Injectable long-acting human immunodeficiency virus antiretroviral prodrugs with improved pharmacokinetic profiles

Abstract

While highly active antiretroviral therapy (HAART) has significantly reduced mortality rates in patients with human immunodeficiency virus type 1 (HIV-1), its efficacy may be impeded by emergence of drug resistance caused by lack of patient adherence. A therapeutic strategy that requires infrequent drug administration as a result of sustained release of antiretroviral drugs would put less burden on the patient. Long-acting antiretroviral prodrugs for HIV therapy were synthesized through modification of the active drugs, emtricitabine (FTC) and elvitegravir (EVG), with docosahexaenoic acid (DHA) in one-step, one-pot, high-yielding reactions. The in vitro drug release profiles of these synthetic conjugates demonstrated sustained and controlled release of the active drug over a period of 3–4weeks attributable to the hydrolysis of the chemical linker in conjunction with the hydrophilicity of the parent drug. Both conjugates exhibited superior antiviral activities in tissue culture models of HIV replication as compared to those of the free drugs, strengthening their role as potent prodrugs for HIV therapy. Pharmacokinetic analysis in CD1 mice further confirmed the long-acting aspect of these conjugates with released drug concentrations in plasma detected at their respective IC90/IC95 values over a period of 2 weeks and discernable amounts of active drug even at 6weeks. Our findings suggest that the injectable small molecule conjugates could be used as long-acting controlled release of FTC and EVG in attempts to mitigate adherence-related HIV resistance.

Long-acting HIV pre-exposure prophylaxis (PrEP) approaches: recent advances, emerging technologies, and development challenges

“…The palmitic acid prodrug of DTG has been formulated into biodegradable microparticles [ 74 ], and PK evaluation in rabbits (SC injection, 30 mg/kg) showed that the IC 90 of DTG was maintained for >3 months. LA polyunsaturated fatty-acid prodrugs of FTC and elvitegravir (EVG) exhibited superior antiviral activities in HIV replication tissue models and LA characteristics in mice [ 75 ].…”

A New Approach to Developing Long-Acting Injectable Formulations of Anti-HIV Drugs: Poly(Ethylene Phosphoric Acid) Block Copolymers Increase the Efficiency of Tenofovir against HIV-1 in MT-4 Cells

“…However, the majority of the investigated antiretroviral agents are not well suited for formulation as long-acting injectables due to suboptimal physicochemical properties limiting their formulation as conventional drug suspensions, as well as insufficient antiviral potency resulting in high monthly dosing requirements. The identification of single vehicles capable of dissolving multiple drugs for solution-based long-acting injections provides a number of hurdles, especially when attempting to overlay various partition coefficients to maintain the dose ratios over extended periods [ 7 , 8 , 9 ]. It is thus clear that novel formulation approaches capable of achieving extended-duration pharmacokinetics for molecules of diverse physicochemical properties, at practical injection volumes and with a limited number of injections, are highly desirable.…”