A novel all-in-one injectable composed of tenofovir alafenamide–dolutegravir-lamivudine exhibits long-acting plasma and cell drug persistence for 8 weeks

OBJECTIVE: To investigate the novel 3-in-one long-acting injectable product composed of tenofovir alafenamide (TAF), dolutegravir (D), and lamivudine (L), as a complete TAF-DL product for pediatric HIV treatment. DESIGN: TAF-DL sterile injectable product is assembled with 3-HIV drugs and amphipathic lipids. It is built on the drug-combination-nanoparticle (DcNP) platform via a well-defined manufacturing process. Plasma concentrations for all 3 drugs were determined in 12 juvenile nonhuman primates (NHP, M. nemestrina) following subcutaneous administration. Safety parameters monitored. RESULTS: Following a single dose of TAF-DL-in-DcNP, all drugs exhibited long-acting cell-and plasma profiles in juvenile NHP for 8 weeks. Time-to-peak occurred within 24 hr, for all drugs. Compared to free-soluble counterpart, DcNP formulation enhanced TAF, D and L half-life by 23, 5.8, 8.3-fold; and AUC by 41, 18, 3.1-fold. Cell targeting enabled by DcNP is noted as higher intracellular PBMC versus plasma concentration of TAF, tenofovir (T), D, L in NHP dosed with TAF-DL-in-DcNP product. Safety assessment in 12 juvenile-NHPs noted no injection site reactions, or change in weight, complete blood count, and serum chemistries over 8 weeks. CONCLUSIONS: Current 3-HIV oral drugs, TAF-DL is successfully transformed into a novel, single long-acting injectable product that may support once-every-two-month dosing. TAF-DL-in-DcNP enhanced HIV host-lymphocyte drug exposure. With less than 24 hr to reach Cmax, the all-in-one product may overcome the need for an oral-lead-in typically required to initiate LA injectables. TAF-DL-in-DcNP product appears to be safe in juvenile NHPs.