A novel formulation enabled transformation of 3 HIV drugs Tenofovir-Lamivudine- Dolutegravir (TLD) from Short-Acting to Long-Acting All-in-One Injectable


Perazzolo, Simone; Stephen, Zacharya; Eguchi, Masaa; Xu, Xiaolina; Fratte, Rachele Dellea; Collier, Ann C.b; Melvin, Ann J.c; Ho, Rodney J.Y.a,d. A novel formulation enabled transformation of 3 HIV drugs tenofovir-lamivudine-dolutegravir (TLD) from short-acting to long-acting all-in-one injectable. AIDS ():10.1097/QAD.0000000000003706, August 25, 2023. | DOI: 10.1097/QAD.0000000000003706 

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.