A novel injectable drug-combination nanoparticle containing three antiretrovirals designed for HIV treatment: A first-in-human trial

Abstract

Background Long-acting antiretroviral therapy may improve adherence and decrease stigma, yet affordable combination formulations for global usage are lacking. The TLC-ART program engineered an injectable 3-drug combination in a novel nanoparticle (DcNP) product “TLC-ART 101,” composed of lopinavir (LPV), ritonavir (RTV), and tenofovir (TVF) and two lipid excipients. We report safety and pharmacokinetics from this first-in-human study. Methods Three dose cohorts of people without HIV received a single subcutaneous dose of 1.5, 3.0 or 4.0 mL in an adaptive trial of up to64 days. LPV, RTV, and TFV were measured over time in plasma, peripheral blood mononuclear cells (PBMC), and lymph nodes (n=2). Results All 12 participants completed the study. One participant experienced anaphylaxis, and four had non-serious hypersensitivity events (rash, lip swelling, generalized pruritis). All participants had grade 1-2 injection-site reactions.. At the highest dose, median LPV T1/2 was 17 days, and LPV was detectable through two months in most participants. RTV T1/2 was 12hrs. Plasma TFV T1/2 was 3.5 days; TFV-diphosphate was detected intracellularly through 14 days. Total exposure (AUC) was higher in peripheral blood mononuclear cells versus plasma for all 3 drugs. Conclusions The first human application of this novel HIV DcNP resulted in detection of LPV through two months and TFV up to four days in plasma, and no meaningful prolongation of RTV. Systemic hypersensitivity was common, and although IgE elevation was not observed, additional mechanistic understanding is required prior to further development of this DcNP pipeline.