ArticleJournal of pharmaceutical sciences2020
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 in Journal of pharmaceutical sciences, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05850728 (First in Human Clinical Trial of a Next Generation, Long-acting Injectable, Combination Antiretroviral Therapy Platform), which is not on this map. Cited by 17 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
First in Human Clinical Trial of a Next Generation, Long-acting Injectable, Combination Antiretroviral Therapy Platform
Who cites it
17 citing papers in PubMed.
- A novel all-in-one injectable composed of tenofovir alafenamide-dolutegravir-lamivudine exhibits long-acting plasma and cell drug persistence for 8 weeks.AIDS (London, England) · 2026Article
- Accelerating Generic Long-Acting Antiretrovirals for Global HIV Treatment: Workshop Findings and a Roadmap to Access.Clinical pharmacology and therapeutics · 2026Article
- Classification system proposed to guide the design, development, regulatory approval, and scaling of long acting, small- and macro-molecule parenteral products (CS-BLAP).Journal of pharmaceutical sciences · 2026Review
- Long-acting Injectable Containing Lopinavir Eliminates Reliance on Ritonavir Pharmacokinetic Enhancement.The Journal of infectious diseases · 2025Article
- SAAM II: A general mathematical modeling rapid prototyping environment.CPT: pharmacometrics & systems pharmacology · 2024Article
- Physiologically based Pharmacokinetic Model Validated to Enable Predictions Of Multiple Drugs in a Long-acting Drug-combination Nano-Particles (DcNP): Confirmation with 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products.Journal of pharmaceutical sciences · 2024Article
- Viral dissemination and immune activation modulate antiretroviral drug levels in lymph nodes of SIV-infected rhesus macaques.Frontiers in immunology · 2023Article
- Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 2: Model for the Drug-combination Nanoparticles.Journal of pharmaceutical sciences · 2022Article
- Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 1: Model for the Free-Drug Mixture.Journal of pharmaceutical sciences · 2022Article
- A Systematic Approach for Liposome and Lipodisk Preclinical Formulation Development by Microfluidic Technology.The AAPS journal · 2021Article
- A Concept Evaluation Study of a New Combination Bictegravir plus Tenofovir Alafenamide Nanoformulation with Prolonged Sustained-Drug-Release Potency for HIV-1 Preexposure Prophylaxis.Antimicrobial agents and chemotherapy · 2021Article
- Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective.Journal of pharmaceutical sciences · 2021Article
- Long-acting drugs and formulations for the treatment and prevention of HIV infection.International journal of antimicrobial agents · 2021Review
- Antiviral Drug Delivery System for Enhanced Bioactivity, Better Metabolism and Pharmacokinetic Characteristics.International journal of nanomedicine · 2021Review
- Controlled Solvent Removal from Antiviral Drugs and Excipients in Solution Enables the Formation of Novel Combination Multi-Drug-Motifs in Pharmaceutical Powders Composed of Lopinavir, Ritonavir and Tenofovir.Journal of pharmaceutical sciences · 2020Article
- Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules.Pharmaceutical research · 2020Article
- Bictegravir Plus Tenofovir Alafenamide Nanoformulation as a Long-Acting Pre-Exposure Prophylaxis Regimen: Application of Modeling to Design Non-Human Primate Pharmacokinetic Experiments.Frontiers in pharmacology · 2020Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
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.
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Registered trials
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