New system personalizes chemotherapy doses for cancer patients

When cancer patients undergo chemotherapy, the dose of most drugs is calculated based on the patient’s body surface area. This is calculated by plugging the patient’s height and weight into an equation, dating back to 1916, which was formulated from data from just nine patients.

This simplistic dosing does not take other factors into account and can result in patients receiving either too much or too little medication. As a result, some patients may experience avoidable toxicity or insufficient benefit from the chemotherapy they receive.

To make chemotherapy dosing more precise, MIT engineers have come up with an alternative approach that may allow the dose to be individualized to the patient. Their system measures how much drug is in the patient’s system, and those readings are fed to a controller that can adjust the infusion rate accordingly.

This approach could help compensate for differences in drug pharmacokinetics caused by body composition, genetic makeup, chemotherapy-induced toxicity of drug-metabolizing organs, interactions with other drugs taken, and food consumed and circadian variations in the enzymes responsible for the breakdown. reduce chemotherapy drugs, researchers say.

Recognizing advances in understanding how drugs are metabolized and applying engineering tools to facilitate personalized dosing, we believe can help transform the safety and efficacy of many drugs.”

Giovanni Traverso, associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women’s Hospital and senior author of the study

Louis DeRidder, an MIT graduate student, is the lead author of the paper, which appears today in the journal Med.

Constant observation

In this study, the researchers focused on a drug called 5-fluorouracil, which is used to treat colon cancer, among other things. The drug is usually injected over a 46-hour period, and the dosage is determined using a formula based on the patient’s height and weight, which gives the estimated body surface area.

However, this approach does not take into account differences in body composition that may affect how the drug spreads through the body or genetic variations that affect how it is metabolized. These differences can lead to harmful side effects if there is too much of the drug. If not enough drug is circulating, it may not kill the tumor as expected.

“People with the same body surface area could have very different heights and weights, they could have very different muscle mass or genetics, but since the height and weight tied into this equation give the same body surface area, the dose they are the same. ” says DeRidder, a doctoral candidate in the Medical Engineering and Medical Physics program of the Harvard-MIT Program in Health Sciences and Technology.

Another factor that can change the amount of drug in the bloodstream at any given time is circadian fluctuations of an enzyme called dihydropyrimidine dehydrogenase (DPD), which breaks down 5-fluorouracil. DPD expression, like many other enzymes in the body, is regulated in a circadian rhythm. Thus, the degradation of 5-FU by DPD is not constant but changes with the time of day. These circadian rhythms can result in tenfold variations in the amount of 5-fluorouracil in the patient’s bloodstream during an infusion.

“By using body surface area to calculate chemotherapy dose, we know that two people can have profoundly different toxicity from 5-fluorouracil chemotherapy. Looking at a patient, they may have cycles of treatment with minimal toxicity and then have a cycle of abysmal toxicity. “Something has changed in the way a patient metabolizes chemotherapy from one cycle to the next, and our antiquated dose fails to capture that change, and patients suffer as a result,” says Douglas Robinson, a clinical oncologist at the Dana-Farland Cancer Institute. Farber and author of the paper.

One way to try to address the variability in the pharmacokinetics of chemotherapy is a strategy called therapeutic drug monitoring, in which the patient gives a blood sample at the end of a course of treatment. After this sample is analyzed for drug concentration, the dose can be adjusted, if necessary, at the start of the next cycle (usually two weeks later for 5-fluorouracil). This approach has been shown to lead to better outcomes for patients, but is not widely used for chemotherapies such as 5-fluorouracil.

The MIT researchers wanted to develop a similar type of monitoring, but in a way that was automated and allowed for real-time medication personalization, which could lead to better outcomes for patients. In their “closed-loop” system, drug concentrations can be monitored continuously, and this information is used to automatically adjust the infusion rate of the chemotherapy drug and keep the dose within the target range. Such a closed-loop system allows drug dosing to be individualized in a way that takes into account circadian rhythm changes in the levels of drug-metabolizing enzymes, as well as any changes in the patient’s pharmacokinetics since their last treatment, such as toxicity that caused by chemotherapy the organs that metabolize the drugs.

The new system they designed, known as CLAUDIA (Closed-Loop Automated Drug Infusion regulAtor), uses commercially available equipment for each step. Blood samples are taken every five minutes and quickly prepared for analysis. The concentration of 5-fluorouracil in the blood is measured and compared to the target range. The difference between the target and the measured concentration is fed into a control algorithm, which then adjusts the infusion rate if necessary to keep the dose within the range of concentrations between which the drug is effective and non-toxic.

“What we developed is a system where you can continuously measure the drug concentration and adjust the infusion rate accordingly to keep the drug concentration within the therapeutic window,” says DeRidder.

Quick adjustment

In animal tests, researchers found that using CLAUDIA, they could keep the amount of drug circulating in the body within the target range about 45 percent of the time. Drug levels in animals receiving chemotherapy without CLAUDIA remained in the target range only 13 percent of the time, on average. In this study, the researchers did not test the effectiveness of the drug levels, but keeping the concentration within the target window is believed to lead to better results and less toxicity.

CLAUDIA was also able to keep the dose of 5-fluorouracil within the target range even when the researchers administered a drug that inhibits the DPD enzyme. In animals given this inhibitor without continuous monitoring and adjustment, 5-fluorouracil levels increased up to eightfold.

For this demonstration, the researchers performed each step of the process manually, using off-the-shelf equipment, but now plan to work on automating each step so that monitoring and adjusting the dose can be done without human intervention.

To measure drug concentrations, the researchers used high-performance liquid chromatography-mass spectroscopy (HPLC-MS), a technique that could be adapted to detect almost any type of drug.

“We envision a future where we can use CLAUDIA for any drug that has the right pharmacokinetic properties and is detectable by HPLC-MS, thereby allowing individualized dosing for many different drugs,” says DeRidder.

The research was funded by the National Science Foundation Graduate Research Fellowship Program, a MathWorks grant, MIT’s Karl van Tassel Career Development Professorship, the MIT Department of Mechanical Engineering, and the Bridge Project, a collaboration between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.

Other authors of the paper include Kyle A. Hare, Aaron Lopes, Josh Jenkins, Nina Fitzgerald, Emmeline MacPherson, Niora Fabian, Josh Morimoto, Jacqueline N. Chu, Ameya R. Kirtane, Wiam Madani, Keiko Ishida, Johannes LP Kuosmanen, Zacharias , Christopher M. Colangelo, Hen-Wei Huang, Makaya Chilekwa, Nikhil B. Lal, Shriya S. Srinivasan, Alison M Hayward, Brian M. Wolpin, David Trumper, Troy Quast, and Robert Langer.