title: Using Physiologically Based Pharmacokinetic (PBPK) Modeling to Evaluate the Impact of Pharmaceutical Excipients on Oral Drug Absorption: Sensitivity Analyses.
abstract: Drug solubility, effective permeability, and intestinal metabolism and transport are parameters that govern intestinal bioavailability and oral absorption. However, excipients may affect the systemic bioavailability of a drug by altering these parameters. Thus, parameter sensitivity analyses using physiologically based pharmacokinetic (PBPK) models were performed to examine the potential impact of excipients on oral drug absorption of different Biopharmaceutics Classification System (BCS) class drugs. The simulation results showed that changes in solubility had minimal impact on Cmaxand AUC0-tof investigated BCS class 1 and 3 drugs. Changes in passive permeability altered Cmaxmore than AUC0-tfor BCS class 1 drugs but were variable and drug-specific across different BCS class 2 and 3 drugs. Depending on the drug compounds for BCS class 1 and 2 drugs, changes in intestinal metabolic activity altered Cmaxand AUC0-t. Reducing or increasing influx and efflux transporter activity might likely affect Cmaxand AUC0-tof BCS class 2 and 3 drugs, but the magnitude may be drug dependent. Changes in passive permeability and/or transporter activity for BCS class 2 and 3 drugs might also have a significant impact on fraction absorbed and systemic bioavailability while changes in intestinal metabolic activity may have an impact on gut and systemic bioavailability. Overall, we demonstrate that PBPK modeling can be used routinely to examine sensitivity of bioavailability based on physiochemical and physiological factors and subsequently assess whether biowaiver requirements need consideration of excipient effects for immediate release oral solid dosage forms.
authors: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.|, 10903 New Hampshire Ave., Bldg. 75, Room 4690, Silver Spring, Maryland, 20993, USA.
authors: Edwin Chiu Yuen
authors: EC
authors: Chow
authors: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.|, 10903 New Hampshire Ave., Bldg. 75, Room 4690, Silver Spring, Maryland, 20993, USA.
authors: Arjang
authors: A
authors: Talattof
authors: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.|, 10903 New Hampshire Ave., Bldg. 75, Room 4690, Silver Spring, Maryland, 20993, USA.
authors: Eleftheria
authors: E
authors: Tsakalozou
authors: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.|, 10903 New Hampshire Ave., Bldg. 75, Room 4690, Silver Spring, Maryland, 20993, USA.
authors: Jianghong
authors: J
authors: Fan
authors: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.|, 10903 New Hampshire Ave., Bldg. 75, Room 4690, Silver Spring, Maryland, 20993, USA.
authors: Liang
authors: L
authors: Zhao
authors: Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA. Xinyuan.Zhang@fda.hhs.gov.|, 10903 New Hampshire Ave., Bldg. 75, Room 4690, Silver Spring, Maryland, 20993, USA. Xinyuan.Zhang@fda.hhs.gov.
authors: Xinyuan
authors: X
authors: Zhang
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D005079:Excipients / Q000737:chemistry*; D008962:Models, Theoretical; D010539:Permeability; D012995:Solubility
chemical_list: D005079:Excipients
keywords: Biopharmaceutics Classification System (BCS); PBPK modeling; excipients; gastrointestinal transporters; oral drug absorption