Pharmacokinetics of anti-HIV agents in rodents
Blue, Shawn Kendale
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The treatment of HIV/AIDS is one of, if not, the most challenging medical enigmas of the 20th and 21st centuries. At the time of its discovery, HIV patients were predominantly homosexual White males in America. The demographics have changed drastically over the past two decades. Now women make up nearly 50% of global HIV/AIDS patients. The current feminization of HIV demographics has led to another obstacle, mother to child transmission (MTCT). These statistics, coupled with the fact that vertical transmission is the largest factor in the number of newly diagnosed juvenile HIV/AIDS patients, create a need to optimize treatment of HIV positive pregnant women, to reduce vertical transmission of HIV. It has been shown that administration of anti-HIV medications during pregnancy, delivery and to the infant after birth greatly reduces the risk of vertical transmission. Understanding the pharmacokinetics of HIV/AIDS medications alone and in combination during pregnancy is necessary in the development of more effective methods of vertical transmission prophylaxis. Using a pregnant rat model, we have developed analytical methods and investigated the pharmacokinetics and placental transport of anti-HIV drugs alone and in combination. These studies allowed us to determine and understand any possible interactions between drugs in combination. Studies were performed on timed-pregnant Sprague-Dawley rats and pharmacokinetic analysis was performed using WinNonlin. While current methods of treating HIV/AIDS patients have been highly successful, the chance of viral mutations and resistance to Anti-Retroviral Therapy often occurs. In order to combat the resistance of reverse transcriptase inhibitors (NRTI and NNRTI) and protease inhibitors, scientists have continually searched for additional targets on HIV. For instance, integrase inhibitors, block the action of integrase, a viral enzyme, which integrates HIV DNA into the target cells. We have determined the pharmacokinetic profile of an investigational integrase inhibitor. In vivo animal studies were being performed on male Sprague-Dawley rats and female PXR-KO and hPXR transgenic mice and pharmacokinetic analysis was performed using WinNonlin.