Facilitating compound progression of antiretroviral agents via modeling and simulation.
Pharmacotherapy in human immunodeficiency virus (HIV)-infected patients and the development of safe and effective antiretroviral dosing regimens has been hindered by numerous issues, including the rapid development of viral resistance to drug therapy, the narrow therapeutic window of the drug compounds, and lack of fundamental knowledge concerning the sources of variation in exposure and response to antiretroviral agents. Sources of variation may include factors such as interpatient differences in genetic expression, immunological response, pathogenesis, epidemiologic and socioeconomic factors, and demographics. Modeling and simulation (M&S) techniques have become valuable tools to identify and quantify variability in exposure and response to antiretroviral agents throughout the drug development process. Before actual entry into human safety and pharmacokinetic (PK) trials, in vitro screening and in vivo pharmacology studies conducted to assess compound potency and compatibility with agents included in acceptable antiretroviral therapy (ART) regimens can be characterized via quantitative relationships. In addition, physiochemical data is initially used to screen drug candidates based on favorable PK and biopharmaceutic properties. Compound progression can likewise be supported with M&S exercises to ensure the traceability of key assumptions and decisions. The underlying techniques utilize nonlinear mixed effect modeling, Monte Carlo simulation, Neural networks, several regression-based approaches, and less computationally intensive techniques. The application of such an approach promises to be an essential component in the development of new agents to treat HIV-1 and is being implemented in the context of evaluating Nk1r antagonists as potential candidates to treat NeuroAIDS.
Barrett
Jeffrey S
JS
Laboratory for Applied PK/PD, Clinical Pharmacology and Therapeutics Division, The Children's Hospital of Philadelphia, Abramson Research Center, Room 916H, 3516 Civic Center Boulevard, Philadelphia, PA 19104, USA. barrettj@email.chop.edu
D000818:Animals; D044966:Anti-Retroviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans
D044966:Anti-Retroviral Agents