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Edagwa B, Nayan MU, Sillman B, et al. An Ultra-Long-Acting Dimeric Bictegravir Prodrug Defined by a Short Pharmacokinetic Tail. Preprint. Res Sq. 2025;rs.3.rs-5959131. doi:10.21203/rs.3.rs-5959131/v1

Ultra-Long-Acting Dimeric Bictegravir Prodrug

Developer(s)

University of Nebraska Medical Center

Originator
https://www.unmc.edu/

United States of America

The University of Nebraska Medical Center (UNMC) is a public academic health-sciences center in Omaha, Nebraska, founded in 1869. UNMC houses six colleges, two degree-granting institutes, and graduate studies, with nearly 40 academic departments offering clinical, research, and graduate programs. They provide guidance and support to help advance early-stage drug discovery projects.

Drug structure

Chemical structure of Bictegravir Dimer Prodrug

Chemical structure of Bictegravir Dimer Prodrug

Edagwa B, Nayan MU, Sillman B, et al. An Ultra-Long-Acting Dimeric Bictegravir Prodrug Defined by a Short Pharmacokinetic Tail. Preprint. Res Sq. 2025;rs.3.rs-5959131. doi:10.21203/rs.3.rs-5959131/v1

Drug information

Associated long-acting platforms

Aqueous drug particle suspension

Administration route

Intramuscular

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 6 months

User acceptance

Not provided

Dosage

Available dose and strength

NMXBIC 45 mg/kg and 90 mg/kg BIC equivalent dose (Preclinical dose - rat) and 30 mg (1mL) IM injection (Preclinical unit dosage - rabbit)

Maximum dose

300 mg

Recommended dosing regimen

Not provided

Additional comments

Not provided

Dosage link(s)

Not provided

Drug information

Drug's link(s)

Not provided

Generic name

Bictegravir

Brand name

Bictegravir

Compound type

Small molecule

Drug class/category

prodrug of bictegravir (integrase strand transfer inhibitor; INSTI)

Summary

This ultra-long-acting bictegravir prodrug is a synthetic lipophilic ester of bictegravir. The homodimeric form of BIC is formulated into a single aqueous nanosuspension (NMXBIC) with Tween 20 and PEG3350 as excipients. The PK profile of NMXBIC—tail phase half-life (t½): 18–26 days; Cmax: 2,328 ng/mL within 24 hours post-injection and a low PK tail phasing duration (70 days). The mechanism of absorption involves a slow dissolution and hydrolysis of the prodrug at the injection site, forming a long-lasting depot. This hydrolysis releases the active BIC via enzymatic and chemical cleavage. Further, the NMXBIC likely undergoes two-step hydrolysis, releasing one BIC molecule at a time, compared to monomeric form (M2BIC), producing a 'controlled plateau.'

Approval status

Not approved

Regulatory authorities

Not approved

Delivery device(s)

No delivery device

Scale-up and manufacturing prospects

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

High-pressure homogenizer

Manufacturing

The synthesized prodrug form is converted into surfactant-stabilized aqueous nanosuspensions through a scalable microfluidization process utilizing high-pressure homogenization. An optimal formulation was developed using polysorbate 20 (Tween 20) and polyethylene glycol 3350 (PEG 3350) as stabilizers. This advanced formulation significantly increased the drug concentration from 120 mg/mL to 300-330 mg/mL.

Specific analytical instrument required for characterization of formulation

1. Nuclear magnetic resonance (NMR), 2. Fourier-transform infrared (FT-IR) spectroscopy, 3. Electrospray ionization mass spectrometry (ESI-MS)

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

1. Polysorbate 20 (Tween-20) 2. Polyethylene glycol 3350 (PEG-3350) 3. Poloxamer 407 (Pluronic F127) 4. PBS (vehicle)

Residual solvents used

No residual solvent used

Patent info

Description

Prodrug comprising dimer of integrase inhibitor (bictegravir) and nanoparticle comprising crystalline form of said prodrug

Brief description

The present invention provides prodrugs and methods of use thereof.

Representative patent

WO2020112931

Category

Compound

Patent holder

BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA

Exclusivity

Not provided

Expiration date

November 27, 2039

Status

Granted: CN Pending: EPO, US

Supporting material

Publications

Edagwa, B., Nayan, M. U., Sillman, B., Das, S., Hanson, B., Sultana, A., Le, N. T. H., Deodhar, S., Dash, A., Cohen, S., & Gendelman, H. (2025). An Ultra-Long-Acting Dimeric Bictegravir Prodrug Defined by a Short Pharmacokinetic Tail. Research square, rs.3.rs-5959131. https://doi.org/10.21203/rs.3.rs-5959131/v1

Ultra-long-acting (ULA) antiretroviral parenteral formulations, with low injection volumes, high resistance barriers, and short pharmacokinetic (PK) tails, can transform HIV-1 therapeutics. Here, we converted bictegravir (BIC), a potent daily oral antiretroviral drug, into monomeric and homodimeric ester prodrugs. The homodimeric prodrug nanosuspension, NMXBIC, shows sustained plasma BIC levels >16 times the protein-adjusted 95% inhibitory concentration (PA-IC95) for six months after a single injection in Sprague Dawley rats. The results paralleled a short PK tail with the potential for late dose forgiveness. The monomeric prodrug nanosuspension, NM2BIC, shows lower year-long plasma BIC concentrations above PA-IC95 after a single injection in Sprague Dawley rats. After repeated injections, NMXBIC and NM2BIC are well tolerated in New Zealand White rabbits. NMXBIC's physicochemical properties and high BIC loading/unit mass of the prodrug contribute to its unique ULA PK profile. These results support its development as a ULA formulation for HIV-1 treatment and prevention.

Additional documents

Useful links

There are no additional links

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

Not provided

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

Not provided

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

Not provided

Comment & Information

Not provided