拉米夫定
药代动力学
药理学
医学
药品
杜鲁特格拉维尔
人类免疫缺陷病毒(HIV)
免疫学
病毒载量
病毒
抗逆转录病毒疗法
乙型肝炎病毒
作者
Simone Perazzolo,Zachary R. Stephen,Masakatsu Eguchi,Xiaolin Xu,Rachele Delle Fratte,Ann C. Collier,Ann J. Melvin,Rodney J. Y. Ho
出处
期刊:AIDS
[Ovid Technologies (Wolters Kluwer)]
日期:2023-08-24
卷期号:37 (14): 2131-2136
标识
DOI:10.1097/qad.0000000000003706
摘要
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.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 ).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.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.
科研通智能强力驱动
Strongly Powered by AbleSci AI