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Physiologically Based Pharmacokinetic Modeling

AP 873

Spring 2020 -- An online course for both on-campus and distance students through K-State Global campus.

Learn online. Develop professionally. Connect globally.

Course Overview

This course is designed to teach physiologically based pharmacokinetic (PBPK) modeling at a very basic level. Development of PBPK models for environmental chemicals, drugs, and nanomaterials in laboratory animals, food-producing animals, companion animals, and/or humans will be introduced. Applications of PBPK models in food safety, toxicology, risk assessment, and pharmaceutical industry will be discussed. This course will cover theory, application software, model development, optimization, validation, evaluation, and extrapolation. The expected outcome is that the student will have PBPK modeling knowledge and skills to develop a PBPK model with some mentoring from an experienced PBPK modeler.

Course objectives

To provide the student with working knowledge of PBPK models and their applications in toxicology

To provide students with the technical ability to develop PBPK models for use in their research and careers

Course Format

The format will include both lectures and hands-on computer lab exercises. A new Module will be posted each week, and the student is expected to:

Read any assigned textbook chapter(s), articles, and/or supplementary materials

Listen/watch any posted lectures

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Participate in the Discussion Board

Do any quizzes/assignments, which must be submitted by Sunday of that week

Work on a selected PBPK modeling project related to the student’s graduate research or work throughout the semester

Course prerequisites

General knowledge of an online learning management system

One semester of physiology, pharmacology, pharmacokinetics, toxicology, or biochemistry

One semester of calculus or permission of the instructor (don’t be afraid of calculus; we only use relatively little of that and we will review it slowly and clearly at the beginning)

Access to a computer with reliable internet access, a microphone, and a webcam, as well as with the PBPK modeling software RStudio and Berkeley MadonnaTM installed. The free version of RStudio is sufficient for this course. The Berkeley MadonnaTM may cost $49-$299/each license depending on the student’s professional status and whether or not ordering as a group. This is a perpetual license, thus the license fee is a one-time fee only and you can use this software for your modeling needs henceforth.

Recommended textbooks

“Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations, Principles, Methods, and Applications in the Pharmaceutical Industry” by Sheila A. Peters (2012) (Students can obtain PDF version of this book through K-State library)

“Physiologically Based Pharmacokinetic Modeling, Science and Application” by Micaela B. Reddy, Raymond S. H. Yang, Harvey J. Clewell III, and Melvin E. Andersen (2005) (Students can obtain this book through K-State Interlibrary loan)

Course Project

Each student’s course project will be selected carefully with proper justification at the beginning of the course. The students will work with the instructor and teaching assistants on their selected projects with inputs from fellow students and/or guest lecturers throughout the semester. The ultimate goal is that a manuscript describing the course project could be published in a peer-reviewed journal, which typically takes longer time than a semester. To achieve this goal, the instructor is happy to continue to collaborate with the students after the course.

Discussion Board

If you have a question about the course content and materials, you are probably not alone. Please share your question with your fellow students, the instructor, teaching assistants, and guest lecturers by posting it in the Discussion Board. Students are highly encouraged to participate in the Discussion Board by posting a new question/topic and/or at least one substantive response to other participants every week. Students are also encouraged to look through previous Discussions to see if anyone else has already asked a related question. The instructor and teaching assistants will monitor the discussions and answer questions as needed.

Netiquette

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To allow for orderly learning and communication, students should follow the rules of online courtesy, including refraining from use of sexist, racist, off-color, or demeaning language or behavior, sometimes referred to as flaming. This is a college course, and student vocabulary and word choice should be appropriate to a college classroom. Students will stay on-topic, handling non-class related matters over off-line posts. The instructor is the ultimate authority and will delete any inappropriate posts. The guidelines set forth by K-State Global Campus regarding Netiquette Rules for Electronic Communication are available by clicking here.

Course evaluation

Grades will be determined from computer lab simulation exercises/assignments (~25%), quizzes (~25%), and two project presentations (mid-term and final exams) which demonstrate the development of a PBPK model and the application of the PBPK model in toxicology (~50%).

Grading scale

The total of all the points accumulated over the course will be converted to a percentage. PASS A: 90% - 100% B: 75% - 89% C: 60% - 74% Fail D: 45% - 59% F: 0 – 44%

Accommodations for students with disabilities

Any student with a disability that needs a classroom accommodation, access to technology or other assistance in this course should contact Disability Support Services and/or their instructor.

Academic honesty

Kansas State University has an Honor & Integrity System based on personal integrity, which is presumed to be sufficient assurance in academic matters to ensure one's work is performed honestly and without unauthorized assistance. Undergraduate and graduate students, by registration, acknowledge the jurisdiction of the Honor & Integrity System. The policies and procedures of the Honor System apply to all full and part-time students enrolled in undergraduate and graduate courses on-campus, off-campus, and via distance learning. A component vital to the Honor & Integrity System is the inclusion of the Honor Pledge which applies to all assignments, examinations, or other course work undertaken by students. The Honor Pledge is implied, whether or not it is stated: "On my honor, as a student, I have neither given nor received unauthorized aid on this academic work." The default in this class is that ALL work will be accomplished individually, UNLESS the instructorʼs permission is given in advance of an assignment/quiz/exam/take-home exam/final. If you are in doubt, please ask. A grade of XF can result from a breach of academic honesty. The F indicates failure in the course; the X indicates the reason is an Honor Pledge violation. For more information, visit the Honor & Integrity System home web page at: http://www.ksu.edu/honor.

Copyright notification

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All the class materials, in PDF format, will be given to the students during the course. Students are prohibited from selling (or being paid for taking) notes during this course to or by any person or commercial firm without the express permission of the instructor.

Course Instructor

Dr. Zhoumeng Lin is an Assistant Professor of Pharmacology and Toxicology in the Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University. He is a Diplomate of American Board of Toxicology (DABT), the Coordinator of the Certara Center of Excellence for Model-informed Drug Development at Kansas State University, and the Principal Investigator at the Midwest Regional Center of the Food Animal Residue Avoidance Databank (FARAD) program. Dr. Lin has 10 years of experience in PBPK modeling for environmental chemicals, drugs, and nanoparticles in laboratory rodents, food-producing animals, companion animals and humans. He received graduate training in Toxicology and PBPK modeling from Dr. Nikolay M. Filipov and Dr. Jeffrey W. Fisher at The University of Georgia. He received postdoc training in Pharmacology, Toxicology, and PBPK modeling from Dr. Jim E. Riviere, Dr. Nancy A. Monteiro-Riviere and Dr. Ronette Gehring at Kansas State University. He learned how to teach PBPK modeling from the PBPK Modeling Workshop for Beginners offered by Dr. Raymond S. H. Yang at Colorado State University. He has been offering this PBPK modeling course every year since Spring 2017. For more information about Dr. Lin’s research and teaching, please visit his laboratory website.

Office: P201 Mosier Hall Tel.: +1-785-532-4087 Fax: +1-785-532-4953 Email: Zhoumeng@ksu.edu Faculty Profile Website: http://www.vet.k-state.edu/education/anatomy-physiology/faculty-staff/faculty/lin/index.html Laboratory Website: http://www.vet.k-state.edu/education/anatomy-physiology/faculty-staff/faculty/lin/lab/index.html

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Guest Lecturers

Dr. Jeffrey W. Fisher is a Research Toxicologist with the U.S. Food and Drug Administration, National Center for Toxicological Research. He was formerly a Professor in the Department of Environmental Health Science, College of Public Health at The University of Georgia (UGA). He joined The University of Georgia in 2000 and served as Department Head of the Department of Environmental Health Sciences from 2000 to 2006 and Director of the Interdisciplinary Toxicology Program at UGA from 2006-2010. He spent most of his career at the Toxicology Laboratory, Wright Patterson AFB, where he was Principal Investigator and Senior Scientist in the Toxics Hazards Division and Technical Advisor for the Operational Toxicology Branch. Dr. Fisher's research interests are in the development and application of biologically based mathematical models to ascertain health risks from environmental, food-borne and occupational chemical exposures and develop pediatric PBPK models for drugs. Dr. Fisher’s modeling experience includes working with chlorinated and non-chlorinated solvents, fuels, pesticides, perchlorate and bisphenol A. He has developed PBPK models for use in cancer risk assessment, estimating lactational transfer of solvents, understanding in utero and neonatal dosimetry, quantifying metabolism of solvent mixtures and developing biologically motivated models for the hypothalamic-pituitary-thyroid axis in rodents and humans. He has developed PBPK model for methylphenidate to address age specific pharmacokinetic questions. Dr. Fisher has 30 years of experience in physiological modeling and has trained several graduate students and postdoctoral fellows on the concepts and application of physiological models. He was a Visiting Scientist at the Chemical Industry Institute of Toxicology in 1996 and at the NIOSH Taft Laboratory in 1999. During this time, he also served as Adjunct Professor in the Department of Pharmacology and Toxicology at Wright State University. Dr. Fisher has published over 150 papers on pharmacokinetics and PBPK modeling in laboratory animals and humans. He has served on several national panels and advisory boards for the DoD, ATSDR, USEPA and non-profit organizations. He was a U.S. delegate for the North Atlantic Treaty Organization. Dr. Fisher served on the International Life Sciences Institute Steering Committee, which evaluated chloroform and dichloroacetic acid using EPA-proposed Carcinogen Risk Guidelines. He is Past President of the Biological Modeling Specialty Section of the Society of Toxicology, reviewer for several toxicology journals, and was Co-Principal Investigator on a NIH-supported workshop on Mathematical Modeling at The University of Georgia in the fall of 2003. He was a member of the National Academy of Sciences subcommittee on Acute Exposure Guideline Levels (AEGLs) from 2004-2010 and Science Advisory Board for the US EPA (2007-2010). He is an ad hoc member of the SAB for dioxin. He is a fellow of the Academy of Toxicological Sciences and an Associate Editor for Toxicological Sciences. Dr. Fisher has a B.S. degree in Biology from the University of Nebraska at Kearney, a M.S. degree in Biology from Wright State University, and a Ph.D. in Zoology/Toxicology from Miami University.

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Dr. Raymond S. H. Yang is Professor Emeritus of Toxicology and Cancer Biology, Department of Environmental and Radiological Health Sciences, Colorado State University. Dr. Yang has more than 50 years of experience in academic, industrial and government research settings including the National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP), Union Carbide Corporation, North Carolina State University, Cornell University, Albany Medical College, Colorado State University, and the USEPA National Center for Environmental Assessment (NCEA) at Cincinnati. His research interests include toxicology of chemical mixtures, toxicologic interactions, carcinogenesis, developmental toxicology, and physiologically-based pharmacokinetics/pharmacodynamics (PBPK/PD) and other biologically-based computer modeling. He has had extensive experience in training and mentoring graduate students, postdoctoral fellows, junior and senior faculty members and he created and developed an interdisciplinary research program on Quantitative and Computational Toxicology at Colorado State University. Since 1992, Dr. Yang has organized 26 national and international workshops on PBPK/PD Modeling and Risk/Safety Assessment at Colorado State University (1992, 1994, 1996, 1999, 2001, 2003, 2005, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015), Pfizer Inc., Groton, CT (October 2002), California Environmental Protection Agency/OEHHA, Oakland, CA (September 2000), the National Health Research Institutes, Zhunan, Taiwan (August-November, 2006), and USEPA, National Center for Environmental Assessment (NCEA), Cincinnati (April-May 2008; March-August 2009), and British American Tobacco, Southhampton, UK (November 2009), California Environmental Protection Agency/Department of Pesticide Regulation, Sacramento, CA (two Workshops in May and September, 2011; one to be held in June 2016), California Environmental Protection Agency/OEHHA, Sacramento, CA (August-September, 2011; November-December 2015).

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Dr. Melvin (Mel) Andersen, now semi-retired, continues to serve as a Senior Program Advisor at ScitoVation LLC in Research Triangle Park, NC. Over a nearly 50-year career in toxicology, Mel worked in multiple organizations. In the past 25 years, he was Chief Science Officer at the Hamner Institutes for Health Sciences (2002-2015), Professor of Environmental Health at Colorado State (1999 – 2002) and was in various capacities the at K.S. Crump Group of ICF Kaiser Consulting (1994-1998). Between 1971 and 1994, he worked in toxicology research programs in the federal government (DoD and US EPA) and private industry (Chemical Industry Institute of Toxicology). During his active duty tenure in the Navy and as a civilian employee for the Air Force he worked with interdisciplinary teams to bring PBPK modeling tools into common use in toxicology and chemical risk assessment. Throughout his career he has primarily focused on developing biologically realistic models of the uptake, distribution, metabolism, and biological effects of various chemicals and applying these models in safety assessments and quantitative health risk assessments. Among his contributions in this area were: (1) a multi-dose route PBPK model with styrene (1984), (2) use of a PBPK model for methylene chloride and its metabolites in a risk assessment (1987), (3) a PBPK/PD model for dioxin (2,3,7,8-tretrachlorodibenzo-p-dioxin) accounting for induction of a dioxin binding protein (CYP1A2) in liver (1990), (4) a PBPK model with persistent perfluoroalkyl substances with saturable renal absorption to account for long half-lives (2006), (5) PBPK modeling with manganese to include tissue binding throughout the body (2009; 2018), and (6) work with highly lipophilic volatile siloxanes to understand the difference between these chemicals and lipophilic compounds considered as persistent organic pollutants (2001; 2017). Over the past 30 plus years, he has designed and taught in over 30 short-courses in pharmacokinetics, pharmacodynamics and computational cell biology and trained over 25 graduate students and post-doctoral fellows. His awards include the Herbert Stokinger Award (American Conference of Industrial Hygienists, 1988), the Kenneth Morgareidge Award (International Life Sciences Institute, 1989), the George Scott Award

(Toxicology Forum, 1993), the Mildred S. Christian career achievement Award (Academy of Toxicological Sciences, 2016), and the Frank R. Blood (1982), Achievement (1984), Arnold J. Lehman (2004) and Merit (2016) Awards from the Society of Toxicology. The Merit and Mildred A. Christian Awards specifically

identified his career contributions in bringing physiologically based pharmacokinetic (PBPK) and physiologically based pharmacodynamic (PBPD) modeling tools into toxicology and risk assessment. His talk from the Eminent Toxicologist Lecture Series in 2016, available as either a pdf or in video, https://player.vimeo.com/video/163856814, provides a good history of the early development of PBPK modeling in toxicology. Mel is board certified in industrial hygiene and toxicology and a Fellow of the Academy of Toxicological Sciences. He is author or co-author of some 500 papers and book chapters, the majority related to PBPK and PBPD modeling. A more complete listing of his peer-reviewed contributions is available at My NCBI at the link below, www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/?sortby=pubDate&sdirection=descending

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Dr. Robert (Rob) S. DeWoskin is an independent consultant and educator with over 35 years of previous laboratory, human health risk assessment (HHRA), and biologically based modeling experience at the US Environmental Protection Agency (EPA; 1998-2015) and the Research Triangle Institute (RTI; 1980-1998) in the Research Triangle Park, North Carolina. He has worked with numerous interdisciplinary teams to generate or evaluate data, develop biologically based models, and apply computational tools to predict the effects of stressors on human health. Dr. DeWoskin received his PhD in toxicology from North Carolina State University (NCSU), and is currently an adjunct Associate Professor at NCSU’s Department of Population Health and Pathobiology in the College of Veterinary Medicine. He has been certified as a Diplomate of the American Board of Toxicology since 1997. Dr. DeWoskin was the chemical manager (i.e., primary author) for peer reviewed hazard assessments at: 1) EPA’s Integrated Risk Information System (IRIS; https://www.epa.gov/iris) – including the IRIS Toxicological Review of Acrylamide (2010) and IRIS Toxicological Review of Acrolein (2003); and 2) the Agency for Toxic Substances and Disease Registry (ATSDR; https://www.atsdr.cdc.gov/toxprofiledocs/index.html) – including the Toxicological profile for Mercury (1999), Toxicological profile for Cadmium (1999), and

Toxicological profile for Chloromethane (1998). He was lead author on a seminal paper

comparing the use of a PBPK model versus hemoglobin adducts in the development of EPA

toxicity values. Dr. DeWoskin was the co-managing editor/co-author of EPA’s Advancing the

Next Generation of Risk Report and Environmental Health Perspective article; and the lead

author on the Virtual Models chapter in the 2014 edition of the Encyclopedia of Toxicology. He

served as the subject matter expert and technical contract support to develop two eLearning

courses - History and Overview of Adverse Outcome Pathways (AOPs) and the AOP-Wiki, both

of which were sponsored by the Humane Society of the US, the Humane Society International,

and the Human Toxicology Project Consortium. Boith courses are freely available online. Dr.

DeWoskin is a long-standing member of the Society of Toxicology (SOT), and served as the

President of SOT’s Biological Modeling Specialty Section (four year cycle, 2008-2012) and the

Secretary/Treasurer of SOT’s Molecular and Systems Biology Specialty Section (2015-2019).

His current interest include the use of computational models and novel diagnostics to improve

human health risk assessment, integrative and precision medicine.

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Course Schedule:

Module 1 - Introduction, History, Expectation (January 21-26, 2020)

Learning Objectives: 1. Define PBPK modeling 2. Describe the differences between PBPK modeling and traditional

pharmacokinetic modeling 3. Identify advantages of PBPK modeling compared to traditional

pharmacokinetic modeling 4. Describe the history of PBPK modeling 5. Know your fellow students’ knowledge background and research

interests Scheduled Lectures:

1. Course description and expectation 2. Introduction of PBPK modeling 3. History of PBPK modeling part 1 4. History of PBPK modeling part 2 5. PBPK modeling software 6. Introduction of Berkeley Madonna 7. R program and PBPK modeling 8. A one-compartment model in R language

Module 2 - Model Structure and Parameters (January 27-February 2, 2020)

Learning Objectives: 1. To describe typical PBPK model structure 2. To list common physiological parameters 3. To name chemical-specific parameters 4. To describe factors affecting physiological and chemical-specific

parameters 5. To discuss the rationale of designing a PBPK model 6. To understanding the principles and underlying considerations of in

silico methods for predicting tissue:plasma partition coefficients 7. To develop a simple 2-compartment PK model

Scheduled Lectures: 1. PBPK model structure 2. Physiological parameters in a PBPK model 3. Chemical-specific parameters in a PBPK model 4. Prediction of partition coefficients – part 1 5. Prediction of partition coefficients – part 2 6. Prediction of partition coefficients – part 3 7. Development of a simple 2-compartment model 8. A two-compartment model in R language

Module 3 - Mathematical Description of Absorption and Distribution (February 3-9, 2020)

Learning Objectives: 1. To describe the rationale of selecting a PBPK modeling project 2. To understand the physiological significance of PBPK model code 3. To describe absorption and distribution of chemicals or nanomaterials

using mathematical equations 4. To develop a simple 4-compartment PBPK model 5. To decide your PBPK modeling projects

Scheduled Lectures: 1. Select your interested PBPK modeling project 2. Model development - mathematical description of absorption 3. Model development - mathematical description of distribution 4. Development of a simple PBPK model using Berkeley Madonna

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5. A simple PBPK model in R language

Module 4 - Project Introduction and Coding Exercise (February 10-16, 2020)

Learning Objectives: 1. To describe the objective, significance, novelty, feasibility, and

justifiability of your project 2. To debug PBPK models 3. To develop a 7-compartment PBPK model using both Berkeley

Madonna and R program Scheduled Lectures:

1. Objective, significance, novelty, feasibility, and justifiability 2. Pharmacokinetic data search – part 1 3. Pharmacokinetic data search – part 2 4. PBPK model debugging 5. Development of a 7-compartment PBPK model 6. A 7-compartment PBPK model in R language

Module 5 - Reviewing the Basic Concepts and Doing Additional Exercise (February 17-23, 2020)

Learning Objectives: 1. To review the basic concepts about PBPK modeling 2. To extract pharmacokinetic data from published literature 3. To describe slowly and richly perfused tissues 4. To develop a membrane-limited PBPK model

Scheduled Lectures: 1. Learning the Lingo 2. Pharmacokinetic data extraction 3. Slowly and richly perfused tissues 4. Development of a membrane-limited PBPK model 5. A membrane-limited PBPK model in R language

Module 6 - Mathematical Description of Metabolism (February 24-March 1, 2020)

Learning Objectives: 1. To derive the Michaelis-Menten equation 2. To describe different ways of mathematically simulate the metabolism

of chemicals 3. To develop a membrane-limited PBPK model with intramuscular

injection Scheduled Lectures:

1. Derivation of Michaelis-Menten equation 2. Model development – mathematical description of metabolism 3. Development of an intramuscular injection PBPK model 4. An intramuscular injection PBPK model in R language

Module 7 - Mathematical Description of Excretion (March 2-8, 2020)

Learning Objectives: 1. To describe different excretion pathways of chemicals 2. To understand the mechanisms of renal excretion and hepatobiliary

excretion 3. To describe different ways of mathematically simulate renal excretion

of chemicals 4. To describe different ways of mathematically simulate biliary

excretion of chemicals 5. To develop a multiroute PBPK model with intravenous injection,

intramuscular injection, and oral exposure Scheduled Lectures:

1. Excretion pathways 2. Model development - Mathematical description of renal excretion 3. Model development - Mathematical description of biliary excretion

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4. Development of a multiroute PBPK model 5. A multiroute PBPK model in R language

Spring Break (March 9-15, 2020) (Society of Toxicology Meeting Week)

Learning Objectives: 1. No activity is planned

Scheduled Lectures: 1. No lecture is scheduled

Module 8 - Allometric Scaling (March 16-22, 2020)

Learning Objectives: 1. To understand the basic concepts of allometric scaling 2. To describe the application of allometric scaling in traditional PK

modeling 3. To describe the application of allometric scaling in PBPK modeling 4. To incorporate allometric equations into a PBPK model

Scheduled Lectures: 1. What is with the scaling 2. Allometric scaling - traditional PK parameters 3. Allometric scaling - PBPK parameters

Allometric scaling - coding examples

Module 9 - Review of Modules 1-8 (March 23-29, 2020)

Learning Objectives: 1. We have reached the halfway mark of the semester! This week we

will review what we have learned so far. All lecture PDF files of Modules 1-8 will be posted. Please go through these files one more time to refresh your memory, continue working on your course projects, and then you can proceed with the mid-term exam.

2. Complete and submit your mid-term exam. Scheduled Lectures:

1. No lecture is scheduled

Module 10 - Model Calibration and Evaluation (March 30-April 5, 2020)

Learning Objectives: 1. To calibrate a PBPK model by estimating parameters of which

measured values are not available 2. To evaluate a PBPK model by simulating independent datasets

based on WHO PBPK modeling guidelines 3. To assess PBPK model simulation results using quantitative

statistical approaches 4. To develop a PBPK model for enrofloxacin and its main metabolite

ciprofloxacin in cattle Scheduled Lectures:

1. PBPK model calibration and parameterization 2. PBPK model evaluation 3. PBPK model performance assessment 4. Development of a PBPK model for enrofloxacin and its metabolite

ciprofloxacin 5. Demonstration of a PBPK model for enrofloxacin and its metabolite

Module 11 - Sensitivity, uncertainty and

Learning Objectives: 1. To conduct local sensitivity analysis 2. To conduct uncertainty and variability analysis 3. To perform Markov chain Monte Carlo simulation 4. To develop a population PBPK model for penicillin G in cattle

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variability analysis (April 6-12, 2020)

5. To run Monte Carlo simulation using the population PBPK model Scheduled Lectures:

1. Sensitivity analysis 2. Uncertainty and variability analysis 3. Markov chain Monte Carlo (MCMC) simulation in R using the FME

package 4. Development of a population PBPK model for penicillin G - Part 1 5. Development of a population PBPK model for penicillin G - Part 2 6. A population PBPK model for penicillin G in R program – Part 1 7. A population PBPK model for penicillin G in R program – Part 2

Module 12 - GastroPlus and Simcyp (April 13-19, 2020)

Learning Objectives: 1. To learn the basic modeling environment of GastroPlus 2. To learn how to predict partition coefficients using GastroPlus 3. To learn how to develop a PBPK model from the chemical structure

using GastroPlus 4. To learn how to use different Modules of GastroPlus 5. To reproduce a published PBPK model for buprenorphine using

Simcyp Scheduled Lectures:

1. Basics of GastroPlus before using it for PBPK modeling 2. Using GastroPlus to predict tissue to plasma partition coefficients 3. How to build up a PBPK model from chemical structures in

GastroPlus 4. Demonstrations of Modules in GastroPlus - Part 1 5. Demonstrations of Modules in GastroPlus - Part 2 6. PBPK model establishment and validation for buprenorphine using

Simcyp - Part 1 7. PBPK model establishment and validation for buprenorphine using

Simcyp - Part 2

Module 13 - Special Topics: IVIVE, Pediatric Modeling, BBDR, and Probablistic Risk Assessment (April 20-26, 2020)

Learning Objectives: 1. To learn the basic concepts about In Vitro to In Vivo Extrapolation

(IVIVE) 2. To understanding pediatric PBPK modeling 3. To understand biologically based dose-response (BBDR) modeling 4. To understand probabilistic risk assessment using PBPK models

Scheduled Lectures: 1. In Vitro to In Vivo Extrapolation (IVIVE) 2. Advances in pediatric modelling - Part 1 3. Advances in pediatric modelling - Part 2 4. Advances in pediatric modelling - Part 3 5. Lecture 13.5 Biologically Based Dose Response (BBDR) modeling for

the Lactating Mother – Using biologically motivated models for thyroid hormone production and hypothyroxinemia

6. Probabilistic risk assessment using PBPK models

Module 14 - Model Application in Risk Assessment - Part I

Learning Objectives: 1. To learn some background information about risk assessment using

PBPK models 2. To apply the TCA PBPK model for non-cancer risk assessment 3. To learn some specifics of PBPK modeling of dichloromethane

(methylene chloride) in mice and humans Scheduled Lectures:

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(April 27-May 3, 2020)

1. Overview of risk assessment (RA) and the derivation of toxicity values – Part 1

2. Overview of risk assessment (RA) and the derivation of toxicity values – Part 2

3. Overview of risk assessment (RA) and the derivation of toxicity values – Part 3

4. Non-cancer risk assessment using TCA PBPK model 5. Cancer risk assessment using DCM PBPK model – part 1

Module 15 - Model Application in Risk Assessment - Part II and Future Perspective (May 4-10, 2020)

Learning Objectives: 1. To learn to use PBPK and BMDS [(Benchmark Dose Software,

USEPA, National Center for Environmental Assessment (NCEA)] modeling to do dose-response and risk assessment

2. To learn different forms of presenting cancer risk: slope factor, unit risk, and risk based on 1/10000, 1/100000, or 1/1000000

3. To learn to address the issue of uncertainty and variability using Monte Carlo simulation

4. To understand the application of PBPK modeling to polypharmacy Scheduled Lectures:

1. Examples of PBPK models in risk assessment – Part 1 2. Examples of PBPK models in risk assessment – Part 2 3. Dichloromethane cancer risk assessment – part 2A 4. Dichloromethane cancer risk assessment – part 2B 5. Dichloromethane cancer risk assessment – part 3 6. Future perspective – PBPK modeling of polypharmacy

Final Exam Week (May 11-15, 2020)

Learning Objectives: 1. Complete the Final Exam

Scheduled Lectures: 1. No lecture is scheduled

Note: This is a tentative schedule based on the Spring 2019 schedule. New content will be added, so the actual schedule for Spring 2020 will be slightly different.

Registration

On-campus K-State students can enroll in this course through KSIS and should select session “AP 873-A”. Distance students and non-K-State students can enroll in this course through K-State Global Campus and should select session “AP 873-ZA” (https://eis.global.ksu.edu/CreditReg/CourseSearch/Course.do?open=true&sectionId=127171). Individuals not enrolled at KSU can enroll in this course as “Nondegree-seeking Graduate Students”. Click here for detailed instructions. The maximum enrollment is 20 students.

Fees

In the Spring 2019 semester, the registration fee for degree-seeking and nondegree-seeking graduate students was $2,551.60. The registration fees for the Spring 2020 semester will be similar.

Cancellation and Refund Policy

This course will be cancelled if a minimum of 4 students is not reached. Cancellation by Dr. Lin: 100% refund. According to K-State Academic Calendar, February 11th is the last day for 100% refund for a regular session course and February 18th is the last day for 50% refund for a

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regular session course for Spring 2019 semester. Please check the updated dates for Spring 2020 semester. Please contact Dr. Lin at zhoumeng@ksu.edu for further information.