Modeling and simulation (M&S) has been widely accepted and adopted by biopharmaceutical companies and global regulatory agencies. However, its implementation in clinical care has been modest to date. Model-based approaches are essential to realize the goal of precision dosing—providing the right drug dose to maximize therapeutic benefit, while reducing risk for each individual patient. The emerging precision dosing field harnesses the explosion of genomic data and various markers of bodily functions using mathematical modeling to ensure that individuals get the best possible treatment. In this blog post, I’ll discuss the benefits of model-informed precision dosing (MIPD) as well as the hurdles that this approach must overcome to become a standard part of patient care.
What is the “sweet spot” for model-informed precision dosing?
Model-informed precision dosing stands to yield the greatest return on investment in situations where certain patient, disease, and drug characteristics are present. The patients who benefit the most from MIPD comprise a substantial subpopulation, have well characterized physiology, are difficult to study in clinical trials due to fragility, and are highly motivated. Likewise, the ideal diseases for this approach have high unmet medical need and biomarkers that can drive dose selection. Finally, the optimal drug candidates for MIPD are expensive, well-characterized, and have a narrow therapeutic index.
For example, patients undergoing allogeneic hematopoietic cell transplants (alloHCT) for inherited immune defects or refractory cancers take extremely high doses of toxic chemotherapy drugs to destroy their bone marrow prior to graft infusion. Getting the dose right for these patients is critical to support successful engraftment while avoiding life-threatening toxicity. But, alloHCT patients are too rare to be studied in conventional clinical trials. And needless to say, any patient that is motivated enough to undergo this major procedure is likely amenable to MIPD if it can substantially improve clinical outcomes. Indeed, PK-guided dosing of busulfan, an alloHCT conditioning agent, has become the clinical standard-of-care since the late 1990s.
Barriers to widespread adoption of MIPD
While MIPD shows great promise in improving clinical care, its implementation is still largely restricted to local efforts in academic medical centers. What barriers must be overcome for MIPD to deliver its full potential?
First, we need to engage clinicians as partners in implementing MIPD. Ideally, these models would power handheld, web-based decision-support “dashboards” that could be used in the clinic. Because most clinicians do not receive training in quantitative pharmacology, these tools must be intuitive to non-modelers.
Next, the successful implementation of MIPD requires harmonizing pharmacokinetic (PK) data collection, analysis, and reporting. Variability in bioanalytical measurement of drug concentrations can result in variability of dosing recommendations. Likewise, consensus must be attained in what models (population PK, physiologically-based PK, decision trees, etc) are the most reliable for predicting a drug’s plasma exposure to estimate individual clearance and then personalize a patient’s dosing strategy. In addition, the lack of standardization in PK reporting contributes the risk of making dangerous errors in dosing. For example, for some drugs, the units for reporting the area under the time-concentration curve differ in the United States and Europe.
Finally, MIPD is a “team sport.” For MIPD to become the standard of care, modelers must be able to successfully communicate the value of this approach to both healthcare providers and patient groups. The embrace of modeling and simulation by both the pharmaceutical industry and regulatory agencies over the last few decades has reaped numerous benefits already. We will make even greater strides in optimizing the risk-benefit profile of complex drugs as MIPD moves into patient care.
The MIPD revolution is picking up momentum
Last May, Certara and the University of Manchester co-hosted the Inaugural Model-based Personalized Drug Dosing in Healthcare Conference. Speakers from eight countries—representing research institutions, academia, pharmaceutical companies, former regulators, and legal authorities—spoke at the Summit. Sessions were organized around special populations representing the most fragile and complex population cohorts, including oncology, HIV+, pediatric, obese, renally-impaired, cell transplant, adolescent psychiatric patients, and pregnant women. In addition to demonstrating how modeling and simulation facilitated individualized dosing, the conference focused on linking personalized dosing and its impact on public health. A paper based on the insights yielded at the conference, “Why has model-informed precision dosing not yet become common clinical reality? Lessons from the past and a roadmap for the future,” was just published in Clinical Pharmacology and Therapeutics.
All information presented derive from public source materials.
We recently had the pleasure of hosting a webinar on MIPD with Drs. Niloufar Marsousi (Geneva University Hospitals) and Jeannine McCune (Fred Hutchinson Cancer Center at the University of Washington). I hope that you’ll watch the webinar and let me know what you think in the comments section!