Lopinavir, Ritonavir, and Tenofovir (LRT) TLC-ART 101

Drug information

Delivery device(s)

No delivery device

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

1. Spray dryer 2. High-shear mixers or homogenizers (for mixing and size reduction) 3. High-pressure homogenizer or microfluidizer 4. Sterile filtration units 5. Aseptic filling systems

Manufacturing

1. Dissolve all drugs and lipids in ethanol (with minimal aqueous buffer) at 65–75 °C 2. Spray-dry the solution under controlled conditions (ProCepT or Buchi spray dryer) 3. Collect powder and convert to nanosuspension via homogenization 4. Add Excipients: DSPC and DSPE-PEG2000 5. Final product: Nanoparticles (~50–200 nm) with a multi-drug motif (MDM) structure

Specific analytical instrument required for characterization of formulation

Not provided

First in Human Clinical Trial of a Next Generation, Long-acting Injectable, Combination Antiretroviral Therapy Platform TLC-ART 101 (ACTU 2001)

Identifier

NCT05850728

Link

https://clinicaltrials.gov/study/NCT05850728?intr=TLC-ART&rank=1

Phase

Phase I

Status

Recruiting

Sponsor

NIH

More details

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.

Purpose

Safety, tolerability and PK of single subcutaneous injection of TLC-ART 101 in healthy adults

Interventions

Intervention 1

Countries

Sites / Institutions

Trials dates

Anticipated Start Date
2023-04-01

Actual Start Date
2023-04-01

Anticipated Date of Last Follow-up
Not provided

Estimated Primary Completion Date
2025-10-25

Estimated Completion Date
2025-12-01

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
Yes

Comments about the studied populations

18 Years to 65 Years (Adult, Older Adult ) of any sex

Health status

Study type

Interventional (clinical trial)

Enrollment

16

Allocation

Non-randomized

Intervention model

Single group assignment

Intervention model description

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.

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

Proprietary excipients used

No proprietary excipient used

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

1. 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) 2. 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000)

Residual solvents used

No residual solvent used

Description

Lopinavir, Ritonavir, and Tenofovir (LRT) combination, formulation, and method of administration

Brief description

combination pharmaceutical compositions and methods thereof. The present invention relates to combination pharmaceutical compositions, which include a combination of hydrophilic and hydrophobic therapeutic agents (i.e., drugs) that are assembled together with excipients under specific conditions, forming a homogeneous pharmaceutical powder with multiple motif structure. unified repetitive drugs (mdm). Unlike currently available drug combination powders, which are amorphous, the combination pharmaceutical compositions (e.g., combination therapeutic agent powders) of the present invention have long-range order, in the form of unified, repetitive multidrug motifs. .

Representative patent

WO2020146788

Category

Combination, Formulation

Patent holder

University Of Washington

Exclusivity

Not provided

Expiration date

January 10, 2040

Status

Pending: BR, CN, US

Publications

Perazzolo S, Flexner CW, Stephen ZR, Acosta EP, Bender Ignacio RA, Ho RJY. Long-acting Injectable Containing Lopinavir Eliminates Reliance on Ritonavir Pharmacokinetic Enhancement. J Infect Dis. Published online June 24, 2025. doi:10.1093/infdis/jiaf319

High-extraction protease inhibitors (e.g., for HIV and COVID-19) typically require ritonavir to enhance bioavailability by overcoming first-pass metabolism. However, in the long-acting subcutaneous injectable dosage form TLC-ART 101, lopinavir persisted in plasma for 57 days, while ritonavir was detectable for only 3-7 days. The remarkable duration of lopinavir suggests that ritonavir may be unnecessary in long-acting injectable products, potentially reducing side effects and drug-drug interactions.

Kraft JC, McConnachie LA, Koehn J, et al. Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma. AIDS. 2017;31(6):765-770. doi:10.1097/QAD.0000000000001405

Objective: The aim of the present study was to determine whether a combination of anti-HIV drugs - tenofovir (TFV), lopinavir (LPV) and ritonavir (RTV) - in a lipid-stabilized nanosuspension (called TLC-ART101) could enhance and sustain intracellular drug levels and exposures in lymph node and blood cells above those in plasma.

Design: Four macaques were given a single dose of TLC-ART101 subcutaneously. Drug concentrations in plasma and mononuclear cells of the blood (PBMCs) and lymph nodes (LNMCs) were analysed using a validated combination LC-MS/MS assay.

Results: For the two active drugs (TFV, LPV), plasma and PBMC intracellular drug levels persisted for over 2 weeks; PBMC drug exposures were three- to four-fold higher than those in plasma. Apparent terminal half-lives (t1/2) of TFV and LPV were 65.3 and 476.9 h in plasma, and 169.1 and 151.2 h in PBMCs. At 24 and 192 h, TFV and LPV drug levels in LNMCs were up to 79-fold higher than those in PBMCs. Analysis of PBMC intracellular TFV and its active metabolite TFV-diphosphate (TFV-DP) indicated that intracellular exposures of total TFV and TFV-DP were markedly higher and persisted longer than in humans and macaques dosed with oral TFV prodrugs, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF).

Conclusions: A simple, scalable three-drug combination, lipid-stabilized nanosuspension exhibited persistent drug levels in cells of lymph nodes and the blood (HIV host cells) and in plasma. With appropriate dose adjustment, TLC-ART101 may be a useful HIV treatment with a potential to impact residual virus in lymph nodes.

Freeling JP, Koehn J, Shu C, Sun J, Ho RJ. Anti-HIV drug-combination nanoparticles enhance plasma drug exposure duration as well as triple-drug combination levels in cells within lymph nodes and blood in primates. AIDS Res Hum Retroviruses. 2015;31(1):107-114. doi:10.1089/aid.2014.0210

HIV patients on combination oral drug therapy experience insufficient drug levels in lymph nodes, which is linked to viral persistence. Following success in enhancing lymph node drug levels and extending plasma residence time of indinavir formulated in lipid nanoparticles, we developed multidrug anti-HIV lipid nanoparticles (anti-HIV LNPs) containing lopinavir (LPV), ritonavir (RTV), and tenofovir (PMPA). These anti-HIV LNPs were prepared, characterized, scaled up, and evaluated in primates with a focus on plasma time course and intracellular drug exposure in blood and lymph nodes. Four macaques were subcutaneously administered anti-HIV LNPs and free drug suspension in a crossover study. The time course of the plasma drug concentration as well as intracellular drug concentrations in blood and inguinal lymph nodes were analyzed to compare the effects of LNP formulation. Anti-HIV LNPs incorporated LPV and RTV with high efficiency and entrapped a reproducible fraction of hydrophilic PMPA. In primates, anti-HIV LNPs produced over 50-fold higher intracellular concentrations of LPV and RTV in lymph nodes compared to free drug. Plasma and intracellular drug levels in blood were enhanced and sustained up to 7 days, beyond that achievable by their free drug counterpart. Thus, multiple antiretroviral agents can be simultaneously incorporated into anti-HIV lipid nanoparticles to enhance intracellular drug concentrations in blood and lymph nodes, where viral replication persists. As these anti-HIV lipid nanoparticles also prolonged plasma drug exposure, they hold promise as a long-acting dosage form for HIV patients in addressing residual virus in cells and tissue.

Additional documents

No documents were uploaded

Useful links

• LEAP - TS2023 - Physiological based Pharmacokinetic Modeling to Support a LA HIV Drug-combination Formulation