A novel formulation enabled transformation of 3-HIV drugs tenofovir-lamivudine-dolutegravir from short-acting to long-acting all-in-one injectable.
A novel formulation enabled transformation of 3-HIV drugs tenofovir-lamivudine-dolutegravir from short-acting to long-acting all-in-one injectable.
复制标题
一种新的配方使 3-HIV 药物替诺福韦-拉米夫定-多替拉韦从短效注射剂转变为长效注射剂。
DOI：
10.1097/qad.0000000000003706
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Ho,RodneyJY
中科院分区：
文献类型：
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作者：
Perazzolo,Simone;Stephen,ZacharyR;Eguchi,Masa;Xu,Xiaolin;DelleFratte,Rachele;Collier,AnnC;Melvin,AnnJ;Ho,RodneyJY
目的：开发一种注射剂型的每日口服HIV药物，替诺福韦（T），拉米夫定（L），和dolutegravir（D），创造一个单一的，完整的，所有在一个E13-药物组合，展示了长效的potential.Design：使用药物组合纳米颗粒（DcNP）技术，以稳定多种HIV药物，3-HIV药物组合，具有不同的物理化学性质，稳定和组装与脂质赋形剂，形成TLD-在-DcNP。经验证，TLD-in-DcNP稳定且适合皮下给药。为了表征所有3种药物的血浆时程和PBMC浓度，对非人灵长类动物（NHP，M.结果：在单剂量TLD-在-DcNP中后，所有药物在NHP血浆中表现出长效特征，其水平持续4周高于联合用药的预测病毒有效浓度。所有NHP中所有药物的达峰时间均在24小时内。与游离可溶性的TcNP相比，TLD-in-DcNP提供了暴露增强和延长的持续时间，AUC增加为7.0、2.1和20倍，半衰期延长为10、8.3和5.9倍。此外，DcNP可以提供更多的药物暴露在细胞中比血浆与PBMC-血浆药物比超过1，这表明细胞靶向的药物组合deliveration.Conclusions：这项研究证实，具有不同属性的ESTA可以由DcNP稳定，使ESTA浓度为4周的NHP。研究结果强调了TLD-in-DcNP作为一种方便的全合一、完整的HIV长效产品用于临床开发的潜力。
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.