Atazanavir + Ritonavir + Tenofovir Nanoparticle suspension

Drug information

Drug's link(s)

Not provided

Generic name

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

Brand names

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.

Therapeutic area(s)

Use case(s)

Treatment

Administration route

Subcutaneous

Associated long-acting platforms

Inorganic nanoparticles, Drug Combination Nanoparticles (DcNP)

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

Associated compounds, formulations and regimens

Not provided

Associated technologies

Not provided

Additional information

Not provided

Developer(s)

Originator

United States of America

University of Washington

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

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)

Excipients & delivery device(s)

Proprietary excipients used

Not provided

Novel excipients or existing excipients at a concentration above Inactive Ingredient 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

Delivery device(s)

No delivery device

Safety, Efficacy and Evidence Summary

Safety

Not provided

Efficacy

Not provided

Evidence Summary

Not provided

References and relevant studies

Not provided

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