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MedChemExpress

Drug name

Tenofovir-Lamivudine-Dolutegravir (TLD) - long-acting injectable (LAI) (TLD LAI)

Originator/manufacturer

Drug information

Drug's link(s)

Not provided

Generic name

Not yet developed

Brand names

Not yet assigned

Compound type

Small molecule

Summary

Tenofovir disoproxil fumarate/Lamivudine/Dolutegravir (TLD; TDF/3TC/DTG) is a fixed-dose antiretroviral drug combination used for the treatment of HIV. It consists of two NNRTIs (TDF/3TC) and an InSTI (DTG). Since 2018, WHO HIV treatment guidelines have recommended daily oral TLD as the preferred first-line regimen for initiating antiretroviral therapy (ART) among adults and adolescents living with HIV. In most PEPFAR-supported countries, more than 80% of people receiving HIV-ART were prescribed oral TLD as of March 2022. Researchers at the University of Washington are currently developing a long-acting injectable version of tenofovir+lamivudine+dolutegravir via drug-combination-nanoparticle (DcNP) technology platform which would enable effective TLD concentrations for up to 4 weeks.

Approval status

Still in clinical development

Regulatory authorities

Still in clinical development

Therapeutic area(s)

  • HIV
  • HBV
Use case(s)
  • Treatment

Administration route

Subcutaneous

Associated long-acting platforms

Aqueous drug particle suspension, Based on other organic particles

Use of drug

Ease of administration
  • Administered by a community health worker
  • Administered by a nurse
  • Administered by a specialty health worker
  • Self-administered
  • To be determined
User acceptance

Not provided

Comment & Information

Not provided

Originator/manufacturer

University of Washington
United States

The University of Washington is a public research university based in Seattle, Washington, USA. Originally founded in 1861, the institution has an extraordinary track record of scientific inventions & discoveries. Its Targeted Long-acting Combination Antiretroviral Therapy (TLC-ART) program aims to develop safe, stable, scalable and tolerable long-acting ART combinations for the treatment of HIV.

Drug structure

Scale-up and manufacturing prospects

Scale-up prospects

A novel long-acting TLD drug-combination nano-particulate (DcNP) formulation for subcutaneous injection was prepared with biocompatible lipid excipients. The highly-scalable DcNP technology enables drugs with disparate physiochemical properties to be formulated into products that remain stable in aqueous suspension. First, TLD was dissolved with lipid-excipients in hydrated-alcohol, followed by a controlled solvent-removal process to create the TLD-DcNP powder. Next, the TLD-DcNP particle-size was reduced (60-80 nm) resulting in a stable-injectable TLD product suitable for subcutaneous dosing.

Tentative equipment list for manufacturing

Rotary evaporator (rotavap). High pressure homogeniser (e.g. Emulsiflex-c5; Avestin Inc., Canada). Spray-dryer (e.g. 4M8Trix Unit; ProCepT, Belgium).

Manufacturing

TLD-in-DcNP injectable suspension was prepared by dissolving 40.27 mmol DSPC, 5.97mmol HCl, 5.66 mmol DTG and 4.49mmol mPEG2000-DSPE in 472 ml ethanol at 70°C. Following dissolution, 28 ml of 200 mM NaHCO3 buffer containing 5.85 mmol TFV and 5.85 mmol 3TC was added. The solution was then spray-dried under controlled-solvent-removal process to generate the TLD-in-DcNP powder.  The powder in 0.45% w/v NaCl–20 mM NaHCO3 buffer suspension was held at 75°C and homogenised to achieve stable particles (50–70 nm). The suspension was cooled to 25°C and stored at 4°C.

Specific analytical instrument required for characterization of formulation

Particle size determined by photon correlation spectroscopy using a NICOMP 380 ZLS (Particle Sizing Systems, Santa Barbara, CA). Osmolality (Vapro 5520 osmometer; Wescor, Logan, UT) and pH (Hydrion paper). Drug quantification via LC-MS/MS using acetonitrile precipitation.

Excipients

Proprietary excipients used

Lipid excipients: DSPC and DSPE-mPEG2000

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

Not provided

Residual solvents used

Not provided

Delivery device(s)

No delivery device

Publications

Perazzolo S, Stephen ZR, Eguchi M, Xu X, Delle Fratte R, Collier AC, Melvin AJ, Ho RJY. A novel formulation enabled transformation of 3-HIV drugs tenofovir-lamivudine-dolutegravir from short-acting to long-acting all-in-one injectable. AIDS. 2023 Nov 15;37(14):2131-2136. DOI: 10.1097/QAD.0000000000003706. Epub 2023 Aug 24. PMID: 37650755; PMCID: PMC10959254.

Objective: To develop an injectable dosage form of the daily oral HIV drugs, tenofovir (T), lamivudine (L), and dolutegravir (D), creating a single, complete, all-in-one TLD 3-drug-combination that demonstrates long-acting pharmacokinetics.

Design: Using drug-combination-nanoparticle (DcNP) technology to stabilize multiple HIV drugs, the 3-HIV drugs TLD, with disparate physical-chemical properties, are stabilized and assembled with lipid-excipients to form TLD-in-DcNP . TLD-in-DcNP is verified to be stable and suitable for subcutaneous administration. To characterize the plasma time-courses and PBMC concentrations for all 3 drugs, single subcutaneous injections of TLD-in-DcNP were given to nonhuman primates (NHP, M. nemestrina ).

Results: Following single-dose TLD-in-DcNP , all drugs exhibited long-acting profiles in NHP plasma with levels that persisted for 4 weeks above predicted viral-effective concentrations for TLD in combination. Times-to-peak were within 24 hr in all NHP for all drugs. Compared to a free-soluble TLD, TLD-in-DcNP provided exposure enhancement and extended duration 7.0-, 2.1-, and 20-fold as AUC boost and 10-, 8.3-, and 5.9-fold as half-life extension. Additionally, DcNP may provide more drug exposure in cells than plasma with PBMC-to-plasma drug ratios exceeding one, suggesting cell-targeted drug-combination delivery.

Conclusions: This study confirms that TLD with disparate properties can be made stable by DcNP to enable TLD concentrations of 4 weeks in NHP. Study results highlighted the potential of TLD-in-DcNP as a convenient all-in-one, complete HIV long-acting product for clinical development.