Graduation Date

Spring 5-4-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Interdisciplinary Graduate Program in Biomedical Sciences

First Advisor

Benson J. Edagwa, Ph.D.

Second Advisor

Howard E. Gendelman, M.D.

Abstract

While antiretroviral therapy (ART) has significantly reduced human immunodeficiency virus type one (HIV-1) co-morbidities and mortality, adherence to daily oral therapy remains a key barrier to all therapeutic and preventative outcomes. Over the past years, the emergence of long-acting (LA) ART has gained considerable enthusiasm amongst people living with HIV (PLWH) and could potentially simplify dosing regimens and improve treatment outcomes. LA ART could also improve drug adherence, reduce viral transmission, and limit viral drug resistance and systemic toxicities. In response to these needs, a combination of two LA injectable nanocrystalline drugs (CABENUVA) was recently approved for bimonthly administration in adults and adolescents who are virologically suppressed. Further, a bimonthly extended-release cabotegravir (CAB) injectable suspension (APPRETUDE) monotherapy has been approved and shown to be superior to daily oral Truvada for pre-exposure prophylaxis (PrEP) in men who have sex with men and transgender women. However, the key challenge for CABENUVA and APRETUDE is the frequent dosing that exerts pressure on healthcare workers and allied facilities. This limitation, combined with the need to synchronize CD4+ T cell and viral load tests, could potentially affect compliance. Poor compliance has been shown to increase infection rates and the emergence of drug resistance. Other barriers linked to the injectable formulations include prolonged subtherapeutic terminal drug decay curves [pharmacokinetic (PK) tail] following drug regimen cessation and increased risk of resistance to rilpivirine, especially in patients who have much higher baseline viral loads. Another potent LA ART SUNLENCA (lenacapavir) has been approved for six-monthly administration in heavily treatment-experienced adults with multidrug-resistant (MDR) HIV-1 infection who have failed their current ART regimen. However, at present, there is no other LA antiretroviral that can be combined with SUNLENCA as a complete synchronous regimen for the treatment of HIV-1 infection. To overcome these challenges of existing injectable LA ARVs, we transformed native bictegravir (BIC), a potent integrase strand transfer inhibitor (INSTI) with a high genetic barrier to resistance, into a library of ester prodrugs. These included a BIC stearate monomer (M2BIC) and BIC octadecanedioate dimer (MXBIC). Surfactant-stabilized aqueous nanosuspensions of M2BIC (NM2BIC) and MXBIC (NMXBIC) enhanced intracellular drug uptake, retention, release, and antiretroviral activities. When administered to rodents and nonhuman primates (NHP) as a single intramuscular (IM) dose NMXBIC and NM2BIC generated BIC plasma concentrations above the protein-adjusted 95% inhibitory concentration (PA-IC95) for six months or longer. Notably, a single IM injection of 45 mg/kg BIC equivalent dose of NMXBIC in Sprague Dawley (SD) rats provided a "plateau" phase of BIC exposure, sustaining active drug levels above fourteen to twenty-four times the PA-IC95 for six months. This was followed by a short PK tail. By contrast, a similar dose of NM2BIC produced lower but more prolonged plasma BIC levels that were sustained at or above the PA-IC95 for a year. Readily detectable injection site depot, lymphoid, mucosal, and gut tissue BIC levels were recorded without adverse reactions in rodents, rabbits, and rhesus macaques. The promising preclinical data sets demonstrate the potential for a tolerable and safe six-month BIC prodrug formulation with a short PK tail.

Comments

2024 Copyright, the authors

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