Azole Antifungals: Physiologically-Based Pharmacokinetic (PBPK) Modeling and Prediction of Drug-Drug Interactions (DDIs)

Azole Antifungals: Physiologically-Based Pharmacokinetic (PBPK) Modeling and Prediction of Drug-Drug Interactions (DDIs)

Authors: Fraczkiewicz G, Lukacova V, Parrott N, Bolger MB, Woltosz WS
Keywords: ADMET, azole antifungals, gut, liver, metabolic clearance, PBPK, PEAR, Population Estimates for Age-Related (PEAR™) Physiology™
Software: ADMET Predictor®, GastroPlus®
Division: PBPK

Develop PBPK models for azole antifungals for prediction of DDIs. The absorption and pharmacokinetics of azole antifungals were simulated using GastroPlus™. The program's Advanced Compartmental and…

Azole Antifungals: Physiologically-Based Pharmacokinetic (PBPK) Modeling and Prediction of Drug-drug Interactions (DDIs)

Azole Antifungals: Physiologically-Based Pharmacokinetic (PBPK) Modeling and Prediction of Drug-drug Interactions (DDIs)

Authors: Fraczkiewicz G, Lukacova V, Parrott N, Bolger MB, Woltosz WS
Conference: Rosenon
Keywords: azole antifungals, drug-drug interactions (DDIs), Physiologically based pharmacokinetic (PBPK) modeling
Software: GastroPlus®
Division: PBPK

Download the poster presented at the Rosenon conference in 2009 on the development of PBPK models for common azole antifungals and DDI predictions

Use of a clinically derived exposure-response relationship to evaluate potential tigecycline-Enterobacteriaceae susceptibility breakpoints

Use of a clinically derived exposure-response relationship to evaluate potential tigecycline-Enterobacteriaceae susceptibility breakpoints

Authors: Ambrose PG, Meagher AK, Passarell JA, Van Wart S, Van Wart SA, Cirincione BB, Rubino CM, Korth-Bradley JM, Babinchak T, Ellis-Grosse E
Publication: Diagn Microbiol Infect Dis
Keywords: AUC, MIC, PK, simulation, tigecycline-Enterobacteriaceae
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Potential tigecycline-Enterobacteriaceae susceptibility breakpoints were evaluated using 2 approaches, which differed in the nature of the probabilities assessed by MIC value.

Prediction of drug-drug interaction (DDI) between cilostazol and substrates or inhibitors of CYP 2C19 and 3A4

Prediction of drug-drug interaction (DDI) between cilostazol and substrates or inhibitors of CYP 2C19 and 3A4

Authors: Lukacova V, Chung J, Fraczkiewicz G, Woltosz WS, Bolger MB
Keywords: ACAT model, CYP, drug-drug interactions (DDIs), metabolic clearance, pharmacokinetics (PK)
Software: GastroPlus®
Division: PBPK

The aim of this study was to validate the utility of physiologically based pharamcokinetic (PBPK) models fore predictioin of DDI between cilostazol, kectoconazole, omeprazole and quindine. 

Understanding the effect of API properties on bioavailability through absorption modeling

Understanding the effect of API properties on bioavailability through absorption modeling

Authors: Kesisoglou F, Wu Y
Publication: AAPS J
Keywords: absorption, biological availability, biological models, computer simulation, drug stability, gastrointestinal transit, humans, kinetics, particle size, pharmaceutical chemistry, solubility, theoretical models
Software: GastroPlus®

Selection of API phase is one of the first decision points in the formulation development process.

Prediction of Drug Clearance by Glucuronidation from in Vitro Data: Use of Combined Cytochrome P450 and UDP-Glucuronosyltransferase Cofactors in Alamethicin-Activated Human Liver Microsomes

Prediction of Drug Clearance by Glucuronidation from in Vitro Data: Use of Combined Cytochrome P450 and UDP-Glucuronosyltransferase Cofactors in Alamethicin-Activated Human Liver Microsomes

Authors: Kilford P, Stringer R, Sohal B, Houston JB, Galetin A
Publication: Drug Metab Dispos
Keywords: Human liver cell models, in vitro clearance, in vitro data
Division: PBPK

Glucuronidation via UDP-glucuronosyltransferase (UGT) is an increasingly important clearance pathway.

Toward an improved prediction of human in vivo brain penetration

Toward an improved prediction of human in vivo brain penetration

Authors: Summerfield S, Lucas AJ, Porter RA, Jeffrey P, Gunn RN, Read KR, Stevens AJ, Metcalf AC, Osuna MC, Kilford P, Passchier J, Ruffo AD
Publication: Xenobiotica
Keywords: blood brain barrier penetration, drug discovery, plasma concentration
Division: PBPK

The penetration of drugs into the central nervous system is a composite of both the rate of drug uptake across the blood–brain barrier and the extent of distribution into brain tissue compartments.

General Approach to Calculation of Tissue:Plasma Partition Coefficients for Physiologically Based Pharmacokinetic (PBPK) Modeling

General Approach to Calculation of Tissue:Plasma Partition Coefficients for Physiologically Based Pharmacokinetic (PBPK) Modeling

Authors: Lukacova V, Parrott N, Lavé T, Fraczkiewicz G, Bolger MB
Conference: AAPS
Keywords: Kp, Kps, tissue:plasma, volume of distribution
Software: GastroPlus®
Division: PBPK

To conduct a comprehensive evaluation of methods for calculation of tissue/plasma partition coefficients with a focus on correct prediction of volume of distribution and recommendation for a general…

Role of Fraction Unbound in Plasma in Calculations of Tissue:Plasma Partition Coefficients

Role of Fraction Unbound in Plasma in Calculations of Tissue:Plasma Partition Coefficients

Authors: Lukacova V, Parrott N, Lavé T, Fraczkiewicz G, Bolger MB, Woltosz WS
Conference: AAPS
Keywords: fraction unbound in plasma, Fup, Kps, lipophilicity, logP, pKa, Rbp, tissue:plasma
Software: ADMET Predictor®, GastroPlus®
Division: PBPK

Previous investigations have shown that the Rodgers and Rowland method [Rodgers 2007] for prediction of tissue:plasma partition coefficients (Kps) provides good prediction for compounds with low to moderate…

Level A IVIVC Using a Comprehensive Absorption/PBPK Model for Metoprolol

Level A IVIVC Using a Comprehensive Absorption/PBPK Model for Metoprolol

Authors: Chung J, Lukacova V, Crison JR, Bolger MB, Woltosz WS
Conference: AAPS
Keywords: convolution, deconvolution, in vitro-in vivo correlation (IVIVC), IVIVC, Loo-Riegelmann, Wagner–Nelson Method
Software: GastroPlus®
Division: PBPK

Wagner-Nelson,  Loo-Riegelman,  numerical  deconvolution,  and  convolution-based  methods  are conventional ways to form an in vitro-in vivo correlation (IVIVC). The ultimate goal for forming an IVIVC is to…

Modeling Effects of Exenatide on the Pharmacokinetics of Acetaminophen, Digoxin, and Warfarin

Modeling Effects of Exenatide on the Pharmacokinetics of Acetaminophen, Digoxin, and Warfarin

Authors: Fraczkiewicz G, Parrott N, Lavé T, Lukacova V, Bolger MB, Crison JR, Woltosz WS
Conference: AAPS
Keywords: absorption, absorption model, exenatide, permeability, Type 2 diabetes
Software: ADMET Predictor®, GastroPlus®

Exenatide, a 39-amino acid peptide used for treatment of type 2 diabetes, is known to inhibit gastric emptying and as a result to alter the absorption of orally administered concomitant medications.

Pharmacokinetic/pharmacodynamic modeling and simulation of neutropenia during phase I development of liposome-entrapped paclitaxel

Pharmacokinetic/pharmacodynamic modeling and simulation of neutropenia during phase I development of liposome-entrapped paclitaxel

Authors: Fetterly GJ, Grasela TH, Sherman JW, Dul JL, Grahn A, Lecomte D, Fiedler-Kelly J, Damjanov N, Fishman M, Kane MP, Rubin EH, Tan AR
Publication: Clin Cancer Res
Keywords: 80 and over, administration & dosage, adult, adverse effects, aged, analysis, antineoplastic agents, chemically induced, drug therapy, female, humans, incidence, Liposomes, male, maximum tolerated dose, middle-aged, Phytogenic
Division: Clinical Pharmacology and Pharmacometrics (CPP)

To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel...

Structural Requirements for Drug Inhibition of the Liver Specific Human Organic Cation Transport Protein 1

Structural Requirements for Drug Inhibition of the Liver Specific Human Organic Cation Transport Protein 1

Authors: Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergstrom CAS, Artursson P
Publication: J Med Chem
Keywords: anticancer agents, cationic drugs, imatinib, oral drug absorption, organic cation transport protein (OCT1), oxaliplatin
Software: ADMET Predictor®

The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib.