A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

Abstract

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbits and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a dose of 10 µg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. Inflammation in the primates was markedly lower in the placebo group than the active implant. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve sustained target dose we observed unacceptable inflammatory response locally at the implant tissue interface.

Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant

“…Another notable drug candidate for LA platform is tenofovir alafenamide (TAF), a potent drug widely used as a first-line ART regimen in combination with other antiretrovirals. For HIV-1 pre-exposure prophylaxis (PrEP), TAF is under development as a single-agent LA in several drug delivery systems [ 17 , 18 , 19 , 20 , 21 , 22 ], however, none of these systems have yet been tested for HIV-1 treatment.…”

Design of a Drug-Eluting Subcutaneous Implant of the Antiretroviral Tenofovir Alafenamide Fumarate

“…We note, other sealing conditions in this experiment also gave implant sets that met our phase 1 test selection standard. We subsequently manufactured hundreds of implants composed of the PEU Tecoflex™ EG-85A for subsequent studies using these sealing conditions, with no detected evidence of dose dumping, leaking, or implant failure in vitro or in vivo (27) or during any phase 2 mechanical stress test applied to them.…”

“…With these data in hand, we designed a TAF implant whose pharmacokinetics could be evaluated in an animal model (27). Figure 8 shows the release rates of representative implants and the mole fraction of TAF related species versus time of 0.8 cm lumen length implants.…”

“…We recently reported the pharmacokinetics and local histopathology of implants described in this paper. (27) The published TAF implants have a core with a means of controlling the mass transport of drug from the reservoir. Other designs, e.g., Nexplanon or Mirena, have polymer occupying a significant mass fraction of the core.…”

“…(d) TAF parent (1) is tenofovir alafenamide without the fumarate salt, which undergoes pH-dependent hydrolysis into two main related substances monophenyl PMPA (2) and PMPA monoamidate (3). These are the Generation A implants of the recent Su et al(27).…”