials: S
authors.lastname: Vaithianathan
authors.affiliation: Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Sam H
authors.initials: SH
authors.lastname: Haidar
authors.affiliation: Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Wenlei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Christopher
authors.initials: C
authors.lastname: Avon
authors.affiliation: Department of Pharmacy Practice, Ferris State University, Grand Rapids, Michigan 49503.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Dowling
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Changxing
authors.initials: C
authors.lastname: Shao
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Maureen
authors.initials: M
authors.lastname: Kane
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Hoag
authors.affiliation: Department of Gastroenterology and Hepatology, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Flasar
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Tricia Y
authors.initials: TY
authors.lastname: Ting
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201. Electronic address: jpolli@rx.umaryland.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage* / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D001702:Biopharmaceutics / Q000145:classification; D002927:Cimetidine / Q000008:administration & dosage* / Q000378:metabolism*; D018592:Cross-Over Studies; D004347:Drug Interactions / Q000502:physiology; D005079:Excipients / Q000008:administration & dosage* / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology
chemical_list: D005079:Excipients; D002927:Cimetidine; D000212:Acyclovir
keywords: Biopharmaceutics Classification System (BCS); acyclovir; bioequivalence; cimetidine; excipients; oral absorption; permeability