Science is a global endeavor. Indeed, one of the most exciting things about drug development is working with scientists doing important research all over the globe. The use of modeling and simulation (M&S) to support drug development has been embraced by pharmaceutical researchers in some parts of the world and is still gaining traction in others.
Prof. Yusuke Tanigawara—a professor of clinical pharmacokinetics (PK) and pharmacodynamics (PD) in the School of Medicine at Keio University in Japan—joined me to discuss his teaching and research programs as well as the growing use of model-informed drug development (MIDD) by Japanese drug developers. Prof. Tanigawara teaches medical students and performs clinical pharmacology research.
Suzanne Minton: How do you think Japan’s Pharmaceutical and Medical Devices Agency’s (PMDA) view of modeling and simulation will evolve in the next couple of years?
Yusuke Tanigawara: Over the last couple of years, the PMDA’s attitude towards MIDD has drastically evolved. We had two important MIDD symposia recently. The first one was the PMDA-Keio Joint Symposium on Pharmacometrics in 2015. And this year, the PMDA organized a Pharmacometrics Symposium where they sent a clear message that the agency plans to become more involved in pharmacometrics.
At the same time, the PMDA encourages industry scientists to utilize a pharmacometric approach to expedite drug development. And the PMDA just started receiving drug submissions electronically. They also intend to expand their activity to in-house analysis of sponsor-submitted electronic data. The PMDA is eager to utilize pharmacometric approaches to inform their regulatory decisions.
Suzanne Minton: In the early 90s, you took a research sabbatical at the University of Manchester in the United Kingdom. Can you discuss any differences in the approach to pharmacological research in the West versus Japan that you think are particularly interesting?
Yusuke Tanigawara: So first, spending time in the UK was wonderful. Some things were different; some were similar.
You asked me about pharmacological research, and how it differs between the West and the East. In Japan, academic pharmacologists conduct more experimental “wet lab” work than in silico modeling and simulation. That’s because they are focusing on early stage drug target discovery or biochemistry research on the mechanisms of drug transport, metabolism, and absorption that uses in vitro or clinical studies.
My primary interest is on in silico modeling and simulation. But, it’s very difficult to get research funding because the funding agencies prefer investing in more traditional pre-clinical and clinical studies. There’s a lack of awareness regarding the benefits of M&S approaches.
This has resulted in fewer opportunities in Japan to teach pharmacometrics. We have many talented young people who are potentially good pharmacometricians. But they don’t have a chance to learn pharmacometrics. That’s why I started a course in Japan to teach pharmacometrics.
Suzanne Minton: Would you say that there’s growing enthusiasm for modeling and simulation in Japan?
Yusuke Tanigawara: Yes. I hope that there is growing acceptance. But so far, it hasn’t been easy!
Suzanne Minton: Much of your research is focused on antibiotics and oncology drugs. Can you discuss your thoughts on how modeling and simulation can support developing new antibiotics in the era of increasing antibiotic-resistant bacterial infections?
Yusuke Tanigawara: Absolutely yes. The field of infectious disease and antimicrobial agents has been one of the most successful areas that pharmacometrics has been implemented in― not only new drug development, but also in clinical practice. Nowadays, many clinicians, not just pharmacometricians, know about applying PK/PD concepts to antimicrobial agents. Also, therapeutic drug monitoring (TDM) concepts have been established in clinical practice.
So I think this is due to the simplicity of the pharmacodynamics of antibiotics which are targeted against exogenous bacteria. Also, we have very good in vitro systems to measure the threshold antibiotic concentrations required to kill bacteria. By combining in vitro knowledge of minimum inhibitory concentrations with clinical pharmacokinetic data, we’ve been able to apply PK/PD concepts to anti-microbial treatments.
So pharmacometric concepts are being used to treat patients with bacterial infections, and these concepts can be further utilized for developing new drugs for antibiotic-resistant bacteria. In addition, pharmacometrics can be applied to developing anti-fungal or anti-viral agents.
Suzanne Minton: You hold many patents on methods to assess patients’ susceptibility to anti-cancer agents. What do you predict are the major trends in using modeling and simulation for oncology drug development in the next few years?
Yusuke Tanigawara: There’s a tremendous opportunity for applying pharmacometrics to oncology. The growth in drugs targeted at cell signaling pathways and immuno-oncology are some of the biggest changes to happen in oncology treatment in the last decade. Traditionally, oncologists used the concept of the maximum tolerated dose for chemotherapeutic agents to drive dosing. But nowadays, new oncology drugs are targeted treatments. As pharmacologists, we are tasked with characterizing their efficacy/safety profiles. We’re trying to find the dose with the optimal risk-benefit profile, not just the maximum tolerated dose.
Each drug has a pharmacological target. We can measure specific biomarkers to determine what dose is required to efficiently modulate its target. This is the new paradigm for oncology drug development. Pharmacometrics is playing a more and more important role in the development of oncology drugs.
Suzanne Minton: What is the state of model-informed precision dosing (MIPD) in Japan and what are the biggest barriers to making MIPD a standard part of healthcare?
Yusuke Tanigawara: A critical precursor to MIPD—therapeutic drug monitoring—is already established. This September, I will chair the 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology in Kyoto, Japan. It’s relatively easy to measure plasma drug concentrations and optimize dosing based on TDM. This practice is particularly well established for antibiotics and immunosuppressants for organ-transplant patients.
Now we are looking for new applications of TDM for oncology. Many years ago, oncology drugs were all highly cytotoxic agents. Now many oncology drugs are targeted agents where we must optimize their dosing. That’s why monitoring of drug exposure is essential to personalize dosing.
In addition to considering a drug’s pharmacological properties, the other major component to personalized dosing is pharmacogenomics. Genetic variability can impact how different people respond to a drug. But, not many pharmacogenetic tests have been implemented in routine patient care. In Japan, only one pharmacogenomic test—genetic testing for UGT1A1 for the oncology drug irinotecan to predict toxicity—has been implemented in clinical practice and supported by the government’s national healthcare insurance.
So we need to convince the relevant stakeholders that implementing pharmacogenetic tests helps inform the use of other medications.
One major cause for the slow implementation of MIPD is a lack of education in pharmacogenomics. The regular curriculums of medical and pharmacy schools don’t teach pharmacogenomics beyond an introductory lecture. That’s why still we lack partners in medicine for pharmacogenomics. Attaining genetic information also poses ethical issues due to its highly personal information. So, figuring out the ethical and operational logistics to handle this sensitive information is a big barrier for us.
Suzanne Minton: We have similar debates about how to best use genetic information in the West. Going back to your role as an educator, what advice would you give to an early career pharmacometrician?
Yusuke Tanigawara: Good question. My advice would be to hone your communication skills. The ability to effectively communicate is much more important than technical prowess. When you want to conduct pharmacometric research, you need clinical data. So you must persuade clinicians—often the decision makers in research and drug development—that pharmacometrics has value. Otherwise, you can’t get the data. You need to clearly explain what new findings pharmacometrics research can yield.
And you need to do this using language that they can understand, not technical jargon. Some pharmacometricians use such highly technical language that clinicians don’t understand the ideas that the modeler is trying to convey.
Likewise, after you build a model, you must let the other people—including non-modelers—understand your model. People outside of the pharmacometrics community generally aren’t interested in the technical aspects of modeling and simulation. They’re interested in the clinical implications and the clinical utility of your results. Sometimes, pharmacometricians tend to focus on the computational technical issues, rather than the results and how they can impact clinical practice or expand our knowledge of drug mechanisms.
Good communication skills are critical to your success as a pharmacometrician. Please remember that you should not be the only person who understands your model!
Suzanne Minton: [Laughs] That’s great advice. We talk about the importance of being able to communicate modeling results to non-modelers all the time. Thank you so much for talking with me!
Please visit his website at Keio University to learn more about Prof. Tanigawara’s research.
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