How do all of these substances affect how HIV drugs work and how do HIV drugs, in turn, affect the other drugs a patient takes?
That question is at the heart of research being conducted by the University at Buffalo's Laboratory for Antiviral Research, where researchers are developing innovative new methods of testing the blood and cells of HIV patients for these interactions.
The work is supported by a new, $2.3 million National Institutes of Health/National Institute for Drug Abuse grant to complete the first major study of complex drug interactions in AIDS patients.
"Fifteen years ago, we were treating people with one basic goal in mind: to prolong their lives," said Gene Morse, Pharm.D., principal investigator, professor and chair of the UB Department of Pharmacy Practice and associate dean of the School of Pharmacy and Pharmaceutical Sciences. "Now we have the drugs to suppress viral replication, but with them come another set of complications. Many of these drugs are interacting and it has been difficult to study all possible interactions during the FDA development process. We want to find out their net effect." The decision to propose a comprehensive study on how antiretroviral drugs interact with other drugs HIV patients take grew out of a recent, multi-year clinical pharmacology study of interactions with methadone by Morse and psychiatrists at New York City's Montefiore Hospital. "A big factor in treating HIV infection are those patients with concurrent substance addiction," explained Morse. "For example, some of the drugs patients take to treat HIV could actually put them into withdrawal from methadone."
UB is the lead institution on the project, conducting laboratory-based studies to measure concentrations of drugs a patient is taking in blood and cells and to analyze the pharmacogenetic basis of different drugs, or how patients' genetic makeup may influence their response to the drugs.
Morse explained that UB is well-positioned to head up the study because its Laboratory for Antiviral Research, an established group of researchers, was formed early in the HIV epidemic to focus on issues on HIV pharmacotherapy.
The lab has aggressively developed innovative methods to analyze quantitatively and qualitatively how multiple antiretroviral drugs and other pharmaceuticals are metabolized in individuals and their effects -- both desirable and undesirable -- on patients.
The UB researchers also will examine complex drug interactions during chronic antiretroviral therapy using pharmacokinetic and pharmacodynamic modeling, the study of how drugs affect the body's systems over time. Pharmacodynamic modeling originated at UB's School of Pharmacy and Pharmaceutical Science in the 1960s and UB has been a major international source of new research in the field ever since.
Alan Forrest, Pharm.D., clinical professor in the UB Department of Pharmacy Practice, heads the Biometrics Study Unit in the department and is a co-investigator on the grant.
During the study, blood samples will be collected from a total of 500 patients enrolled at four clinical sites: Montefiore Hospital in New York City, the University of Rochester, Case Western Reserve University and the University of Miami in Florida. Each site has had prior clinical research collaborations with UB's Laboratory for Antiviral Research.
The study will be conducted and coordinated through the HIV ePharmacotherapy Network, a Web site developed by Morse and his colleagues in 1998 to coordinate HIV clinical pharmacology research. "Considerable variation exists among individuals as to how AIDS drugs are absorbed, distributed and metabolized," he said, "but right now are all prescribed as though 'one size fits all,' according to fixed-dose regimens."
In addition to looking at blood concentrations of drugs and interactions, Morse said the study will examine the levels of multiple drugs that bind to plasma proteins in each patient. "The amount of plasma protein-binding can vary from patient to patient and that can have important clinical implications," said Morse. "For example, the more highly bound to protein the drug is in plasma, then the less there is to get to the tissue sites where HIV can replicate." The study, he added, also is aimed at uncovering some of the long-term toxicities from these drugs, which are becoming an increasing concern because people are living longer with HIV infection.