Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis

Abstract

Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the compliance burden associated with frequent dosing. We, and others, are exploring the development of complementary subdermal implant technologies delivering the potent prodrug, tenofovir alafenamide (TAF). The current report addresses knowledge gaps in the preclinical pharmacology of long-acting, subdermal TAF delivery using several mouse models. Systemic drug disposition during TAF implant dosing was explained by a multi-compartment pharmacokinetic (PK) model. Imaging mass spectrometry was employed to characterize the spatial distribution of TAF and its principal five metabolites in local tissues surrounding the implant. Humanized mouse studies determined the effective TAF dose for preventing vaginal and rectal HIV-1 acquisition. Our results represent an important step in the development of a safe and effective TAF implant for HIV-1 prevention.

Women for science and science for women: Gaps, challenges and opportunities towards optimizing pre-exposure prophylaxis for HIV-1 prevention

“…The lymphocytopenia was transient and normalized once the islatravir was discontinued, however the risk of depleted lymphocytes predisposes to increased risk for infections. Under early stage clinical evaluation is also an annual TAF implant and an elvitegravir (EVG)/TAF vaginal insert ( 35 , 82 , 83 ). Preclinical proof-of-concept for preventing vaginal transmission of simian human immunodeficiency virus (SHIV) in non-human primates has been demonstrated for this product ( 35 ).…”

In Situ Imaging of Subcutaneous Drug Delivery Systems Using Microspatially Offset Low-Frequency Raman Spectroscopy

“…Long-acting subcutaneous delivery systems as a form of implantable/injectable drug delivery technology have received an increased interest in recent years due to their ability to overcome pertinent challenges particularly for biological drugs, due to lack of oral bioavailability, and drugs requiring an inconveniently high frequency of injection because of their capability to sustain a desired therapeutic dose over an extended period of time. , For example, these attributes have been successfully exploited for drugs for growth disorders, birth control as well as to help with treatment of opioid-dependent patients . Long-acting implants have also been proposed as an effective avenue to enable HIV prophylaxis . However, from an analytical and clinical perspective, it has been difficult to characterize these drug delivery platforms in situ after implantation to enable decisions on when to readminister or to project timeframes for effectiveness in individuals.…”

“…5 Long-acting implants have also been proposed as an effective avenue to enable HIV prophylaxis. 6 However, from an analytical and clinical perspective, it has been difficult to characterize these drug delivery platforms in situ after implantation to enable decisions on when to readminister or to project timeframes for effectiveness in individuals. Typically, for diagnostic purposes, ultrasound imaging has been applied to identify changes in uniformity, placement, and overall structure of the implant.…”

“…However, from an analytical and clinical perspective, it has been difficult to characterize these drug delivery platforms in situ after implantation to enable decisions on when to readminister or to project timeframes for effectiveness in individuals. Typically, for diagnostic purposes, ultrasound imaging has been applied to identify changes in uniformity, placement, and overall structure of the implant. , For a more in-depth in vivo characterization, advanced analytical techniques such as matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) or three-dimensional (3D)-fluorescence imaging have been utilized to determine the drug distribution both in the implant and in the surrounding tissue. However, these approaches can be invasive (especially MALDI-IMS that requires excision) and are limited in their scalability and practical accessibility to healthcare environments.…”

An injectable in situ crosslinkable platform for ultra-long-acting delivery of hydrophilic therapeutics

“…Multiple long-acting implants and injectables are in clinical use for the treatment and prevention of different diseases. 12, 13 Although implantable devices have shown success for the long-term delivery of both hydrophobic 9,14–18 and hydrophilic drugs 9, 16 , they require invasive, time-consuming medical procedures for insertion, which may pose significant challenges, particularly in low resource settings and low-middle income countries. Furthermore, implants in general tend to be more susceptible to local inflammation when compared to injectable alternatives.…”