PRINCETON, NJ - Feb 7, 2019 - Certara®, the global leader in model-informed drug development, regulatory science, real-world evidence and market access services, today announced its latest advances in bringing model-informed precision dosing (MIPD) to the point of care. Certara scientists have been engaged in critical assessments of hurdles to MIPD (starting with a white paper in 2017) and now have published four new MIPD papers1-4 in the past months delineating the vision and practical path(s) for making individualized dosing a reality under the efforts for “Precision Medicine.”

MIPD uses computer modeling and simulation to predict the drug dose for a given patient which, based on their individual characteristics, is most likely to improve efficacy and/or lower toxicity compared with traditional dosing. MIPD is particularly useful when dosing patients who belong to a vulnerable population, such as neonatal or pediatric patients, patients with significant renal or hepatic impairment or the frail elderly who receive multiple drugs and hence are susceptible to drug interactions.3 Those patients are at increased risk of drug-related harm, so improved dosing will likely enhance their care. This is a significant problem for society as well as individual patients because drug-related harm is estimated to cost about US $42 billion per annum globally.5

“Certara recognized several years ago that model-informed drug development (MIDD) could also provide tremendous value if used by healthcare providers (HCPs) to determine the optimal drug dose for individual patients in the clinic,” said Certara Chief Scientific Officer Professor Amin Rostami. “We decided to apply our experience in making MIDD operational by collaborating with colleagues in pharma, academia and global regulatory agencies in the area of MIPD to achieve widespread adoption and practical use in clinic instead of the current restricted applications in academic research settings.”

“We believe that MIPD will enable the healthcare industry to complete the transition from the traditional ‘one size fits all’ drug dosing through the current ‘stratified/average population’ dosing to reach the goal of ‘individualized’ dosing,” said Professor Rostami.

This transition is being facilitated by several factors that are improving researchers’ understanding of inter- and intra-individual variability in drug response. They include the availability of fast and affordable genetic testing, the rise of multi-omic technologies to identify biomarkers to monitor handling of the drug by individual patient and the specific effects in each patient, improved medical imaging, rapid pathology testing, characterization of the gut microbiome, superior analysis of biological samples, and powerful computational tools to analyze large quantities of patient data.2,4

“MIPD will be especially valuable for HCPs dosing drugs with a narrow therapeutic index - where a small change in dose can have a large impact on the drug’s therapeutic effect or risk of an adverse reaction - and when treating patients from vulnerable populations, which tend to be more complex cases due to changing physiology or polypharmacy,” said Tom Polasek, MD, PhD, Medical Director of MIPD at Certara and lead author on three of the new MIPD papers. Drugs with a narrow therapeutic index include anti-arrhythmics, anti-coagulants, anti-epileptics, aminoglycoside antibiotics, and immunosuppressants.4 Dr. Polasek is also a clinical pharmacology registrar at Royal Adelaide Hospital and an adjunct senior lecturer at the Centre for Medicines Use and Safety at Monash University in Australia.

Historical Perspective

Certara, in partnership with The University of Manchester, organized the first-ever Health Care Summit on MIPD in the UK in May 2016. The Summit attracted speakers from research institutions, academia, pharmaceutical companies, and legal authorities in eight countries. During that meeting, 15 case studies were presented that demonstrated the successful use of MIPD in the hospital research environment.

The Summit conclusions, prepared by more than 20 of the participants, were published in Clinical Pharmacology & Therapeutics in May 20176. In addition to describing early examples of the successful clinical application of MIPD, the paper outlined a framework for the broader integration of MIPD into healthcare. Summit participants drew three main conclusions:

• Computer models exist that can assess individualized dosing but more data are required to feed them.
• Further consideration needs to be given to the implications of using MIPD tools from both a regulatory policy and pharmaceutical development standpoint.
• The biggest challenge will be getting clinicians to adopt MIPD and that will require evidence-based efficacy and cost-benefit analyses.

Building on MIPD Momentum

Certara has been working diligently with its industry partners to address those points. It created a broader range of clinically-relevant drug profiles and population files for its physiologically-based pharmacokinetic Simcyp® Population-based Simulator.

Certara also published its first ‘virtual twin’ study in which it used the Simcyp Simulator to create a computer-simulated model for each patient to predict their olanzapine exposure.7 Olanzapine is an antipsychotic drug that is used to treat schizophrenia and bipolar disorder. Certara’s Virtual Twin Technology was used to replicate all of the patient’s attributes that would affect the drug’s fate in their body and hence its effects. They included the patient’s age, weight, height, sex, ethnicity and genetics and activities of the drug metabolizing enzymes important for olanzapine’s elimination from the body. 

“Certara is proud to be collaborating with MIPD pioneers and conducting scientific research to generate the data needed to advance this field3 and improve patient care. We believe that the co-development of companion MIPD devices and/or apps during drug development will help drive adoption and we are strongly supporting those efforts,” added Dr. Polasek.

The company has also been helping to gather evidence demonstrating the successful real-time use of MIPD in treating infectious diseases and pediatric cases. Those are particularly strong case studies. 

Then in December 2017, Certara organized the 1st Asian Symposium on Precision Dosing in Busan, Korea in partnership with Inje University. That meeting drew participants from Korea, Thailand, Singapore, Japan, India, Africa, Australia, New Zealand and the United States. They represented academia, the pharmaceutical industry, healthcare, and government agencies. The conference conclusions were published in TheAAPS Journal in January 2019, together with participants’ commitment to continuing research into the clinical implementation of MIPD and educating other healthcare professionals about its benefits. 4

Partnering with Regulators

Global regulatory agencies are also following MIPD developments closely. In fact, the US Food and Drug Administration (FDA) approved its first companion MIPD tool for octocog alfa, which is used for the treatment and prevention of bleeding in patients with hemophilia A.

In July 2019, Japan’s Pharmaceuticals and Medical Devices Agency will host a workshop in Tokyo entitled “Challenges for Further Utilization of Pharmacometrics in Drug Developments.” Dr. Polasek will address MIPD advances during his presentation at that meeting.

Then in August 2019, FDA will be hosting a workshop entitled “Precision Dosing: Defining the Need and Approaches to Deliver Individualized Drug Dosing in the Real‐World Setting.” One of the presenters at Certara’s inaugural Health Care Summit on MIPD, Bob Powell, PharmD, an adjunct professor in the Division of Pharmacotherapy and Experimental Therapeutics at the University of North Carolina is co-chair of the FDA workshop. In addition, Larry Lesko, PhD, FCP, who is a member of Certara’s Scientific Advisory Board and Strategic Council, and director of the Center for Pharmacometrics and Systems Pharmacology at the University of Florida in Lake Nona, is a presenter at the workshop. Dr. Polasek has also been invited to speak at this workshop.

Scientific interest in and research into MIPD are growing and gaining momentum. It is anticipated that MIPD adoption will follow a similar path to MIDD, which will result in it becoming a required element in clinical practice within a few years.  

References

1. Martyn Howard, Jill Barber, Naved Alizai and Amin Rostami-Hodjegan. Dose Adjustment in Orphan Disease Populations: The Quest to Fulfill the Requirements of Physiologically-based Pharmacokinetics. Expert Opinion on Drug Metabolism & Toxicology. https://doi.org/10.1080/17425255.2018.1546288.
2. Thomas M. Polasek, Sepehr Shaki and Amin Rostami-Hodjegan. Precision Dosing in Clinical Medicine: Present and Future. Expert Review of Clinical Pharmacology. 2018, Vol. 11, No. 8, 743-746. https://doi.org/10.1080/17512433.2018.1501271.
3. Thomas M. Polasek, Craig R. Rayner, Richard W. Peck, Andrew Rowland, Holly Kimko, and Amin Rostami-Hodjegan. Toward Dynamic Prescribing Information: Codevelopment of Companion Model-Informed Precision Dosing Tools in Drug Development. Clinical Pharmacology in Drug Development. 2018, 0(0) 1-8 ©2018, The American College of Clinical Pharmacology DOI: 10.1002/cpdd.638.
4. Thomas M. Polasek, Amin Rostami-Hodjegan, Dong-Seok Yim, Masoud Jamei, Howard Lee, Holly Kimko, Jae Kyoung Kim, Phuong Thi Thu Nguyen, Adam S. Darwich, and Jae-Gook Shin. What Does it Take to Make Model-informed Precision Dosing Common Practice? Report from the First Asian Symposium on Precision Dosing. The AAPS Journal (2019) 21:17. DOI: 10.1208/s12248-018-0286-6.
5. World Health Organization. Medication Without Harm - Global Patient Safety 476 Challenge on Medication Safety. Geneva; 2017.
6. AS Darwich, K Ogungbenro, AA Vinks, JR Powell, J-L Reny, N Marsousi, Y Daali, D Fairman, J Cook, LJ Lesko, JS McCune, CAJ Knibbe, SN de Wildt, JS Leeder, M Neely, AF Zuppa, P Vicini, L Aarons, TN Johnson, J Boiani and A Rostami-Hodjegan. Why Has Model-Informed Precision Dosing Not Yet Become Common Clinical Reality? Lessons From the Past and a Roadmap for the Future. Clin Pharmacol Ther. 2017 May;101(5):646-656. doi: 10.1002/cpt.659. Epub 2017 Apr 4.
7. Polasek TM, Tucker GT, Sorich MJ, Wiese MD, Mohan T, Rostami-Hodjegan A, Korprasertthaworn P, Perera V, Rowland A. Prediction of olanzapine exposure in individual patients using physiologically based pharmacokinetic modelling and simulation. Br J Clin Pharmacol. (2018) 84: 462-476. doi: 10.1111/bcp.13480.

About Certara

Certara enables superior drug development and patient care decision-making through model-informed drug development, regulatory science, real-world evidence solutions and knowledge integration. As a result, it optimizes R&D productivity, commercial value and patient outcomes. Its clients include hundreds of global biopharmaceutical companies, leading academic institutions, and key regulatory agencies across 60 countries. For more information, visit www.certara.com.