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...

Use of structure-activity landscape index curves and curve integrals to evaluate the performance of multiple machine learning prediction models

Use of structure-activity landscape index curves and curve integrals to evaluate the performance of multiple machine learning prediction models

Authors: LeDonne NC Jr, Rissolo K, Bulgarelli J, Tini L
Publication: J Cheminform
Keywords: machine learning method, predictive models, structure-activity landscape index (SALI), structure−activity relationships (SAR)
Software: ADMET Predictor®

Standard approaches to address the performance of predictive models that used common statistical measurements for the entire data set provide an overview of...

Evolving hERG Inhibition Model

Evolving hERG Inhibition Model

Authors: Lee AC, Fraczkiewicz G, Fraczkiewicz R, Clark RD, Woltosz WS
Conference: ACS
Keywords: ADMET, ANNE, artificial neural network ensembles (ANNE), hERG, hERG inhibition, U.S. FDA
Software: ADMET Predictor®
Division: PBPK

Modeling hERG inhibition has significantly gained popularity since 2005, when the FDA recognized the correlation between hERG inhibition and a prolonged QT interval by issuing guidance for the…

Physiologically-Based Pharmacokinetic (PBPK) Model for Prediction of Tobramycin Pulmonary Absorption and Pharmacokinetics in Children

Physiologically-Based Pharmacokinetic (PBPK) Model for Prediction of Tobramycin Pulmonary Absorption and Pharmacokinetics in Children

Authors: Lukacova V, Chaudhuri S, Woltosz WS, Bolger MB
Keywords: absorption, additional dosage routes, ADMET, Cp-Time, PBPK, PEAR, Population Estimates for Age-Related (PEAR™) Physiology™, pulmonary, pulmonary playlist, tissue:plasma, tobramycin
Software: ADMET Predictor®, GastroPlus®
Division: PBPK

To fit an absorption-pharmacokinetic model for simulation of tobramycin in adult and pediatric populations. Tobramycin pulmonary absorption and pharmacokinetics were simulated using GastroPlus™.

Physiologically-based pharmacokinetic {PBPK) models for prediction of time-dependent enzyme inhibition (TDI): effect of diltiazem on midazolam and quinidine

Physiologically-based pharmacokinetic {PBPK) models for prediction of time-dependent enzyme inhibition (TDI): effect of diltiazem on midazolam and quinidine

Authors: Lukacova V, Chung J, Woltosz WS, Bolger MB
Keywords: ACAT model, CYP, diltiazem, midazolam, PBPK model, pharmacokinetic, time-dependent enzyme inhibition (TDI)
Software: GastroPlus®
Division: PBPK

Purpose of the study was to optimize a PBPK model to predict time­dependent and competitive inhibition of CYP 3A4 by diltiazem...

Pharmacokinetics of dietary cancer chemopreventive compound dibenzoylmethane in rats and the impact of nanoemulsion and genetic knockout of Nrf2 on its disposition

Pharmacokinetics of dietary cancer chemopreventive compound dibenzoylmethane in rats and the impact of nanoemulsion and genetic knockout of Nrf2 on its disposition

Authors: Lin W, Hong JL, Shen G, Wu RT, Wang Y, Huang MT, Newmark HL, Huang Q, Khor TO, Heimbach T, Kong AN
Publication: Biopharm Drug Dispos
Keywords: bioavailability, hepatic blood clearance, in vitro-in vivo correlation (IVIVC), intravenous administration, oral administration, pharmacokinetics, rats
Software: GastroPlus®

The pharmacokinetic disposition of a dietary cancer chemopreventive compound dibenzoylmethane (DBM) was studied in male Sprague-Dawley rats after intravenous...