Why the dose matters: Study shows levels and anti-tumor effectiveness of
a common drug vary widely
Researchers find a sixfold variation in the levels of itraconazole in the blood and tumors of patients - even at the same dosage

Date:
September 17, 2020
Source:
UT Southwestern Medical Center
Summary:
When used to manage infections, the drug itraconazole is generally
given at a single, fixed dose to all patients. But determining the
correct dosage of the drug to help treat cancer isn't that simple,
new research suggests.



FULL STORY ==========================================================================
When used to manage infections, the drug itraconazole is generally given
at a single, fixed dose to all patients. But determining the correct
dosage of the drug to help treat cancer isn't that simple, new research
by UT Southwestern suggests.


==========================================================================
When the team of researchers and clinicians measured how much itraconazole ended up in the bloodstreams and tumors of 13 patients treated for
lung cancer, they found a sixfold variation in drug levels in tumor
samples. Moreover, the levels in the patients' bodies correlated with
how effectively the drug shrank their tumors.

"What this means going forward is that, in future studies of itraconazole
for the treatment of cancer, it may be important to check each patient's
drug level and tailor the dose," says David Gerber, M.D., a professor
of internal medicine and population and data sciences at UTSW and
first author of the new paper, published online in the journal Clinical
Cancer Research. "In this context, there's no one-size-fits-all dose,"
notes Gerber, also Associate Director of Clinical Research in the Harold
C. Simmons Comprehensive Cancer Center.

Itraconazole, sold as Sporonox, Sporaz, or Orungal, has been used for more
than 25 years to treat fungal infections. Ten years ago, James Kim, M.D., Ph.D., an associate professor of internal medicine at UTSW and senior
author of the study, was part of a team to discover that the antifungal
drug also shuts down pathways used by cancer cells to grow. Further
research has shown that itraconazole may help treat lung, prostate,
skin, and other cancers by both blocking cellular growth pathways and
stopping the formation of new blood vessels initiated by cancers.

"There was growing evidence that itraconazole conveyed a survival
advantage to patients," says Kim. "But, in this new work, we wanted to
take a step back and look more at the biology and pharmacology of what was going on with this drug in cancer patients." For infections, itraconazole
is typically given in two 100 milligram doses per day. Other cancer
trials have used doses of the drug ranging from 200 to 600 milligrams
per day. Gerber, Kim, and other colleagues studied the effect of a
steady dose of itraconazole -- 300 milligrams twice a day with food --
in 13 patients with non-small cell lung cancer who were already scheduled
for surgery to remove their tumors. After each surgery, the researchers analyzed resected tumor samples to determine how much itraconazole had accumulated in the cancer cells.

Levels of itraconazole detected within patients' tumors ranged from
1,244 ng/ g to 7,094 ng/g. This nearly sixfold variation could not be
fully explained by factors known to affect drug dosing, including body
mass and kidney or liver function. Over the 14-day treatment period,
change in tumor size ranged from a 26 percent decrease to 13 percent
growth. Patients with the highest blood and tumor levels of itraconazole
also had the largest decreases in their tumor volumes.

Further tissue analysis and imaging studies revealed corresponding changes
in the growth of tumor blood vessels and blood flow; the patients with
higher levels of itraconazole also had greater reductions in both of
these parameters.

"This study highlights the need, when repurposing drugs, to look closely
at the dosing," says William Trey Putnam, Ph.D., director of the Clinical Pharmacology Center at Texas Tech University Health Sciences Center, who collaborated with Gerber and Kim on the research. "In different diseases,
the dosing can end up needing to be quite different." The current study
was not designed to look for side effects, but the researchers say the
dose being used was within the range previously determined to be safe.

Because it's been used as an antifungal drug for decades, itraconazole
is significantly cheaper than most other cancer drugs that have similar molecular effects on tumor growth and tumor blood vessels. The researchers
say future studies will examine the use of itraconazole in combination
with other cancer drugs to reveal why the drug is processed so differently
by different patients.

"We had a small number of patients enrolled in this trial, but we
were able to optimize the use of specimens and clinical data to get statistically significant results," says Farjana Fattah, Ph.D., a UTSW assistant professor with the Harold C. Simmons Comprehensive Cancer
Center who helped lead the research. "Larger studies might be able to
draw even more conclusions."

========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. David E. Gerber, William C Putnam, Farjana J. Fattah, Kemp
H. Kernstine,
Rolf A. Brekken, Ivan Pedrosa, Rachael Skelton, Jessica
M. Saltarski, Robert E. Lenkinski, Richard D Leff, Chul Ahn,
Chyndhri Padmanabhan, Vaidehi Chemburkar, Sahba Kasiri, Raja
Reddy Kallem, Indhumathy Subramaniyan, Qing Yuan, Quyen N. Do,
Yin Xi, Scott I Reznik, Lorraine Pelosof, Brandon Faubert, Ralph
J. DeBerardinis, James Kim.

Concentration-dependent early anti-vascular and anti-tumor
effects of itraconazole in non-small cell lung cancer. Clinical
Cancer Research, 2020; clincanres.1916.2020 DOI:
10.1158/1078-0432.CCR-20-1916 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200917105356.htm

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