Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection

Abstract

Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography-tandem mass spectrometry. Plasma and PBMC levels of the active drugs (LPV, TFV, and 3TC) were sustained for 5 weeks; PBMC exposures to LPV, ritonavir, and 3TC were 12-, 16-, 42-fold higher than those in plasma. Apparent T_1/2z of LPV, TFV, and 3TC were 219.1, 63.1, and 136.3 h in plasma; 1045.7, 105.9, and 127.7 h in PBMCs. At day 8, LPV, TFV, and 3TC levels in LNMCs were 4.1-, 5.0-, and 1.9-fold higher than in those in PBMCs and much higher than in plasma. Therefore, 1 dose of a 4-drug nanosuspension exhibited persistent drug levels in LNMCs, PBMCs, and plasma for 5 weeks. With interspecies scaling and dose adjustment, this 4-in-1 HIV drug-combination could be a long-acting treatment with the potential to target residual virus in tissues and improve patient adherence.

Keywords: HIV treatment; lamivudine; long-acting; nanoparticle; targeted delivery; tenofovir.

Figure 1.

Plasma, PBMC, and LNMC drug concentration versus time plots. (a) The open circles (○) represent the PBMC data, the closed squares (■) are plasma data, and the crosses (X) represent lymph node data. The data plotted are the mean ± SD, n = 4 macaques over 840 h (5 wks) following a single subcutaneous administration of the 4-in-1 DcNP. Time scales are interrupted to show more detail from the first 8 h. (b) PBMC and LNMC cell volumes were assumed to be 0.2829 pL/cell. The dotted lines represent the EC₅₀ concentration for each respective single agent, and the shaded section in the 3TC graph is the reported range of EC₅₀ values. C_max, maximum drug concentration; T_1/2z, apparent terminal half-life.