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Subcutaneous TAF Implants Pass 63-Day Test in
Rabbits for Long-Acting PrEP
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HIV Research for Prevention (HIVR4P), October 21-25, 2018, Madrid
Mark Mascolini
A subcutaneous implant tested in rabbits supplied inhibitory doses of tenofovir alafenamide (TAF) and tenofovir diphosphate (TFV-DP) for 63 days [1]. All implants remained intact and could be retrieved after 63 days.
The goal of this program by RTI International is to develop a biodegradable, removable implant system to release an antiretroviral for 6 months or more as preexposure prophylaxis (PrEP) against HIV. Work so far singled out TAF as the top antiretroviral candidate for this platform and identified attributes favorable to potential female and male users and to healthcare providers. With funding from PEPFAR and the Bill & Melinda Gates Foundation, researchers optimized a subcutaneous delivery device using existing applicator systems.
The implantable device is a cylindrical rod measuring 2.5 x 40 mm. This study aimed to test 3 device designs delivering a low dose of TAF (0.2 mg/day, 1 device), a medium dose (0.4 mg/day, 1 device), or a high dose (0.8 mg/day, 2 devices). Researchers implanted the devices subcutaneously in female New Zealand white rabbits. Each animal got 1 active (drug-delivering) device and 1 placebo device. Researchers used standard methods to determine TAF and tenofovir concentrations on days 1, 7, 14, 21, 35, 49, and 63. They measured TFV-DP in peripheral blood mononuclear cells (PBMCs) on all those days except day 1. In a parallel analysis, the research team measured TAF concentrations released from devices incubated in 40 mL of phosphate-buffered saline.
Daily TAF release rates were similar in rabbits and in vitro, with the release rate depending on implant wall thickness. In vivo rates were 0.15 mg/day with a 200-uM implant wall, 0.42 mg/day with a 100-uM implant wall, and 0.84 mg/day with a 100-uM x 2 implant wall. TFV-DP concentrations were sustained for 63 days. With the highest dose and a 100-uM x 2 implant wall, median TFV-DP concentration in PBMCs stood at 1203 fmol/million cells. Plasma TAF and plasma TFV concentrations were also sustained for 63 days.
At the lowest dose tested, the implant provided TFV-DP levels in PBMCs exceeding the preventive target dose. Median low-dose TFV-DP concentration through 63 days measured 443 fmol/million cells. All 3 doses assessed yielded sustained levels of TAF and TFV in plasma and TDF-DP in PBMCs.
A veterinarian implanted the devices and removed all 30 intact after 63 days. A veterinary histopathologist who evaluated skin and subcutaneous biopsies confirmed minimal tissue reactivity at a level expected for a foreign-body response.
The investigators plan to evaluate this TAF implant for 180+ days in rabbits and to test the implant in dogs before launching phase 1 trials in humans.
Reference
1. Gatto GJ, Brand RM, Girouard N, et al. Development of an end-user informed tenofovir alafenamide (TAF) implant for long-acting (LA)-HIV pre-exposure Prophylaxis (PrEP). HIV Research for Prevention (HIVR4P), October 21-25, 2018, Madrid. Abstract OA20.02LB.
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