Faculty Spotlight: Angela Kashuba — Working with Industry
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Faculty Spotlight: Angela Kashuba — Working with Industry
Working with industry
Kashuba is conducting studies with the four newest antiretroviral drugs to receive FDA approval—darunavir (2006), maraviroc (2007), raltegravir (2007), and etravirine (2008).
Raltegravir and maraviroc represent two new classes of drugs to treat HIV infection. Raltegravir is an integrase inhibitor made by Merck. It targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes. Without integrase, the virus cannot incorporate its DNA into the host cell’s DNA and use the cell to replicate itself.
Maraviroc, a compound produced by Pfizer, is a chemokine receptor antagonist, a class of drugs that binds to immune system cells and prevents the HIV virus from entering the cells. Kashuba says chemokine receptor antagonists are special because all but one of the existing antiretroviral drugs operate inside the cell—after the virus has invaded the cell. Chemokine receptor antagonists, on the other hand, work outside the cell, keeping the virus out altogether, which is the ideal treatment. It is also administered orally, making it a more practical prophylaxis than the other existing extracellular antiretroviral drug, which has to be injected.
Kashuba’s study on maraviroc found that it has a higher drug penetration in the genital tract than all the other antiretroviral drugs that have been investigated. The study also showed that most of the drug was in a protein unbound state, which means most of the drug found at this site is available to do its work. The drug also showed a high concentration in the tissues—the site of the initial infection.
Furthermore, the study found that after a dose, the genital tract concentrations of maraviroc remained high for more than three days.
“These data suggest that this drug may be used only around the time of risky behavior rather than every day,” Kashuba says. “Current studies are designed for people to take a drug or two every day, which is not practical in the long term.”
Kashuba’s study was the first to measure the amount of any drug in a protein unbound state in genital secretions, the first to measure tissue concentrations of any orally administered antiretroviral drug, and the first to investigate whether the pharmacokinetics of antiretroviral drugs would favor episodic dosing (used only around the time of risky behavior rather than daily).
“We recently presented these novel data as a platform presentation at the CROI 2008 meeting on the oral formulation of maraviroc,” Kashuba says. “It created a lot of excitement, and was very well received.”
Kashuba also generated a great deal of buzz at the Microbicides 2008 meeting with her data on the topical formulation of the antiretroviral drug tenofovir.
“No one has ever looked to see how much drug stays in the female genital tract after topical dosing with a gel, or how much drug gets into tissues after the gel is applied,” Kashuba says. “We were the first to design this investigation and found very high concentrations of the drug in vaginal tissues that stay put for at least twenty-four hours after dosing. These data make the topical gel look even more promising than the oral pill.”
The data from Kashuba’s investigation lend support for a current study in South Africa that recently started a trial in which tenofovir gel is applied only around the time of possible HIV exposure.
“There was much controversy in the scientific community when this study was started, because everyone thought that the gel needed to be applied daily, regardless of whether risky behavior would be occurring on that day,” Kashuba says. “Based on our data, it appears that this study can soundly move forward.”