Bioabsorbable, subcutaneous naltrexone implants mitigate fentanyl-induced respiratory depression at 3 months-A pilot study in male canines

Abstract

The aim of this study is to determine if extended-release, bioabsorbable, subcutaneous naltrexone (NTX) implants can mitigate respiratory depression after an intravenous injection (IV) of fentanyl. Six different BIOabsorbable Polymeric Implant Naltrexone (BIOPIN) formulations, comprising combinations of Poly-d,l-Lactic Acid (PDLLA) and/or Polycaprolactone (PCL-1 or PCL-2), were used to create subcutaneous implants. Both placebo and naltrexone implants were implanted subcutaneously in male dogs. The active naltrexone implants consisted of two doses, 644 mg and 1288 mg. A challenge with IV fentanyl was performed in 33 male dogs at 97-100 days after implantation. Following the administration of a 30 μg/kg intravenous fentanyl dose, the placebo cohort manifested a swift and profound respiratory depression with a ~50% reduction in their pre-dose respiratory rate (RR). The BIOPIN NTX-implanted dogs were exposed to escalating doses of intravenous fentanyl (30 μg/kg, 60 μg/kg, 90 μg/kg, and 120 μg/kg). In contrast, the dogs implanted with the BIOPIN naltrexone implants tolerated doses up to 60 μg/kg without significant respiratory depression (<50%) but had severe respiratory depression with fentanyl doses of 90 μg/kg and especially at 120 μg/kg. Bioabsorbable, extended-release BIOPIN naltrexone implants are effective in mitigating fentanyl-induced respiratory depression in male canines at about 3 months after implantation. This technology may also have potential for mitigating fentanyl-induced respiratory depression in humans.

Keywords: bioabsorbable; canines; fentanyl; implants; naltrexone; respiratory depression.

FIGURE 1

Photographs of representative BIOPIN Implant. A caliper shows the implant's dimensions in mm.

FIGURE 2

Acute pharmacokinetic evaluation of the six different BIOPIN implants. Plasma concentration of naltrexone (ng/mL) were evaluated from 3 through 336 h post‐implantation for BIOPIN‐1, 2, 3, 4, 5, and 6. Low‐dose (644 mg; open circle) and high‐dose (1288 mg; filled square) BIOPIN implants are displayed.

FIGURE 3

Extended pharmacokinetic evaluation plasma concentrations of naltrexone. BIOPIN implants were evaluated on days 21 through 183. Low‐dose (644 mg; open circle) and high‐dose (1288 mg; filled square) BIOPIN implants are displayed.

FIGURE 4

Complete BIOPIN 6 implant pharmacokinetic kinetics profile. Plasma concentrations of naltrexone released are displayed for the low‐dose (644 mg; open circle) and high‐dose (1288 mg; filled square) BIOPIN‐6 implants from Days 0 through 365. Naltrexone plasma levels were below the level of detection on day 267 for the low‐dose BIOPIN‐6 implant and on day 295 post‐implantation for the high‐dose BIOPIN‐6 implant.

FIGURE 5

Respiration rates following IV fentanyl challenge for animals with placebo group vs. NTX BIOPIN implants. The placebo group received 30 μg/kg dose, while the NTX implant group received four escalating doses: 30, 60, 90, and 120 μg/kg of fentanyl. Data are displayed for first 90 s after the IV fentanyl injection.

FIGURE 6

Respiration rates following IV fentanyl challenge for animals with placebo group versus NTX BIOPIN implants. The placebo group received 30 μg/kg dose, while the NTX implant group received three escalating doses of fentanyl: 30, 60, 90 μg/kg. Data are displayed for the first 90 s after the IV fentanyl injection. Data suggests BIOPIN implants mitigated the respiratory depression seen at 90 s for the 1× and 2× doses, but not the 3× dose. The 0 s represents the pre‐dose time.

FIGURE 7

A schematic timeline illustrating the sequence of experimental steps performed throughout this project.