A novel formulation enabled transformation of 3-HIV drugs tenofovir-lamivudine-dolutegravir from short-acting to long-acting all-in-one injectable.
AIDS
; 37(14): 2131-2136, 2023 11 15.
Article
em En
| MEDLINE
| ID: mdl-37650755
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 4âweeks 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 4âweeks 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Infecções por HIV
/
Fármacos Anti-HIV
Limite:
Animals
Idioma:
En
Revista:
AIDS
Assunto da revista:
SINDROME DA IMUNODEFICIENCIA ADQUIRIDA (AIDS)
Ano de publicação:
2023
Tipo de documento:
Article