A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and Dogs

Abstract

Human immunodeficiency virus (HIV) infection continues to be a serious global human health issue, with ∼38 million people living with HIV worldwide at the end of 2019. HIV preexposure prophylaxis (PrEP) has introduced the use of antiretroviral therapies as another helpful tool for slowing the spread of HIV worldwide.

Advanced strategies to thwart foreign body response to implantable devices

“…Drug‐device combination can also exacerbate the immune response. For instance, a 28 day sustained infusion of tenofovir alafenamide (TAF) hemifumarate through a subcutaneous catheter connected to a pump, caused an intense immune response in rats and dogs 186 . Severe necrosis and infiltration of proinflammatory cells, limited the prolonged drug delivery at therapeutic dosage due to safety concerns.…”

“…For instance, a 28 day sustained infusion of tenofovir alafenamide (TAF) hemifumarate through a subcutaneous catheter connected to a pump, caused an intense immune response in rats and dogs. 186 Severe necrosis and infiltration of proinflammatory cells, limited the prolonged drug delivery at therapeutic dosage due to safety concerns. Similarly, Su et al evaluated the effect of prolonged subcutaneous delivery of TAF through a semipermeable PU reservoir that controls the drug diffusion rate in rabbits and NHP.…”

An ultralong-acting tenofovir ProTide nanoformulation achieves monthslong HBV suppression

“…However, poor regimen adherence and the desire to meet patient treatment needs have led to an emerging interest in long-acting injectable/implantable drug forms (26). Devices for sustained delivery of TAF were developed and tested in rodents, dogs, and nonhuman primates for Simian-Human Immunodeficiency virus (SHIV) prevention (8,(27)(28)(29). A phase 1/2 clinical trial protocol to assess the safety, acceptability, tolerability, and pharmacokinetics (PK) of a sustained release TAF subdermal implant for HIV prevention in women was generated (CAPRISA 018), and the study is under way (30).…”

“…However, there is no published report on ULA TFV injectables or implants for the treatment of CHB. While TAF-containing implants could provide a sustained target dose for HIV-1 prevention, adverse inflammatory responses at the implant tissue interface were recorded in dogs and nonhuman primates ( 29 , 31 ). This is likely due to extracellular, ionizable breakdown products from an unstable TAF prodrug at the injection site depot or counterions used to produce TAF salts.…”

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

“…A Northwestern University-based consortium developed a non-biodegradable reservoir-based polyurethane (PU) implant containing compressed TAF [ 89 ] and tested it in rabbit and rhesus macaque models, but findings also showed TAF-related local inflammation and severe necrosis around the implant even at the lowest TAF dose of ~10 μg/kg/day [ 90 ]. Intarcia Therapeutics explored its proprietary osmotic pump system to develop non-biodegradable TAF implants [ 91 ], however histopathology of tissue surrounding the SC infusion sites in rats and dogs receiving ≥300 and ≥25 μg/kg/day of TAF, respectively, for 28 days revealed signs of inflammation, edema, mass formation, and fibrosis that was more severe in animals that received TAF compared to vehicle control [ 92 ].…”