The new method achieves more predictable, stable drug levels in patients than the current method and could eventually allow doctors to more accurately adjust doses to accommodate individual differences in metabolism, thus increasing treatment effectiveness while avoiding side effects, said University of North Carolina at Chapel Hill researchers.
The findings were presented at the 2005 annual meeting of the American Society of Clinical Oncology, held May 13 through 17 in Orlando, Fla. The drug busulfan is used in leukemia patients to kill cancerous cells before bone-marrow transplant. Currently, it is administered in intermittent intravenous doses, typically via two-hour infusions of the drug every six hours. Previous studies have reported that frequent dose adjustments are needed to maintain the desired level of drug in patients and that metabolism of the drug varies from patient to patient.
"The new continuous-infusion method achieved more predictable levels of the drug than does the usual delivery method," said Dr. Thomas C. Shea, professor of medicine at UNC, director of the Bone Marrow Transplant Program at the UNC Health Care System and a member of the UNC Lineberger Comprehensive Cancer Center.
"In the relatively small number of patients tested with continuous infusion, there didn't appear to be a change in concentration or clearance of the drug during the 90-hour infusion period."
In 12 patients scheduled for bone marrow transplants, UNC researchers administered a single busulfan test dose of 0.8 mg/kg adjusted body weight over two hours. Blood concentrations of the drug were measured every two hours for eight hours following that test dose.
Then researchers administered busulfan by the novel method - patients received a continuous IV infusion for 90 hours. Blood concentrations of the drug were monitored every six hours.
With the new method, the test dose predicted the patients' blood levels of the drug with less than 10 percent variability.
In a separate study using a test dose and the standard intermittent delivery method, the patients metabolized the drug more slowly as the intermittent doses continued. By the 13th and final dose, on average the variability between the test-dose prediction and the actual levels had grown to more than 20 percent.
The new method may prevent side effects and increase effectiveness by maintaining a more consistent level of drug in the blood and avoiding extreme highs and lows, Shea said. "We hope this novel delivery method will be safer, and we hope it will allow us to give more total drug, which will do a better job by killing more cancer cells."
In the patients' studied, side effects were similar to those seen in current treatment. "This prolonged infusion looks like it's at least as safe as what we've been doing before," Shea said.
Because patients appear to metabolize busulfan more predictably when receiving it by continuous infusion, doctors may be able to more effectively tailor doses to individuals. "This novel delivery method may give us a new opportunity for consistent and targeted dosing for individual patients," Shea said.
Shea and his colleagues are developing a study of such tailored dosing and hope to open a clinical trial by the end of the summer.
UNC researchers along with Shea include Drs. Christine M. Walko and Jason Collins, postdoctoral fellows in UNC's School of Pharmacy; Dr. Celeste Lindley, associate professor of pharmacy; Carol Krasnov, clinical research coordinator, UNC Health Care System's Bone Marrow Program; Dr. Don Gabriel, professor of medicine; Dr. Jonathan Serody, associate professor of medicine; Dr. Terrence Comeau, assistant professor of medicine; and Lisa Patel, graduate student, UNC's Carolina Population Center. Lindley, Gabriel, Serody and Comeau are members of UNC Lineberger.
The research was supported by a grant from the pharmaceutical company ESP Pharma.
By ANGELA SPIVEY
UNC School of Medicine
Note: Contact Shea at (919) 966-7746 or sheat@med.unc.edu.
School of Medicine contact: Leslie Lang, (919) 843-9687 or llang@med.unc.edu
UNC Lineberger contact: Dianne Shaw, (919) 966-7834 or dgs@med.unc.edu