Personalized chemotherapy dosing treatment improves responses, minimizes side effects

A stem cell transplant patient recently returned to MD Anderson for a follow-up visit with sore ribs. But he wasn’t relapsing or experiencing complications from leukemia. The middle-aged construction worker had fallen at work a few months before.

“This is someone who, five years ago, had relapsed acute leukemia, complicated by liver problems and pneumonia. He was barely able to walk to his appointments, much less do manual labor,” remembers Borje Andersson, M.D., Ph.D.

Thanks to our pharmacokinetic-pharmacodynamic research program, the patient quickly recovered after his transplant. He resumed his favorite outdoor hobbies and is now back at work.

The main idea behind personalized treatment is that no two people are alike. The work done in the pharmacokinetic-pharmacodynamic  area by pharmacy research helps ensure each patient gets the right exposure of drugs for his or her metabolism. Pharmacokinetics uses math to study how drugs move through the body, and pharmacodynamics describes how drugs interact with the body and have an effect on cancer.

Patients receive a small test dose of chemotherapy and have blood samples drawn at set intervals over a 12-hour period. These samples are tested for drug concentrations, and then pharmacy research specialists Jitesh Kawedia, Ph.D., and Alan Myers, Pharm.D., Ph.D., are able to analyze how quickly the drugs are metabolized and cleared through patients’ bodies.

With the test results entered into their mathematical models, Kawedia and Myers provide the dose recommendation for an individual patient. The physicians then can make a more informed decision on what dosage the patient will need in a full treatment round.

Reducing side effects

While busulfan is effective at preparing a patient for a transplant, it’s so harsh that it can be toxic to the liver and other vital organs. Before test doses of the drug busulfan for stem cell transplant patients, Andersson watched many patients suffer serious organ damage and pass away due to complications from pre-transplant chemotherapy. The key for patients is to find the therapeutic window where it’s toxic to cancer but leaves healthy organs untouched.

Andersson had seen the precise dosing used by radiation oncologists, and thought, “Why can’t we do the same for chemotherapy?” It’s now been more than 10 years since our researchers first studied IV busulfan’s pharmacokinetic-guided dose adjustment.

Due to differences in genetics, a patient’s overall health and other individual factors, the rate at which a patient’s body clears oral busulfan can vary by more than tenfold. When patients received an average dose, some wouldn’t receive enough to be effective, and some would receive too much, seriously damaging their vital organs. Changing to IV busulfan lowered this variability to about twofold. Adding test doses with therapeutic testing enabled physicians to personalize each patient’s therapy. This meant safer treatments and better treatment results.

Therapeutic pharmacokinetic testing is now standard of care. It was used in more than 700 consults last year, and it’s making a big difference for patients. Today, Kawedia and Myers provide the pharmacokinetic-guided dose adjustment for every patient who receives standard of care busulfan.

“One patient’s labs showed she processed busulfan much more slowly than average, and she’d received 90% of the therapeutic dose within the first two days of her four-day treatment plan,” Myers says.

Knowing this, the care team adjusted the patient’s dose, and she received one fewer day of chemotherapy than planned. Without therapeutic testing, she would have received almost twice the amount of busulfan her body needed and sustained serious liver damage.

Looking forward

While the majority of the samples analyzed currently are for stem cell transplant patients receiving busulfan, the process can be used for many classes of drugs. When new drugs are being developed, researchers use the process to help determine the safe and recommended dosages for patients.

Advances in high resolution equipment and new classes of drugs have brought new protocols to the pharmacy research lab.

“We collaborate with investigators on drug trials and multicenter investigations to test new drugs or drug combinations, and help design the pharmacokinetic aspects of the study when needed,” Kawedia says.

They’re expanding their services to also test for biologics, a type of enzyme that acts like a drug.

The exact dosing of busulfan in patients has opened up new research areas for Andersson’s team.

“We’ve applied this knowledge and started asking questions about how to further improve pre-transplant therapy and improve patient outcomes,” he says. “With the pharmacokinetic process, we can better detect small changes caused by newer combinations of drugs that we couldn’t see before.”

Since pharmacokinetic testing became standard of care in 2010, treatment-related deaths have sharply decreased, Andersson says. He points to a graph of long-term survival, with the line following patients who received personalized dosing much higher than a control group treated with the previous standard.

“We’re doing better for our patients, and we’re working to get that line as close to 100% as possible,” he says.

A longer version of this article originally appeared in Messenger, MD Anderson’s bimonthly employee publication..