This study is a prospective, open-label, single-site, first-in-human study of a long-acting, injectable combination antiretroviral therapy platform, with a pharmacologically-guided adaptive design for dose escalation, de-escalation, and study duration. The study is designed to learn whether the formulation can be used as a platform for other drugs for treatment of HIV. The formulation is a drug combination nanoparticle (DCNP). The study will be conducted by UW Positive Research. The sample size for this study is 12-16. The study population consists of healthy adults without HIV. The study duration is 57 days per participant at the start of the study.

开始日期2023-04-01

申办/合作机构

University of Washington

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100 项与 Lopinavir/Ritonavir/Tenofovir 相关的临床结果

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100 项与 Lopinavir/Ritonavir/Tenofovir 相关的转化医学

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100 项与 Lopinavir/Ritonavir/Tenofovir 相关的专利（医药）

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项与 Lopinavir/Ritonavir/Tenofovir 相关的文献（医药）

2020-05-01·Journal of Pharmaceutical Sciences

Integration of Computational and Experimental Approaches to Elucidate Mechanisms of First-Pass Lymphatic Drug Sequestration and Long-Acting Pharmacokinetics of the Injectable Triple-HIV Drug Combination TLC-ART 101

Article

作者: Lee, Wonsok ; Shireman, Laura M ; Koehn, Josefin ; Ho, Rodney J Y ; Kinman, Loren ; Shen, Danny D ; Collier, Ann C ; McConnachie, Lisa A ; Lane, Sarah ; Perazzolo, Simone

TLC-ART101 is a long-acting triple-HIV drug combination of lopinavir-ritonavir-tenofovir in one nanosuspension intended for subcutaneous injection. After a single TLC-ART 101 administration in nonhuman primates, drug concentrations in both plasma and HIV-target lymph node mononuclear cells were sustained for 2 weeks. Nevertheless, the mechanisms leading to the targeted long-acting pharmacokinetics remain elusive. Therefore, an intravenous study of TLC-ART 101 in nonhuman primates was conducted to elucidate the degree of association of drugs in vivo, estimate subcutaneous bioavailability, and refine a mechanism-based pharmacokinetic (MBPK2) model. The MBPK2 model considers TLC-ART 101 systemic drug clearances, nanoparticle-associated/dissociated species, more detailed mechanisms of lymphatic first-pass retention of associated-drugs after subcutaneous administrations, and the prediction of drug concentration time-courses in lymph node mononuclear cells. For all 3 drugs, we found a high association with the nanoparticles in plasma (>87% lopinavir-ritonavir, 97% tenofovir), and an incomplete subcutaneous bioavailability (<29% lopinavir-ritonavir, 85% tenofovir). As hypothesized by the MBPK2 model, the incomplete SC bioavailability observed is due to sequestration into a lymphatic node depot after subcutaneous absorption (unlike most intramuscular nanodrug products having near-to-injection depots), which contributes to long-acting profiles detected in plasma and target cells. This combined experimental and modeling approach may be applicable for the clinical development of other long-acting drug-combination injectables.

2018-12-01·Journal of Pharmaceutical Sciences3区 · 医学

Three HIV Drugs, Atazanavir, Ritonavir, and Tenofovir, Coformulated in Drug-Combination Nanoparticles Exhibit Long-Acting and Lymphocyte-Targeting Properties in Nonhuman Primates

3区 · 医学

Article

作者: Kraft, John C ; Shireman, Laura M ; Ho, Rodney J Y ; McConnachie, Lisa A ; Koehn, Josefin ; Perazzolo, Simone ; Shen, Danny D

Drug-combination nanoparticles (DcNPs) administered subcutaneously represent a potential long-acting lymphatic-targeting treatment for HIV infection. The DcNP containing lopinavir (LPV)-ritonavir (RTV)-tenofovir (TFV), Targeted-Long-Acting-Antiretroviral-Therapy product candidate 101 (TLC-ART 101), has shown to provide long-acting lymphocyte-targeting performance in nonhuman primates. To extend the TLC-ART platform, we replaced TLC-ART 101 LPV with second-generation protease inhibitor, atazanavir (ATV). Pharmacokinetics of the ATV-RTV-TFV DcNP was assessed in macaques, in comparison to the equivalent free drug formulation and to the TLC-ART 101. After single subcutaneous administration of the DcNP formulation, ATV, RTV, and TFV concentrations were sustained in plasma for up to 14 days, and in peripheral blood mononuclear cells for 8 to 14 days, compared with 1 to 2 days in those macaques treated with free drug combination. By 1 week, lymph node mononuclear cells showed significant levels for all 3 drugs from DcNPs, whereas the free controls were undetectable. Compared with TLC-ART 101, the ATV-RTV-TFV DcNP exhibited similar lymphocyte-targeted long-acting features for all 3 drugs and similar pharmacokinetics for RTV and TFV, whereas some pharmacokinetic differences were observed for ATV versus LPV. The present study demonstrated the flexibility of the TLC-ART's DcNP platform to include different antiretroviral combinations that produce targeted long-acting effects on both plasma and cells.

2018-04-01·Journal of Controlled Release1区 · 医学

Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation

1区 · 医学

Article

作者: Sun, Jianguo ; Shen, Danny D ; Kinman, Loren ; Collier, Ann C ; Collins, Carol ; Koehn, Josefin ; McConnachie, Lisa A ; Ho, Rodney J Y ; Kraft, John C

Existing oral antiretroviral (ARV) agents have been shown in human studies to exhibit limited lymph node penetration and lymphatic drug insufficiency. As lymph nodes are a reservoir of HIV, it is critical to deliver and sustain effective levels of ARV combinations in these tissues. To overcome lymph node drug insufficiency of oral combination ARV therapy (cART), we developed and reported a long-acting and lymphocyte-targeting injectable that contains three ARVs-hydrophobic lopinavir (LPV) and ritonavir (RTV), and hydrophilic tenofovir (TFV)-stabilized by lipid excipients in a nanosuspension. A single subcutaneous (SC) injection of this first-generation formulation of drug combination nanoparticles (DcNPs), named TLC-ART101, provided persistent ARV levels in macaque lymph node mononuclear cells (LNMCs) for at least 1 week, and in peripheral blood mononuclear cells (PBMCs) and plasma for at least 2 weeks, demonstrating long-acting pharmacokinetics for all three drugs. In addition, the lymphocyte-targeting properties of this formulation were demonstrated by the consistently higher intracellular drug concentrations in LNMCs and PBMCs versus those in plasma. To provide insights into the complex mechanisms of absorption and disposition of TLC-ART101, we constructed novel mechanism-based pharmacokinetic (MBPK) models. Based upon plasma PK data obtained after single administration of TLC-ART101 (DcNPs) and a solution formulation of free triple-ARVs, the models feature uptake from the SC injection site that respectively routes free and nanoparticle-associated ARVs via the blood vasculature and lymphatics, and their eventual distribution into and clearance from the systemic circulation. The models provided simultaneous description of the complex long-acting plasma and lymphatic PK profiles for all three ARVs in TLC-ART101. The long-acting PK characteristics of the three drugs in TLC-ART101 were likely due to a combination of mechanisms including: (1) DcNPs undergoing preferential lymphatic uptake from the subcutaneous space, (2) retention in nodes during lymphatic first-pass, (3) subsequent slow release of ARVs into blood circulation, and (4) limited extravasation of DcNP-associated ARVs that resulted in longer persistence in the circulation.

100 项与 Lopinavir/Ritonavir/Tenofovir 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
HIV感染	临床1期	美国	University of Washington	2023-04-01
HIV感染	临床1期	美国	National Institute of Allergy & Infectious Diseases	2023-04-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


IAS2002	N/A	HIV感染	42	Lopinavir/r plus Amprenavir	(選鹹獵淵簾鹽築顧廠憲) = 淵構齋鹹糧衊鹽獵窪壓鏇壓範積製獵鹽衊遞鏇 (窪淵繭蓋艱範築簾鏇窪 ) 更多	-	2002-01-01
				Lopinavir/r plus SaquinavirLopinavir/r plus Saquinavir	(選鹹獵淵簾鹽築顧廠憲) = 構觸廠積壓簾廠獵衊積鏇壓範積製獵鹽衊遞鏇 (窪淵繭蓋艱範築簾鏇窪 ) 更多