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Utilizing Pharmacokinetic and Pharmacodynamic Modeling & Simulation Technologies for Anesthesiology and Pain Medicine

Today, we are interviewing Professor Gyujeong Noh from Anesthesiology and Pain Medicine/Clinical Pharmacology and Therapeutics at University of Ulsan College of Medicine, Asan Medical Center, South Korea to shed a light on his experience as a clinician on how to apply pharmacokinetic and pharmacodynamic analysis to clinical research and practice. Professor Noh adopts a unique method of using modeling and simulation techniques for clinical researches in anesthesiology and pain medicine. Here’s a deep dive into his career journey and why he’s using biosimulation for his anesthesiology and pain medicine research.

Could you please tell me your story what made you decide to study pharmacometrics while you have already achieved a successful careers as a medical doctor?

In the late 1990s, Diprivan® (AstraZeneca, Seoul, South Korea) was introduced with the target-controlled infusion (TCI) pump. Target-controlled infusion is a computer-controlled drug delivery technique based on pharmacokinetic and pharmacodynamic models. Once the target plasma concentration or effect-site concentration of propofol is set, the model built into the pump will be used to constantly calculate the infusion rate to maintain the drug concentration levels. Previously, inhalational anesthetics were mainly used, and limited knowledge about pharmacodynamic and pharmacokinetic models was not an issue
while managing patients in anesthetic practice. However, unlike inhalation anesthesia, the application of the Diprivan® TCI pump required far more pharmacological expertise than was described in textbooks of anesthesiology and pain medicine.

In the early 2000s, a microemulsion propofol, AquafolTM was developed by a Korean company (Daewon Pharmaceutical Co., Ltd., Seoul, Korea). As the principal investigator of the Phase 1 clinical trial in healthy volunteers for population PK/PD modeling and development of a target-controlled infusion pump as well as the Phase 3 clinical trial for market approval, I had the privilege of working in the field for about ten years. Many anesthesiologists in the Korean Society for Anesthetic Pharmacology (KSAP) took part in the pharmacometrics study at this time, including myself.

Can you tell us about your latest pharmacometrics project and publication?

It was quite challenging for me, a non-pharmacologist, to understand numerous pharmacokinetic and pharmacodynamic equations and develop mathematical and statistical knowledge of pharmacometrics. Any doctor would understand where I am coming from. Even though I am an anesthesiologist, the target-controlled infusion algorithm was a challenge for me to grasp. I wrote ‘Pharmacokinetic Equations and Target-Controlled Infusion’ (Shinil Books, Seoul, Korea) in 2019 so younger Korean anesthesiologists would not have to go through what I went through. Anesthesiologists who want to study anesthetic
pharmacology in Korea, as well as clinicians interested in pharmacokinetic equations may find this book useful.

Since 2018, I have been running an expert course for anesthetic pharmacology at the Korean Society of Anesthetic Pharmacology to provide educational opportunities for anesthesiologists interested in pharmacokinetics, pharmacodynamics, and pharmacometrics. This course is available to anyone outside of anesthesiology and pain medicine for free. The Korean Society for Anesthetic Pharmacology secured educational software licenses from Certara, allowing trainees to learn and try out Phoenix WinNonlin. I would like to thank Certara for their assistance.

How is your research project supported by Certara software and technology?

A new benzodiazepine hypnotic agent remimazolam besylate (Byfavo®, HANA PHARM CO., LTD., Seoul, Korea), has been approved in Korea. Given my research experience on microemulsion propofol, I am going to be the principal investigator of the Phase 1 clinical trial of remimazolam in healthy volunteers for population PK/PD modeling and development of a target-controlled infusion pump. Since remimazolam is still relatively new in global clinical practice, I believe we can improve our understanding of Byfavo® by simulating different pharmacokinetic and pharmacodynamic scenarios with Certara’s software and then testing the findings in clinical practice.

The reason why I chose Phoenix for the expert course for anesthetic pharmacology is that this software is an industry standard, and it supports everything from classical WinNonlin PK/PD modeling to population PK/PD modeling in one platform.

Although NONMEM is currently the standard for population PK/PD modeling, it’s difficult for beginners to use because it doesn’t have a graphical user interface. Phoenix NLME’s excellent graphic user interface can alleviate beginners’ difficulty in building pop PK/PD models.

To someone still deciding on their major or future career, what would you say are the benefits of studying pharmacometrics?

Majoring in pharmacology is the most typical way to become an expert in pharmacokinetics, pharmacodynamics, and pharmacometrics. As a physician, I can’t advise pharmacology students on where to focus their studies. However, if you are an anesthesiologist I would strongly advise you to study these fields for the reasons stated above.

There are many sub-specialties in anesthesiology and pain medicine, including cardiac anesthesia, organ transplant anesthesia, neuroanesthesia, pediatric anesthesia, obstetric anesthesia, pain clinic, etc. However, I believe that your research will be improved if you have studied pharmacokinetics and pharmacodynamics and have used nonlinear mixed-effects modeling and pharmacokinetic and pharmacodynamic simulations in population analysis, allowing you to apply your findings to patient care.

Do you have a future goal in mind regarding pharmacometrics/biosimulation technology?

Clinical pharmacologists might find it challenging to deal with hypnotics and opioids due to their narrow margin of safety. The reason I studied population pharmacokinetic and pharmacodynamic analysis using nonlinear mixed effects modelling is to contribute to the clinical pharmacology development of these drugs and to provide better anesthetic care to surgical patients by performing quantitative harmacological researches on the dose-response relationship even after drug approval.

In collaborative research with experts specializing in analysis of biosignals such as electroencephalograms (EEGs) and electrocardiograms (ECGs), we will be able to develop surrogate measures of clinical endpoints which can be employed in quantitative pharmacokinetic and pharmacodynamic studies.

(From left) Mr. Park Do-yang, Ms. Yang Jeong-sim, Dr. Noh Gyu-jeong, Dr. Kim Kyoung-mi, Dr.
Bang Ji-youn, Dr. Choi Byung-moon

About Anesthesiology and Pain Medicine/Clinical Pharmacology and Therapeutics, University
of Ulsan College of Medicine, Asan Medical Center

Professor Noh’s research team at University of Ulsan College of Medicine, Asan Medical Center consists of Professor Gyujeong Noh, three professors of anesthesiology and two professional researchers. They focus on anesthetic pharmacology studies on sleeping pills and opioids and invasive controlled desaturation studies on pulse oximeters.

About the Interviewee

Dr. Noh Gyu-jeong is a professor at the University of Ulsan College of Medicine and Asan Medical Center in the Departments of Anesthesiology and Clinical Pharmacology. He graduated Seoul National University in 1987 and received training in the Department of Anesthesiology and Pain Medicine at Seoul National University Hospital. In 1988-1991. He was awarded a doctorate in medicine from Seoul National University College of Medicine in 1996. In 2005-2006, he took a postdoctoral fellowship course under the late Professor Kim Sung-wan at the center for controlled chemical delivery, University of Utah College of Pharmacy in Salt Lake City, USA.

Dr. Noh Gyu-jeong joined the Department of Clinical Pharmacology and Therapeutics in 2004 and served as the chairperson of the Clinical Pharmacology and Therapeutics from 2007-2011. From 2010-2014, he served as the director of specialty examination and committee for certification of clinical pharmacologists at the Korean Society for Clinical Pharmacology and Therapeutics (KSCPT). In 2011, he created the certification system for clinical pharmacologists for the KSCPT for the first time in Korea. From 2011 to 2014, he served as the president of the Korean Society for Anesthetic Pharmacology (KSAP). From 2000 to the present, he has taught pharmacometrics to anesthesiologists in Korea and has been actively involved in the education of basic pharmacology and pharmacokinetic and pharmacodynamic modeling. In 2019, he wrote Pharmacokinetic Equations and Target-controlled Infusion (Shinil Books, Seoul, Korea) to contribute to establishing a knowledge system for anesthetic pharmacology in Korea.

Currently, Dr. Noh Gyu-jeong regularly runs Anesthetic Pharmacology Expert courses, Basic Pharmacology workshops, and more at the KSAP.