Feasibility of Weekly HIV Drug Delivery to Enhance Drug Localization in Lymphoid Tissues Based on Pharmacokinetic Models of Lipid-Associated Indinavir

Abstract

Compare the simulated pharmacokinetics of lipid-associated and soluble indinavir (IDV) to determine the potential for greater control of virus replication in the lymphoid tissues. Two-compartment mathematical models were developed to simulate the human pharmacokinetics of soluble and lipid-associated forms of IDV in the central compartment and the lymphoid tissue. The lipid-associated IDV model was then used to determine the minimum dosing schedule needed to attain central or lymph drug concentrations comparable to the soluble form. Association of IDV to lipid nanoparticles has a favorable half-life and tissue distribution and allows comparable minimum drug concentration in the lymph (where the majority of viral replication occurs) to be achieved with a dosing schedule of every 95.5 h (approximately 4 days). Presuming pharmacodynamics of lipid-associated IDV are similar to soluble IDV, estimations based on the proposed kinetic model suggest the novel delivery system could have a tremendous impact on the current standard of HIV treatment, particularly for therapy targeted to clear virus sanctuaries in lymphoid tissues. With less frequent and more effective dosing, lipid-associated indinavir delivery as an adjunct to conventional antiviral therapy could lead to better suppression of viral replication, increased immunological benefit, and fewer treatment failures.