Administering repurposed drug to treat TB via lungs vs. orally shows promise
DENVER (Nov. 15, 2016) — Tuberculosis (TB) is responsible for more than 1.8 million deaths each year, according to the World Health Organization, yet there has been little significant improvement in therapies in the past 20 years. This chronic disease is systemic, meaning it affects not only the lungs but also other organs, such as the lymph nodes and spleen. But a promising new treatment may be on the horizon.
New research being presented today at the American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition demonstrates that administering a commonly used drug to treat TB via the lungs as opposed to oral administration is as effective at a fraction of the dose — estimated up to 10 times less — used in the standard treatment of care. The research also shows this treatment has the potential to reduce toxicity to the body and its organs. The 2016 AAPS Annual Meeting and Exposition is taking place in Denver Nov. 13 – 17.
Pyrazinamide (PZA), a first line agent used in treating TB, is administered orally. PZA is thought to act as a "prodrug," converting to pyrazinoic acid (POA), which is the "active moiety" (the part of a drug that makes the drug work the way it does), by microbial enzymatic action. A significant mechanism of PZA resistance is a mutation of the enzyme associated with the conversion to POA. It has historically been determined that oral POA is not effective against disease, and even recent research has shown limited antituberculosis activity for high oral doses.
Delivery of POA and its hydrolysable ester, n-propyl POA (PAE), can provide the active moiety, mitigating resistance. Given locally to the lungs, it can circumvent oral bioavailability issues and might require less drug to reduce the burden in the lungs, which is a major site of infection and transmission for TB.
"When it comes to TB therapy, there have not been a lot of new drugs introduced to market during the past two decades, and progress is slow despite enormous effort in new drug discovery," said Phillip Durham, a biochemist at RTI International in Raleigh-Durham, N.C.
"What we've done in our research," continued Durham, "is to use a derivative of a drug that has been around for many years — Pyrazinoic acid — and repurposed the drug to deliver it to the lungs, with some very promising results."
The study demonstrated that the aerosol was as effective in the lungs and lymph nodes and outperformed the high dose oral PZA in the spleen. Because oral PZA may have toxic side effects, reducing the dose while providing the same level of efficacy has tremendous potential to benefit patients worldwide.
"For drugs that are not orally bioavailable, the alternative is often injection," said Durham. "Given the dose required, daily therapy, and the physical health of the patients, inhaled therapy has the potential to be far less painful, does not generate biohazardous waste like HIV contaminated needles (HIV/TB coinfection is a problem), and does not need to be kept cold, which is required by many injectables."
23T0830 – Evaluation of a Dry Powder Aerosol of Pyrazinoic Acid and Its n-Propyl Ester against Experimental Tuberculosis in Guinea Pigs will be presented on Tuesday, Nov. 15 from 8:30 – 9:00 a.m. in Colorado Convention Center – Exhibit Hall E.
The 2016 AAPS Annual Meeting and Exposition aims to improve global health through advances in pharmaceutical sciences, and there will be over 700 exhibitor booths and an estimated 6,500 attendees. The meeting features nearly 245 programming sessions, including more than 65 symposia and roundtables and more than 1,900 posters. Download the AAPS mobile application for additional information.
Editor's Note: All media must provide press credentials to attend this meeting and register onsite at the Colorado Convention Center in the press room 105. To schedule an interview with Phillip Durham, or for any other press inquiries, please contact Katie Baumer at [email protected] or 703-248-4772 or Hillarie Turner at [email protected] or 301-836-1516 x7. For the most up-to-date program information, please click here.
About AAPS: The American Association of Pharmaceutical Scientists (AAPS) is a professional, scientific organization of approximately 9,000 members employed in academia, industry, government, and other research institutes worldwide. Founded in 1986, AAPS advances the capacity of pharmaceutical scientists to develop products and therapies that improve global health. Visit http://www.aaps.org and follow us on Facebook and Twitter @AAPSComms. The official Twitter hashtag for the meeting is: #AAPS2016.