A novel formulation enabled transformation of 3-HIV drugs tenofovir-lamivudine-dolutegravir from short-acting to long-acting all-in-one injectable

Abstract

Objective: To develop an injectable dosage form of the daily oral HIV drugs, tenofovir (T), lamivudine (L), and dolutegravir (D), creating a single, complete, all-in-one TLD 3-drug-combination that demonstrates long-acting pharmacokinetics.

Design: Using drug-combination-nanoparticle (DcNP) technology to stabilize multiple HIV drugs, the 3-HIV drugs TLD, with disparate physical-chemical properties, are stabilized and assembled with lipid-excipients to form TLD-in-DcNP . TLD-in-DcNP is verified to be stable and suitable for subcutaneous administration. To characterize the plasma time-courses and PBMC concentrations for all 3 drugs, single subcutaneous injections of TLD-in-DcNP were given to nonhuman primates (NHP, M. nemestrina ).

Results: Following single-dose TLD-in-DcNP , all drugs exhibited long-acting profiles in NHP plasma with levels that persisted for 4 weeks above predicted viral-effective concentrations for TLD in combination. Times-to-peak were within 24 hr in all NHP for all drugs. Compared to a free-soluble TLD, TLD-in-DcNP provided exposure enhancement and extended duration 7.0-, 2.1-, and 20-fold as AUC boost and 10-, 8.3-, and 5.9-fold as half-life extension. Additionally, DcNP may provide more drug exposure in cells than plasma with PBMC-to-plasma drug ratios exceeding one, suggesting cell-targeted drug-combination delivery.

Conclusions: This study confirms that TLD with disparate properties can be made stable by DcNP to enable TLD concentrations of 4 weeks in NHP. Study results highlighted the potential of TLD-in-DcNP as a convenient all-in-one, complete HIV long-acting product for clinical development.

Figure 1.. Effects of DcNP dosage form on the time-course of plasma tenofovir (TFV or T), lamivudine (3TC or L), and dolutegravir (DTG or D) in non-human primates (NHPs). Panel A: plasma drug concentrations over time are presented after a single subcutaneous dose of the TLD-in-DcNP or free-soluble mixture given to NHP. Panel B: noncompartmental pharmacokinetic (PK) parameters results.

Panel A. All drugs in NHP receiving TLD-in-DcNP show extended time as prolonged TFV, 3TC, and DTG presence in the plasma as opposed to free-soluble drugs control at equivalent subcutaneous dose of 6.2 mg/kg TFV, 5.1 mg/kg 3TC, and 10 mg/kg DTG. Filled symbols represent plasma drug concentrations of TLD drugs in DcNP for 5 NHP, as mean ± SD. Empty symbols represent TLD given as free-soluble TLD combination in 2 NHP as mean (only one NHP with free DTG was available). Horizontal dashes lines denote the in vitro IC₉₀ values in serum (protein) as a fixed-ratio presented in the TLD-in-DcNP or fee-soluble drug-in-combination. In each graph, there is an inset representing a zoomed-in view of the first 72 hours after injection. Panel B. Noncompartmental PK parameter estimates are based on the concentration-time course data presented in Panel A. Each PK parameter is presented as mean ± SD. Time-to-peak is the time needed for the drug to rise to the first identifiable concentration peak collected at concentration C_max. C_4w is the drug concentration at 4 weeks; AUC is the area under the curve based on integration of plasma time-courses using classical trapezoidal rules for the 4-weeks study; AUC ratio as the fold enhancement of TLD formulated in DcNP after a single dose; t_1/2,z as the apparent terminal elimination half-life.