The Application of Physiologically Based Pharmacokinetic Modelling to Understanding the Clinical Pharmacokinetics of UK-369,003

The Application of Physiologically Based Pharmacokinetic Modelling to Understanding the Clinical Pharmacokinetics of UK-369,003

Authors: Watson KJ, Davis J, Jones HM
Publication: Drug Metab Dispos
Keywords: bioavailability, Cyclic Nucleotide Phosphodiesterases, dose-response relationship drug, humans, intravenous infusions, oral administration, pharmacokinetics, phosphodiesterase inhibitors, pyrimidinones, sulfonamides
Software: GastroPlus®

5-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-pyridin-3-yl]-3-ethyl-2-(2-methoxy-ethyl)-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (UK-369,003) is a phosphodiesterase-5...

Physiological modeling and assessments of regional drug bioavailability of danoprevir to determine whether a controlled release formulation is feasible

Physiological modeling and assessments of regional drug bioavailability of danoprevir to determine whether a controlled release formulation is feasible

Authors: Reddy M, Connor A, Brennan BJ, Morcos PN, Zhou A, McLawhon P, Fretland A, Evans P, Smith P, Tran JQ
Publication: Biopharm Drug Dispos
Keywords: administration and dosage, animals, antiviral agents, biological availability, biological models, humans, intestinal absorption, lactams, macaca fascicularis, oral administration, pharmacokinetics, sulfonamides
Software: GastroPlus®

Danoprevir, a potent, selective inhibitor of HCV NS3/4A protease, has a short half-life in humans. Therefore, the feasibility of a controlled release (CR) formulation to allow less frequent dosing...

Semi-mechanistic PK/PD Model of the Effect of Odanacatib, a Cathepsin K Inhibitor, on Bone Turnover to Characterize Lumbar Spine and Distal Forearm Bone Mineral Density in a Phase IIb Study of Postmenopausal Women

Semi-mechanistic PK/PD Model of the Effect of Odanacatib, a Cathepsin K Inhibitor, on Bone Turnover to Characterize Lumbar Spine and Distal Forearm Bone Mineral Density in a Phase IIb Study of Postmenopausal Women

Authors: Zajic S, Stone J, Jaworowicz DJ, Leung A, Duong LT, Passarell JA, Fiedler-Kelly J, Cohn D, Verbruggen N, Stoch A
Conference: PAGE
Keywords: 1-compartment, biomarker, BMD, bone mineral density, BSAP, dose-response, empirical, functional forms, indirect response model, inhibitory sigmoid Emax function, linear elimination, lumbar spine, MK-0822, ODN, orthopedics, osteoclast, osteoporosis, P1NP, Phase 2, placebo, rate limiting, resorption, resorptive, saturable bioavailability with dose, turnover, uNTx
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Odanacatib (MK-0822), a potent, orally-active inhibitor of cathepsin K, is under clinical development for treatment of postmenopausal osteoporosis. This poster describes base model development of a…

Simulating the Disposition of Triamcinolone Acetonide following Oral and Pulmonary Administration

Simulating the Disposition of Triamcinolone Acetonide following Oral and Pulmonary Administration

Authors: Chaudhuri S, Lukacova V, Woltosz WS
Conference: RDD
Keywords: ACAT, ADMET, Advanced Compartmental Absorption and Transit (ACAT™) model, Cmax, Cp-Time, Km, oral, PBPK, pulmonary, triamcinolone acetonide (TA), Vmax
Software: ADMET Predictor®, GastroPlus®
Division: PBPK

Absorption, distribution and clearance of triamcinolone acetonide (TA) from oral and pulmonary administrations have been simulated using GastroPlus™,1. Simulation of orally administered doses and swallowed…

Simulation of human intravenous and oral pharmacokinetics of 21 diverse compounds using physiologically based pharmacokinetic modelling

Simulation of human intravenous and oral pharmacokinetics of 21 diverse compounds using physiologically based pharmacokinetic modelling

Authors: Jones HM, Gardner IB, Collard WT, Stanley PJ, Oxley P, Hosea NA, Plowchalk D, Gernhardt S, Lin J, Dickins M, Rahavendran SR, Jones BC, Watson KJ, Pertinez H, Kumar V, Cole S
Publication: Clin Pharmacokinet
Keywords: animals, area under curve, biological models, computer simulation, dogs, humans, injections, intravenous, metabolic clearance, oral administration, pharmaceutical preparations, pharmacokinetics, rats, species specificity
Software: GastroPlus®

The importance of predicting human pharmacokinetics during compound selection has been recognized in the pharmaceutical industry. To this end there are many different approaches that are applied.

Mixture Modeling as a Data Imputation Method

Mixture Modeling as a Data Imputation Method

Authors: Willavize S, Fiedler-Kelly J, Hanley W, Mahnke L, Hang Y, Peng JZ, Phillips L
Conference: ACoP
Keywords: metabolizers, NONMEM, Phase 1, Phase 2, PK/PD methodology, R matrix, S matrix
Division: Clinical Pharmacology and Pharmacometrics (CPP)

To demonstrate the use of mixture modeling in population PK analysis to predict drug concentrations for a subset of subjects with missing data for a key categorical covariate.

A Semi-mechanistic Approach to PK/PD Modeling of Complex Response Data: Bone Turnover Example for Odanacatib, a Cathepsin K Inhibitor

A Semi-mechanistic Approach to PK/PD Modeling of Complex Response Data: Bone Turnover Example for Odanacatib, a Cathepsin K Inhibitor

Authors: Stone J, Zajic S, Jaworowicz DJ, Leung A, Duong LT, Passarell JA, Fiedler-Kelly J, Cohn D, Verbruggen N, Stoch A
Conference: ACoP
Keywords: 1-compartment, biomarker, BMD, bone mineral density, BSAP, dose-response, empirical, functional forms, indirect response model, linear elimination, lumbar spine, MK-0822, ODN, orthopedics, osteoclast, P1NP, Phase 2, placebo, rate limiting, resorption, resorptive, saturable bioavailability with dose, turnover, uNTx
Division: Clinical Pharmacology and Pharmacometrics (CPP)

A variety of approaches can be taken to incorporate greater mechanistic understanding into PK/PD models, including a variety of bottom-up, middle-out, and top-down approaches. The osteoporosis field…

New to an Organization: Tools to Assess Projects and Teams

New to an Organization: Tools to Assess Projects and Teams

Authors: Walawander CA, Grasela TH, Zelasko T, Willetts T, Gomathinayagam V, Tsai CF, Macri J
Conference: Project Management Institute (PMI) Pharmaceutical Community of Practice (CoP)
Keywords: drug development process, management, multidisciplinary, optimizing resources, project team, resource allocation, risk, successful organizations
Division: Clinical Pharmacology and Pharmacometrics (CPP)

The complexity of project management and its value increase exponentially as the number and complexity of projects and interdisciplinary team participation increases.

Exposure–Response Analysis of Eslicarbazepine Acetate as Adjunctive Treatment of Patients With Partial-onset Seizures

Exposure–Response Analysis of Eslicarbazepine Acetate as Adjunctive Treatment of Patients With Partial-onset Seizures

Authors: Kharidia J, Passarell JA, Maier G, Zummo J, Ludwig E, Grasela TH, Fiedler-Kelly J
Conference: ASCPT
Keywords: AED, antiepileptic, Cav-ss, central nervous system agents, dose, dosing, EC50, Emax, epilepsy, esli, logit, neurology, placebo, responder rate
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Eslicarbazepine acetate (ESL) is a novel once-daily (QD) antiepileptic drug (AED) currently under clinical development in the US. ESL is rapidly and extensively metabolized to its major active metabolite…

Population Pharmacokinetics of Eslicarbazepine Acetate in Patients With Partial-onset Seizures

Population Pharmacokinetics of Eslicarbazepine Acetate in Patients With Partial-onset Seizures

Authors: Kharidia J, Versavel M, Lu Q, Zummo J, Ludwig E, Grasela TH, Fiedler-Kelly J, Maier G, Soares-da-Silva P
Conference: ASCPT
Keywords: 1-compartment, AED, allometric scaling, Carbamazepine, central nervous system agents, clearance, esli, neurology, once daily, Phase 3, phenobarbital, QD, Sunovion, valproate, volume of distribution
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Eslicarbazepine acetate (ESL) is a novel once-daily antiepileptic drug (AED) currently under clinical development in the US. Following oral administration, ESL is rapidly and extensively metabolized…

Utility of Physiologically Based Absorption Modeling in Implementing Quality by Design in Drug Development

Utility of Physiologically Based Absorption Modeling in Implementing Quality by Design in Drug Development

Authors: Zhang X, Lionberger RA, Davit BM, Yu LX
Publication: AAPS J
Keywords: absorption, anticonvulsants, biological models, Carbamazepine, computer simulation, food-drug interactions, humans, intestinal absorption, pharmacokinetics, solubility, therapeutic equivalency
Software: GastroPlus®

To implement Quality by Design (QbD) in drug development, scientists need tools that link drug products properties to in vivo performance

In Vitro-In Vivo Correlation for Gliclazide Immediate-Release Tablets Based on Mechanistic Absorption Simulation.

In Vitro-In Vivo Correlation for Gliclazide Immediate-Release Tablets Based on Mechanistic Absorption Simulation.

Authors: Grbic S, Parojcić J, Ibric S, Djuric Z
Publication: AAPS PharmSciTech
Keywords: biological models, computer simulation, dosage, Gliclazide, humans, hydrogen-ion concentration, Hypoglycemic, in vitro-in vivo correlation (IVIVC), intestinal absorption, permeability, solubility
Software: GastroPlus®

The aim of this study was to develop a drug-specific absorption model for gliclazide (GLK) using mechanistic gastrointestinal simulation technology (GIST) implemented...

Prediction of Oral Pharmacokinetics of cMet Kinase Inhibitors in Humans: Physiologically Based Pharmacokinetic Model versus Traditional One Compartment Model.

Prediction of Oral Pharmacokinetics of cMet Kinase Inhibitors in Humans: Physiologically Based Pharmacokinetic Model versus Traditional One Compartment Model.

Authors: Yamazaki S, Skaptason J, Romero D, Vekich S, Tan W, Jones HM, Wilner KD, Koudriakova T
Publication: Drug Metab Dispos
Keywords: animals, biological availability, dogs, drug evaluation, heptocyte, humans, metabolic clearance rate, metabolism, oral administration, pharmacokinetics, protein kinase inhibitors, proto-oncogene proteins, pyrazines, pyrazoles, rats
Software: GastroPlus®

The objective of this study was to assess the physiologically based pharmacokinetic (PBPK) model for predicting plasma concentration-time profiles...