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CPT: Pharmacometrics & Systems Pharmacology

Cover image for Vol. 5 Issue 12

Edited By: Piet van der Graaf, PhD, PharmD

Online ISSN: 2163-8306

Associated Title(s): Clinical and Translational Science, Clinical Pharmacology & Therapeutics

Safety Pharmacology


In addition to its growing use and impact in predicting and optimizing drug efficacy, pharmacometrics and systems pharmacology is also increasingly being applied to define and maximize the benefit-risk profile of pharmacological interventions through quantitative assessment of safety liabilities. Model-based approaches such as exposure-response analysis, physiologically-based pharmacokinetics (PBPK), quantitative systems toxicology (QST) and bio-informatics are now being applied across the R&D spectrum and should contribute to the development of safer medicines. The rapid expansion of the drugable target space into novel areas of biology and pathophysiology requires a parallel development of innovative predictive quantitative frameworks for safety and toxicology. The aim of this virtual issue of CPT:PSP is to publish cutting edge development and application of such methods in drug discovery and development and clinical usage, as well as providing readers with state-of-the-art overviews and tutorials.

September 2016

Original Article
Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis
Dr. Ping Chen , Dr. Per Olsson Gisleskog , Dr. Juan Jose Perez-Ruixo , Dr. Jim Xiao , Dr. Justin Wilkins , Adimoolam Narayanan , Dr. John Gibbs-Member Role , Dr. Murad Melhem
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12106
Abstract | Full Text | PDF | Supporting Information

Commentary
Commentary on "Levofloxacin-induced QTc prolongation depends on the time of drug administration"
Christine Garnett, Lars Johannesen
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12128
Abstract | Full Text | PDF | Supporting Information

Original Article
Quantitative Systems Pharmacology Model to Predict the Effects of Commonly Used Anticoagulants on the Human Coagulation Network
Mirjam Trame, Sonja Hartmann, Konstantinos Biliouris, Lawrence Lesko, Ulricke Nowak-Göttl
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12111
Abstract | Full Text | PDF | Supporting Information

June 2016

Original Article
Cardiovascular Safety Assessment in Early-Phase Clinical Studies: A Meta-Analytical Comparison of Exposure-Response Models
Daniela Conrado, Danny Chen, William Denney
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12086
Abstract | Full Text | PDF | Supporting Information

April 2016

Original Article
Edoxaban exposure-response analysis and clinical utility index assessment in patients with symptomatic deep-vein thrombosis or pulmonary embolism

Joakim Nyberg, Kristin Karlsson, Siv Jonsson, Ophelia Yin, Raymond Miller, Mats Karlsson, Ulrika Simonsson
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12077
Abstract | Full Text | PDF | Supporting Information

Original Article
Translational pharmacokinetic-pharmacodynamic modeling and simulation: Optimizing 5-fluorouracil dosing in children with pediatric ependymoma
Clinton Stewart, Vinay Daryani, Yogesh Patel, Michael Tagen, David Turner, Angle Carcaboso, Jennifer Atkinson, Amar Gajjar, Richard Gilbertson, Karen Wright
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12075
Abstract | Full Text | PDF | Supporting Information

Original Article
A systems pharmacology approach for prediction of pulmonary and systemic pharmacokinetics and receptor occupancy of inhaled drugs
Elin Boger, Neil Evans, Michael Chappell, Anders Lundgvist, Par Ewing, Anders Wigenborg, Markus Friden
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12074
Abstract | Full Text | PDF | Supporting Information

March 2016

Original Article
Model-Based Analysis of Unbound Lopinavir Pharmacokinetics in HIV-Infected Pregnant Women Supports Standard Dosing in the Third Trimester
Julie Dumond, Jingxian Chen, Heather Prince, Stephanie Malone, Kristine Patterson
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12065
Abstract | Full Text | PDF | Supporting Information

White Paper
Good Practices in Model-Informed Drug Discovery and Development (MID3): Practice, Application and Documentation
Scott Marshall, Rolf Burghaus, Valerie Cosson, Amy Cheung, Marylore Chenel, Oscar Della Pasqua, Nicolas Frey, Bengt Hamre, Lutz Harnisch, Frederic Ivanow, Thomas Kerbusch, Jorg Lippert, Peter Milligan, Solange ROHOU, Alexander Staab, Jean-Louis Steimer, Christoffer Tornoe, Sandra Visser
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12049
Abstract | Full Text | PDF | Supporting Information

February 2016

Original Article
Application of a physiologically based pharmacokinetic model to study theophylline metabolism and its interactions with ciprofloxacin and caffeine.
Ali Navid, David Ng, Sergio Wong, Felice Lightstone
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12061
Abstract | Full Text | PDF | Supporting Information

Original Article
Modeling Ribavirin-induced Anemia in Chronic Hepatitis C Virus Patients
David D'Argenio, Liviawati Wu, Leah Jimmerson, Christine MacBrayne, Jennifer Kiser
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12058
Abstract | Full Text | PDF | Supporting Information

January 2016

Original Article
Elucidating Differences in the Hepatotoxic Potential of Tolcapone and Entacapone with DILIsym®, a Mechanistic Model of Drug-induced Livery Injury
Scott Siler, Diane Longo, Yuching Yang, Paul Watkins, Brett Howell
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12053
Abstract | Full Text | PDF | Supporting Information

December 2015

Original Article
Quantitative Prediction and Clinical Evaluation of an Unexplored Herb-Drug Interaction Mechanism in Healthy Volunteers
Brandon Gufford, John Barr, Vanessa Gonzalez-Perez, Matthew Layton, John White, Nicholas Oberlies, Mary Paine
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12047
Abstract | Full Text | PDF | Supporting Information

September 2015

Original Article
Application of a systems pharmacology based placebo population model to analyze long term data of postmenopausal osteoporosis
Jan Berkhout, Julie Stone, Katia Verhamme, Bruno Stricker, Miriam Sturkenboom, Meindert Danhof, Teun Post
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12006
Abstract | Full Text | PDF | Supporting Information

Original Article
Physiologically Based Pharmacokinetic Model to Assess the Influence of Blinatumomab-Mediated Cytokine Elevations on Cytochrome P450 Enzyme Activity
Min Zhu, Yang Xu, Youssef Hijazi, Andreas Wolf, Benjamin Wu, Yu-Nien Sun
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12003
Abstract | Full Text | PDF | Supporting Information

Original Article
Integrating Multiple Evidence Sources to Predict Adverse Drug Reactions Based on Systems Pharmacology Model
Dong-Sheng Cao, Nan Xiao, Yuan-Jian Li, Wen-Bin Zeng, Yi-Zeng Liang, Lu Aiping, Qing-Song Xu, Alex F. Chan
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.12002
Abstract | Full Text | PDF | Supporting Information

August 2015

Original Article
Graphic Mining of High-Order Drug Interactions and Their Directional Effects on Myopathy Using Electronic Medical Records
Li Shen, Lei Du, Arindom Chakraborty, Chien-Wei Chiang, Lijun Cheng, Sara Quinney, Heng-Yi Wu, Pengyue Zhang, Lang Li, Li Shen
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.59
Abstract | Full Text | PDF | Supporting Information

Database
Organ Impairment—Drug–Drug Interaction Database: A Tool for Evaluating the Impact of Renal or Hepatic Impairment and Pharmacologic Inhibition on the Systemic Exposure of Drugs
Shiew Mei Huang, Catherine Yeung, Kenta Yoshida, Makiko Kusama, Huixia Zhang, Isabelle Ragueneau-Majlessi, Sophie Argon, Li Li, Peter Chang, Ping Zhao, Lei Zhang, Yuichi Sugiyama, Christine Le
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.55
Abstract | Full Text | PDF | Supporting Information

Original Article
A Mixture Dose-Response Model for Identifying High-Dimensional Drug Interaction Effects on Myopathy Using Electronic Medical Record Databases
Lang Li, Pengyue Zhang, Lei Du, Lei Wang, Ming Liu, Lijun Cheng, Chien-Wei Chiang, Heng-Yi Wu, Sara Quinney, Li Shen, Lang Li
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.53
Abstract | Full Text | PDF | Supporting Information

July 2015

Original Article
Relationships between pharmacovigilance, molecular, structural and pathway data - Revealing mechanisms for Immune-mediated Drug Induced Liver Injury
David Hibbs, Samuel Ho, Andrew McLachlan, Timothy Chen, Romano Fois
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.56
Abstract | Full Text | PDF | Supporting Information

Original Article
Integrated simulation framework for toxicity, dose intensity, disease progression and cost-effectiveness for castration-resistant prostate cancer
Johan van Hasselt, Anubha Gupta, Ziad Hussein, Jos H Beijnen, Jan Schellens, Alwin Huitema
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.48
Abstract | Full Text | PDF | Supporting Information

June 2015

Editorial
Physiologically based pharmacokinetics is impacting drug development and regulatory decision making
Amin Rostami-Hodjegan, Malcolm Rowland, Lawrence Lesko
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.52
Abstract | Full Text | PDF | Supporting Information

April 2015

Perspective
Application of Physiologically-based Pharmacokinetic (PBPK) Modeling to Support Dose Selection - Report of a FDA Public Workshop on PBPK
Ping Zhao, Christian Wagner, Yuzhuo pan, Vicky Hsu, Joseph Grillo, Shiew Mei Huang, Vikram Sinha
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.33
Abstract | Full Text | PDF | Supporting Information

Perspective
Physiologically Based Models in Regulatory Submissions: Output from the ABPI/MHRA Forum on Physiologically Based Modelling and Simulation
Theresa Shepard, Graham Scott, Susan Cole, Anna Nordmark, Francois Bouzom
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.30
Abstract | Full Text | PDF | Supporting Information

March 2015

Perspective
FDA Advisory Meeting Clinical Pharmacology Review utilizes a Quantitative Systems Pharmacology (QSP) Model: A Watershed Moment?
Mark Peterson, Matthew Riggs
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.20
Abstract | Full Text | PDF | Supporting Information

Review
Modeling and Simulation Approaches for Cardiovascular Function and their Role in Safety Assessment
T A Collins, L Bergenholm, T Abdulla, J W T Yates, N Evans, M J Chappell, J T Mettetal
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.18
Abstract | Full Text | PDF | Supporting Information

January 2015

Original Article
Evaluating the use of linear mixed-effect models for inference of the concentration-QTc slope estimate as a surrogate for a biological QTc model
Yeamin Huh and Matt Hutmacher
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1002/psp4.14
Abstract | Full Text | PDF | Supporting Information

October 2014

Review
Implementation of Quantitative and Systems Pharmacology in Large Pharma
Sandra Visser, Julie Stone, Dinesh De Alwis, Thomas Kerbusch, and Sandra Allerheiligen
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.40
Abstract | Full Text | PDF | Supporting Information

September 2014

Original Article
Model-Based Exposure-Response Analysis of Apixaban to Quantify Bleeding Risk in Special Populations of Subjects Undergoing Orthopedic Surgery
Tarek Leil, Charles Frost, Xiaoli Wang, Marc Pfister, and Frank LaCreta
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.34
Abstract | Full Text | PDF | Supporting Information

Original Article
Similarity-based Modeling applied to Signal Detection in Pharmacovigilance
George Hripcsak, Santiago Vilar Varela, Patrick Ryan, David Madigan, Paul Stang, Martijn Schuemie, Carol Friedman, and Nicholas Tatonett
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.35
Abstract | Full Text | PDF | Supporting Information

Original Article
A Mechanistic, Multi-Scale Mathematical Model of Immunogenicity for Therapeutic Proteins: Part 1. Theoretical model
Paolo Vicini, Xiaoying Chen, and Timothy Hickling
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.30
Abstract | Full Text | PDF | Supporting Information

Original Article
A Mechanistic, Multi-Scale Mathematical Model of Immunogenicity for Therapeutic Proteins: Part 2. Model Applications
Paolo Vicini, Xiaoying Chen, and Timothy Hickling
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.31
Abstract | Full Text | PDF | Supporting Information

August 2014

Original Article
Interaction between domperidone and ketoconazole: Towards prediction of consequent QTc prolongation using purely in vitro information
Sebastian Polak, Himanshu Mishra, Masoud Jamei, and Amin Rostami-Hodjegan
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.26
Abstract | Full Text | PDF | Supporting Information

Commentary
Predicting QTc prolongation in man from only in vitro data
Derek Leishman
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.33
Abstract | Full Text | PDF | Supporting Information

July 2014

Perspective
Clinical Translation in The Virtual Liver Network
Adriano Henney, Lars Kuepfer, and Reinhold Kerb
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.25
Abstract | Full Text | PDF | Supporting Information

Original Article
Kinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel-Induced Hematopoietic Toxicity
Yuichi Sugiyama, Akihiro Yamada, Kazuya Maeda, Kazuma Kiyotani, Taisei Mushiroda, and Yusuke Nakamura
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.23
Abstract | Full Text | PDF | Supporting Information

Original Article
Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI
Jeffrey Woodhead, Kyunghee Yang, Kim Brouwer, Scott Siler, Simone Stahl, Jeffrey Ambroso, David Baker, Paul Watkins, and Brett Howell
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.21
Abstract | Full Text | PDF | Supporting Information

May 2014

Original Article
Integrated systems pharmacology analysis of clinical drug-induced peripheral neuropathy
Jane Bai, Junguk Hur, Abra Guo, Wei-Yin Loh, and Eva Feldman
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2014.11
Abstract | Full Text | PDF | Supporting Information

February 2014

Original Article
A Mechanistic Model of Drug-Induced Liver Injury Aids the Interpretation of Elevated Liver Transaminase Levels in a Phase 1 Clinical Trial
Brett Howell, Scott Siler, Lisl Shoda, Yuching Yang, Jeffrey Woodhead, and Paul Watkins
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.74
Abstract | Full Text | PDF | Supporting Information

January 2014

Original Article
Identifying Tinnitus-Related Genes Based on a Side-Effect Network Analysis
Ana Belen Elgoyhen, Berthold Langguth, Wanda Nowak, Martin Schecklmann, Dirk De Ridder, and Sven Vanneste
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.75
Abstract | Full Text | PDF | Supporting Information

December 2013

Original Article
PKPD Modeling of Predictors for Adverse Effects and Overall Survival in Sunitinib treated patients with GIST
Emma Hansson, Guangli Ma, Michael Amantea, Jonathan French, Peter Milligan, Lena Friberg, and Mats Karlsson
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.62
Abstract | Full Text | PDF | Supporting Information

September 2013

Original Article
Medication-Wide Association Studies
George Hripcsak, Patrick Ryan, David Madigan, Paul Stang, and Martijn Schuemie
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.52
Abstract | Full Text | PDF | Supporting Information

June 2013

Original Article
Evaluation of an in silico PBPK post bariatric surgery model through simulating oral drug bioavailability of atorvastatin and cyclosporine
Amin Rostami-Hodjegan, Adam Darwich, Devendra Pade, Karen Rowland-Yeo, Masoud Jamei, Anders Asberg, Hege Christensen, and Darren Ashcroft
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.23
Abstract | Full Text | PDF | Supporting Information

March 2013

Perspective
The Future of Physiologically Based Pharmacokinetic Modeling to Predict Drug Exposure in Pregnant Women
Alexander Vinks
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.9
Abstract | Full Text | PDF | Supporting Information

February 2013

Perspective
The Role of Modelling and Simulation in Development and Registration of Medicinal Products: Output from the EFPIA/EMA Modelling and Simulation Workshop
Efthymios Manolis, Solange ROHOU, Robert Hemmings, Tomas Salmonson, Mats Karlsson, and Peter Milligan
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.7
Abstract | Full Text | PDF | Supporting Information

Perspective
Modeling and Simulation at the Interface of Non-clinical and Early Clinical Drug Development
Sandra Visser, Efthymios Manolis, Meindert Danhof, and Thomas Kerbusch
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.3
Abstract | Full Text | PDF | Supporting Information

Perspective
Modeling and Simulation in Clinical Pharmacology and Dose Finding
Alexander Staab, Elisabeth Rook, Marc Maliepaard, Leon Aarons, and Charles Benson
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.5
Abstract | Full Text | PDF | Supporting Information

Perspective
Modelling and Simulation as a Tool to Bridge Efficacy and Safety Data in Special Populations
Oscar Della Pasqua, Lutz Harnisch, Gerard Pons, and Theresa Shephard
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.6
Abstract | Full Text | PDF | Supporting Information

Perspective
Modeling and Simulation to optimize the design and analysis of confirmatory trials, characterize risk-benefit and support label claims
Scott Marshall, Robert Hemmings, Filip Josephson, Mats Karlsson, Martin Posch, and Jean-Louis Steimer
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2013.4
Abstract | Full Text | PDF | Supporting Information

January 2013

Erratum
A Mechanistic, Model-Based Approach to Safety Assessment in Clinical Development
Lars Kuepfer, Jörg Lippert, Mario Brosch, Oliver Kampen, von, Michaela Meyer, Hans-Ulrich Siegmund, Clemens Schafmayer, Thomas Becker, Bernd Laffert, Linus Görlitz, Stefan Schreiber, Pertti Neuvonen, Mikko Niemi, and Jochen Hampe
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2012.22
Abstract | Full Text | PDF | Supporting Information

November 2012

Original Article
Predicting Nonlinear Changes in Bone Mineral Density Over Time Using a Multiscale Systems Pharmacology Model
Mark Peterson and Matthew Riggs
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2012.15
Abstract | Full Text | PDF | Supporting Information

September 2012

Original Article
Pharmacokinetic–Pharmacodynamic Modeling of Severity Levels of Extrapyramidal Side Effects With Markov Elements
Klas Petersson, Venkatesh Pilla Reddy, Ahmed Suleiman, An Vermeulen, Johannes Proost, and Lena Friberg
CPT: Pharmacometrics Syst. Pharmacol; doi: 10.1038/psp.2012.9
Abstract | Full Text | PDF | Supporting Information

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