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

Abstract

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 three 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 three drugs were determined in 12 juvenile non-human primates (NHP, Macaca 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 h for all drugs. Compared to free-soluble counterpart, DcNP formulation enhanced the half-life of TAF, D, and L by 23-fold, 5.8-fold, 8.3-fold, respectively, and area under the curve (AUC) by 41-fold, 18-fold, 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.

Conclusion: Current 3-HIV oral drugs, TAF-DL is successfully transformed into a novel, single long-acting injectable product that may support once every 2 month dosing. TAF-DL-in-DcNP enhanced HIV host-lymphocyte drug exposure. With less than 24  h 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.