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Accelerating the establishment of precision medicine using PK-PD/TD modeling

Certara’s Japan team first met Dr. Kobuchi when he was studying Pharmacometrics at university for his PhD. He frequently attended our software training courses to learn Phoenix software. His proactive engagement through entire courses left a strong impression on us. He has a clear vision to leverage Certara’s technology to push forward his research and it has been obviously proven through his splendid achievements to this day. Now, Dr. Kobuchi leads his own students in conducting outstanding research at Kyoto Pharmaceutical University with the help of pharmacometrics technology including Pharmacokinetic-Pharmacodynamic/Toxicodynamic (PK-PD/TD) Modeling and Simulation. Today, we interviewed this promising young researcher to shed some light on his work.

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

In the field of oncology, therapeutic drug monitoring (TDM) of 5-fluorouracil (5-FU) has been recommended to improve clinical outcomes. However, circadian variation in plasma concentrations of 5-FU interferes with precise estimation of target therapeutic windows. Recently, we have developed a population pharmacokinetic model to evaluate the circadian patterns of plasma 5-fluorouracil concentrations in rats. These findings could contribute to the development of an appropriate TDM strategy and chronomodulated 5-FU chemotherapy. Results of this pharmacometric approach were published in Journal of Pharmaceutical Sciences [1], and the Editorial Team chose to display this paper in the Features section of the journal’s new website. We have also successfully developed PK-PD/TD models that can help predict the onset and degree of toxicities, including myelosuppression and neuropathy in animals induced by anticancer agents [2, 3]. Now, we’re challenging ourselves to investigate interactions between antiemetic and anticancer drugs to contribute to the establishment of an appropriate dosing strategy with maximum drug efficacy and minimum toxicity.

[1] S. Kobuchi, et al., Population pharmacokinetic model-based evaluation of circadian variations in plasma 5-fluorouracil concentrations during long-term infusion in rats: a comparison with oral anticancer prodrugs. J. Pharm. Sci., 109(7), 2356-2361 (2020).

[2] S. Kobuchi, et al., Mechanism-based pharmacokinetic– pharmacodynamic (PK-PD) modeling and simulation of oxaliplatin for hematological toxicity in rats. Xenobiotica, 50(2), 146-153, (2020).

[3] S. Kobuchi, et al., Semi-Mechanism-based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-induced Acute and Chronic Neuropathy. Pharmaceutics, 12(2), 125 (2020).

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

Certara provides versatile and high-quality software, such as Phoenix WinNonlin and Phoenix NLME, for evaluating pharmacokinetics and pharmacodynamics/toxicodynamics of drugs in preclinical and clinical studies. Certara’s software is widely used by many pharmacometricians in both academic research and the pharmaceutical industry. Researchers have accepted this software as a useful tool for easily analyzing data in the first instance. In our laboratory, we use Phoenix WinNonlin and Phoenix NLME when performing non-compartment model analysis, PK-PD/TD modeling and simulation, and population model analysis with data taken from animals and patients. Certara also helps us share our new findings in pharmacometrics. Moreover, this leading company has trained us in how to conduct pharmacometric analysis using their software, which has helped to update our knowledge and analysis techniques. Both Certara’s software and training have accelerated our research aimed at the establishment of precision medicine.

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

Yes, we do. We believe that use of pharmacometric technology, including PK-PD/TD modeling and simulation, can facilitate more appropriate determination of clinical doses for individual patients. In chemotherapy, doses are almost always determined based on body weight or body surface area. Then, when serious drug toxicity is observed, dose reduction or discontinuation of chemotherapy is performed empirically. Pharmacometric technology can quantitatively simulate drug responses at various dose settings before drugs are administered to patients. These simulated results can help determine the appropriate dose for each patient. This visual simulated data of the timecourse of chemotherapy may also lead to improved patient adherence.

In the future, PK-PD/TD models should be automatically developed and updated using routinely collected data from medical records. Specific models for each hospital could contribute to the establishment of precision medicine in clinical organizations via close co-operation between physicians and pharmacometricians.

In Japan, the reality is that there are very few students studying Pharmacometrics. To someone still deciding on their major or future career, what would you say are the benefits of studying Pharmacometrics?

Pharmacometrics widely contributes to medical developments, such as the development of new drugs, approval processes, and academic studies focused on improving the clinical outcomes of chemotherapy. At first glance, pharmacometrics may seem like a difficult field as it requires knowledge of mathematics, statistics, physiology, pharmacokinetics, and pharmacodynamics. However, modeling and simulation using pharmacometrics are essential skills for efficiently evaluating and estimating the characteristics of drugs. If you study pharmacometrics in depth at university, you can use your knowledge and skills to become a pharmacometrician in the pharmaceutical industry or a research organization such as a university, hospital, or public institute (such as the FDA, EMA, or PMDA). In fact, some students who have studied and gained pharmacometric skills in our laboratory have gone on to work in the pharmaceutical industry or the PMDA after graduation. As information technology continues to develop, so does pharmacometrics. Today, we can easily get information about the weather, like predicted paths of hurricanes and typhoons, based on mathematical models. Similarly, in the future, prediction of drug responses after administration to patients using pharmacometrics skills may become a standard in a new drug development process and the setting of doses for individual patients. I hope that many students will become interested in Pharmacometrics and use it to benefit patients undergoing chemotherapy.

About the Department of Pharmacokinetics, Kyoto Pharmaceutical University

Kyoto Pharmaceutical University is one of the oldest and most traditional private pharmaceutical universities in Japan. The laboratory of the Department of Pharmacokinetics is managed by Prof. Toshiyuki Sakaeda, Dr. Yukako Ito, and Dr. Shinji Kobuchi. These researchers investigate the relationships between pharmacokinetics and pharmacodynamics/toxicodynamics (PK-PD/TD) to contribute to the establishment of precision medicine for individual patients. They focus on oncology, and development of appropriate chemotherapy for treatment of patients with diabetes, dyslipidemia and infections. Basic research using animal disease models is aimed at revealing the impact of pharmacokinetic alterations on drug effects and finding biomarkers that can predict drug responses. In the collaborated studies with clinical organization, drug concentrations in patients are determined and their relationships with drug efficacy and safety are assessed. The researchers also take advantage of pharmacometrics approaches including PK-PD/TD, physiologically based pharmacokinetics (PBPK), and population model analysis to help simulate time-course profiles of drug efficacy and degrees of toxicity, hereby working towards dose setting for individual patients.

About the Interviewee

Dr. Shinji Kobuchi is an Assistant Professor at the Department of Pharmacokinetics, Kyoto Pharmaceutical University. Dr. Kobuchi graduated from Kyoto Pharmaceutical University and received his Ph.D. at Kyoto Pharmaceutical University’s Graduate School.

Dr. Kobuchi has a strong interest in the relationship between PK and PD/TD of anticancer drugs, antibacterial drugs, and lifestyle-related disease drugs by leveraging animal models of such diseases. He utilizes modeling & simulation technologies like Phoenix WinNonlin and NLME for his research of precision medicines.
In order to develop better pharmacotherapy from both approaches of basic and clinical research, Dr. Kobuchi conducts population pharmacokinetic analysis with real-world patient data and examines their respective clinical challenges.

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