Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles

Abstract

Treatment and prevention of human immunodeficiency virus type one (HIV-1) infection was transformed through widespread use of antiretroviral therapy (ART). However, ART has limitations in requiring life-long daily adherence. Such limitations have led to the creation of long-acting (LA) ART. While nucleoside reverse transcriptase inhibitors (NRTI) remain the ART backbone, to the best of our knowledge, none have been converted into LA agents. To these ends, we transformed tenofovir (TFV) into LA surfactant stabilized aqueous prodrug nanocrystals (referred to as NM1TFV and NM2TFV), enhancing intracellular drug uptake and retention. A single intramuscular injection of NM1TFV, NM2TFV, or a nanoformulated tenofovir alafenamide (NTAF) at 75 mg/kg TFV equivalents to Sprague Dawley rats sustains active TFV-diphosphate (TFV-DP) levels ≥ four times the 90% effective dose for two months. NM1TFV, NM2TFV and NTAF elicit TFV-DP levels of 11,276, 1,651, and 397 fmol/g in rectal tissue, respectively. These results are a significant step towards a LA TFV ProTide.

Prodrug Therapies for Infectious and Neurodegenerative Diseases

“…We and others have made significant advances in extending the apparent half-life of numerous ART as well as improving their safety of administration and ease of manufacturing. Indeed, the innovative prodrug molecular design and improved physicochemical properties have been shown to affect pharmacokinetic and targeting properties of native drugs and have repeatedly been used to treat a spectrum of infectious and/or degenerative disorders [ 139 , 140 , 141 , 142 , 147 , 151 , 156 ]. Thus, continuous research attempts and in-depth knowledge of molecular and cellular mechanisms underlying pathogen-mediated neuronal damage may establish the way to find new preventative and therapeutic strategies that are aimed at reducing the advancement of these devastating pathologies.…”

“…Tenofovir alafenamide (TAF) [146,147] AT-527 (Bemnifosbuvir) [156] Remdesivir [157] Prodrug of abacavir (M3ABC) [136] Prodrug of tenofovir (M1TFV) [140] Prodrug of darunavir (M2DRV) [123] Pradefovir [149,150] Molnupiravir [158] Fosamprenavir [159] 0.5 H2SO4 1 0…”

“…While NRTIs represent some of the most prescribed ART, their inherent physicochemical properties have limited their transformation into sustained release formulations. To overcome such limitations, our laboratory successfully produced ProTide libraries for darunavir [ 123 ], abacavir [ 136 ], emtricitabine [ 137 , 138 ], lamivudine [ 139 ], and tenofovir [ 140 ], all of which exhibit extended drug half-lives and efficient intracellular active metabolite delivery ( Table 2 ). The most notable preclinical advancement was demonstrated for integrase inhibitors where a nanoformulated lipophilic ester prodrug of cabotegravir (NM2CAB) exhibited sustained plasma active drug levels above the protein-adjusted IC 90 for a year in mice and rats ( Figure 2 ) [ 135 , 141 , 142 ].…”

3D Spheroids of Human Primary Urine-Derived Stem Cells in the Assessment of Drug-Induced Mitochondrial Toxicity

“…Each drug with 3 doses was added into a culture medium and incubated, Mito-Tox was evaluated in 3D spheroids, as compared to 2D cultures a three-time points (3 day, 2, and 4 weeks) Three FDA approved anti-HIV drugs were tested compared to two controls, including (1) ddC (0.1, 2, 10 µM) [ 39 , 40 ] known for significantly inducing Mito-Tox, 0.1 µM ddC is a typical single dose maximal plasma concentration (Cmax) [ 40 ]; (2) TFV (3, 30, 300 µM) [ 41 , 42 , 43 ] known for inducing only minimal Mito-Tox, 2.12µM TFV is a typical single dose maximal plasma concentration [ 40 , 41 , 42 , 43 , 44 ] (3) RAL (2, 20, 200 µM) [ 45 , 46 , 47 ] that is controversial in its ability to cause Mito-Tox, 2.25 µM is a typical RAL maximal plasma concentration [ 48 ], (4) rotenone (10 µM) [ 49 ] as a positive control; and (5) 0.1% DMSO as a negative control, see Table 1 .…”

Oral antivirals for the prevention and treatment of SARS-CoV-2 infection

“…Indeed, pre-exposure prophylaxis has shown its benefit in the prevention of viral acquisition in uninfected individuals engaged in high-risk behaviors 54 . Recent advances in chemical pharmacology have led to the emergence of ultra-long-acting (XLA) antiviral formulations that may provide drug exposure for several months or up to 1 year [55][56][57][58][59] . The advent of these medicines might transform the way to confront new COVID-19 surges.…”