Closed-loop drug delivery system may improve chemotherapy treatment

When cancer patients undergo chemotherapy, doses of most drugs are calculated based on the patient’s body surface area. This is estimated using an equation that takes the patient’s height and weight into account. This equation was formulated in 1916 based on data from just nine patients.

This simplified approach to dosing does not take into account other factors and may result in a patient being given too much or too little of a drug. As a result, some patients may experience unnecessary toxicity or insufficient effectiveness from the chemotherapy they receive.

To improve the accuracy of chemotherapy dosing, MIT engineers have developed an alternative approach that allows the dose to be personalized for each patient. Their system measures the amount of drug in the patient’s body and feeds that data into a controller that can adjust the infusion rate accordingly.

This approach could help compensate for differences in drug pharmacokinetics caused by body composition, genetic predisposition, chemotherapy-induced organ toxicity, interactions with other drugs and food, and circadian variations in the enzymes responsible for breaking down chemotherapy drugs, the researchers say.

"By recognizing advances in understanding how drugs are metabolized and applying engineering tools to simplify personalized dosing, we believe we can help transform the safety and effectiveness of many drugs," said Giovanni Traverso, an associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women's Hospital, and senior author of the study.

Louis DeRidder, a graduate student at MIT, is the lead author of the paper published in the journal Med.

Continuous monitoring

In this study, the researchers focused on a drug called 5-fluorouracil, which is used to treat colorectal cancer and other cancers. The drug is typically administered over a 46-hour period, and its dosage is determined using a formula based on the patient's height and weight, which gives an estimate of body surface area.

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

"People with the same body surface area can have very different heights and weights, different muscle mass, or different genetics, but as long as the height and weight plugged into that equation yields the same body surface area, their dose is identical," says DeRidder, a PhD candidate in the medical engineering and medical physics program at the Harvard-MIT Program in Health Sciences and Technology.

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

"By using body surface area to calculate chemotherapy dose, we know that two people can have very different toxicities from 5-fluorouracil. One patient can have treatment cycles with minimal toxicity, and then a cycle with terrible toxicity. Something has changed in the way that patient metabolized the chemotherapy from one cycle to the next. Our outdated dosing method doesn't capture these changes, and patients suffer as a result," says Douglas Rubinson, a clinical oncologist at Dana-Farber Cancer Institute and an author of the paper.

One way to try to compensate for 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 one treatment cycle. After this sample is analyzed for drug concentrations, the dosage can be adjusted, if necessary, at the beginning of the next cycle (usually two weeks for 5-fluorouracil).

This approach has been shown to lead to better outcomes for patients, but has not been widely used for chemotherapies such as 5-fluorouracil.

The MIT researchers wanted to develop a similar type of monitoring, but in an automated fashion that would allow drug dosing to be personalized in real time, which could lead to better outcomes for patients.

In their closed-loop system, drug concentrations can be continuously monitored and this information is used to automatically adjust the infusion rate of the chemotherapy drug to maintain the dose within the target range.

This closed-loop system allows drug dosing to be personalized to take into account circadian rhythms of drug-metabolizing enzyme levels, as well as any changes in the patient's pharmacokinetics since the last treatment, such as chemotherapy-induced organ toxicity.

To make chemotherapy dosing more precise, MIT engineers have developed a way to continuously measure the amount of drug in a patient’s body during a multi-hour infusion. This will help compensate for differences caused by body composition, genetics, drug toxicity, and circadian oscillations. Source: Courtesy of the researchers.

The new system developed by the researchers, 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 measured concentrations is entered into a control algorithm, which then adjusts the infusion rate as necessary to maintain the dose within the range of concentrations at which the drug is effective and non-toxic.

"We have developed a system where we can continuously measure the drug concentration and adjust the infusion rate accordingly to maintain the drug concentration in the therapeutic window," DeRidder says.

Quick adjustment

In animal tests, the researchers found that using CLAUDIA they could keep the amount of drug circulating in the body in the target range about 45 percent of the time.

Drug levels in animals given chemotherapy without CLAUDIA remained in the target range only 13 percent of the time on average. The researchers did not test the effectiveness of drug levels in this study, but maintaining concentrations in the target window is thought to result in better outcomes and less toxicity.

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

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

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

"We see a future where we can use CLAUDIA for any drug that has the appropriate pharmacokinetic properties and is detectable by HPLC-MS, allowing for personalized dosing for many different drugs," says DeRidder.