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https://pubchem.ncbi.nlm.nih.gov/

Atazanavir + Ritonavir + Tenofovir Nanoparticle suspension

Developer(s)

University of Washington

Originator
https://washington.edu/

United States of America

The University of Washington is a public research university in Seattle, Washington, United States. Founded in 1861, it is one of the oldest universities on the West Coast. The university has a 700-acre main campus in the city's University District, with satellite campuses in nearby cities of Tacoma and Bothell.

Drug structure

Structure of Atazanavir: C₃₈H₅₂N₆O₇ Ritonavir: C₃₇H₄₈N₆O₅S₂ Tenofovir: C₉H₁₄N₅O₄P

Structure of Atazanavir: C₃₈H₅₂N₆O₇ Ritonavir: C₃₇H₄₈N₆O₅S₂ Tenofovir: C₉H₁₄N₅O₄P

https://pubchem.ncbi.nlm.nih.gov/

Drug information

Associated long-acting platforms

Inorganic nanoparticles, Drug Combination Nanoparticles (DcNP)

Administration route

Subcutaneous

Therapeutic area(s)

HIV

Use case(s)

Treatment

Use of drug

Ease of administration

Administered by a community health worker
Administered by a nurse
Administered by a specialty health worker

Frequency of administration

Every 2 weeks

User acceptance

No significant adverse events (AE) , toxicity, deaths, were reported in the preclinical studies

Dosage

Available dose and strength

Strength - ATV - 25mg/mL; RTV - 12.8 mg/mL; TFV - 15.3 mg/mL (invivo preclinical dosage)

Maximum dose

ATV: 137.5 mg RTV: 70.4 mg TFV: 84.2 mg (for 5.5kg macaque)

Recommended dosing regimen

Not provided

Additional comments

Not provided

Dosage link(s)

Not provided

Drug information

Drug's link(s)

Not provided

Generic name

Atazanavir (ATV) + Ritonavir (RTV) + Tenofovir (TFV) drug-combination nanoparticle (DcNP) suspension

Brand name

Not provided

Compound type

Small molecule

Drug class/category

Protease Inhibitor (PI) + Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NRTI)

Summary

1. Clinical Pharmacology: In nonhuman primates, single SC dose of ATV/RTV/TFV DcNP sustained plasma concentrations for 14 days and PBMC concentrations for 8-14 days versus 1-2 days with free drugs. ATV showed 110-fold longer t½ (469 vs 4.3 h), 5-fold higher AUC (3.2 vs 0.6 h·µM), and 116-fold longer MBRT (650 vs 5.6 h). TFV demonstrated 35-fold higher AUC (3057 vs 85 h·µM). 2. Safety: The formulation (25 mg/kg ATV, 12.8 mg/kg RTV, and 15.3 mg/kg TFV) was successfully administered subcutaneously and was well tolerated in the study; no significant safety concerns were reported, although findings remain preclinical. 3. Efficacy: DcNP increased intracellular exposure with 33-fold higher ATV PBMC AUC (435 vs 13 h·µM) and 5-fold higher TFV PBMC AUC (1134 vs 260 h·µM) versus free drug.

Approval status

Under preclinical investigation, not approved yet.

Regulatory authorities

Under preclinical investigation, not approved yet.

Delivery device(s)

No delivery device

Scale-up and manufacturing prospects

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

1. Weighing and dispensing booths (Grade D/C) 2. Analytical balances and precision scales 3. Solvent preparation tanks/vessels 4. Glass-lined or stainless-steel mixing reactors 5. Nitrogen gas supply and evaporation system 6. Vacuum drying/desiccation unit 7. Temperature-controlled rehydration vessel (60°C) 8. High-pressure homogenizer (5,000-6,000 psi) 9.Bath sonicator (for development/small-scale batches) 10. Sterile filtration system (where applicable) 11. Aseptic holding vessels 12. pH meter 13. Osmometer

Manufacturing

The ATV/RTV/TFV drug-combination nanoparticle (DcNP) is manufactured as a sterile injectable nanosuspension under GMP-compliant aseptic conditions. Production involves solvent-based lipid-drug mixing (chloroform/ethanol), nitrogen evaporation, vacuum drying, rehydration at 60°C for 2 h, and high-pressure homogenization (5,000-6,000 psi). Critical environmental controls include microbial and particulate monitoring, maintenance of pH 7.2-7.6, osmolality of ~213.5 mOsm/kg, and refrigerated storage at 4-8°C. Key quality attributes include particle size (6-62 nm).

Specific analytical instrument required for characterization of formulation

1. Dynamic Light Scattering (DLS) 2. Zeta Potential Analyzer 3. HPLC/LC-MS/MS 4. Gas Chromatography (GC) 5. Transmission Electron Microscopy (TEM/Cryo-TEM)

Clinical trials

Not provided

Excipients

Proprietary excipients used

Not provided

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

(i) 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) (ii) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly (ethylene glycol)2000] (DSPE-mPEG2000) DSPC and DSPE-mPEG2000 at a molar ratio of 9:1

Residual solvents used

Not provided

Patent info

Description

Long-acting therapeutic agent combinations and methods thereof

Brief description

The present disclosure describes simple, stable, and scalable antiviral therapeutic agent compositions that transform short-acting antiviral (e.g., anti-HIV) therapeutic agents that would otherwise require daily short-acting oral administration into long-acting injectable forms that lasts for many weeks per administration. A mixture of water-soluble and water-insoluble antiviral therapeutic agents can be present in the long-acting and drug-combination composition.

Representative patent

US20230270677A1

Category

Not provided

Patent holder

University of Washington

Exclusivity

Not provided

Expiration date

Not provided

Status

Pending

Supporting material

Publications

Perazzolo S, Shireman LM, Koehn J, et al. Three HIV Drugs, Atazanavir, Ritonavir, and Tenofovir, Coformulated in Drug-Combination Nanoparticles Exhibit Long-Acting and Lymphocyte-Targeting Properties in Nonhuman Primates. J Pharm Sci. 2018;107(12):3153-3162. doi:10.1016/j.xphs.2018.07.032

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.

Additional documents

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Useful links

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Access principles

Collaborate for development

Consider on a case by case basis, collaborating on developing long acting products with potential significant public health impact, especially for low- and middle-income countries (LMICs), utilising the referred to long-acting technology

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Share technical information for match-making assessment

Provide necessary technical information to a potential partner, under confidentiality agreement, to enable preliminary assessment of whether specific medicines of public health importance in LMICs might be compatible with the referred to long-acting technology to achieve a public health benefit

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Work with MPP to expand access in LMICs

In the event that a product using the referred to long-acting technology is successfully developed, the technology IP holder(s) will work with the Medicines Patent Pool towards putting in place the most appropriate strategy for timely and affordable access in low and middle-income countries, including through licensing

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Comment & Information

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