Characterizing a Monoclonal Antibody for the Reversal and Prevention of Fentanyl-Induced Hypoventilation in Rhesus Monkeys

Abstract ID 90672 Poster Board 101 Nearly 70% of drug overdose deaths in 2022 involved fentanyl or fentanyl analogs. Due to a significant increase in the presence of fentanyls in the opioid and non-opioid drug supply (e.g., stimulants, illicitly manufactured prescription pain pills), both opioid and non-opioid preferring drug users are at increased risk of potentially fatal overdose. The mu-opioid receptor antagonists naloxone and nalmefene are used to reverse overdose. Vivitrol®, a long-acting formulation of the opioid antagonist naltrexone, can prevent overdose; however, nonselectively inhibiting the actions of opioid agonists precludes the use of agonist maintenance therapies and some pain medications. In contrast, highly selective monoclonal antibodies (mAbs) are an alternative for preventing fentanyl-induced overdose. Fentanyl-targeting mAbs are designed to bind and sequester fentanyl in the serum and other organs. Their high degree of selectivity could permit co-administration of other opioid agonist medications. In rats, a promising fentanyl-targeting mAb reversed fentanyl-induced hypoventilation, bradycardia, and antinociception as effectively as naloxone. To extend these findings, the present study characterized the utility of the mAb to reverse and prevent fentanyl-induced hypoventilation in rhesus monkeys. Baseline ventilation was measured over a 30-min habituation period and 45-min test session using head plethysmography. In an initial study, the smallest dose of fentanyl that reliably decreased minute volume (VE) to <70% of the within-session baseline was determined in four monkeys (1 male, 3 females). In subsequent sessions, naloxone, mAb, or vehicle (saline or phosphate-buffered saline) was administered after fentanyl. The mAb was as effective as naloxone in restoring VE to baseline. To examine the magnitude and duration of protection, a cumulative dosing procedure was used to determine a within-session fentanyl dose-effect curve in five monkeys (2 males, 3 females). The dose of fentanyl increased in 0.25 or 0.5 log units up to a dose that decreased VE to <70% of the within-session baseline (maximum, 3 doses/session). Once the dose-effect curve was stable between sessions, the mAb was administered. Post-treatment, larger doses of fentanyl were studied, and the dose sequence was adjusted as sensitivity to fentanyl recovered. The time-course of protection was examined by determining the dose-effect curve 24 hours post-treatment, and then weekly, until the fentanyl ED₇₀ value returned to the pre-treatment baseline. In four monkeys, there was a 3.5 (± 0.64 SD)-fold rightward shift in the fentanyl dose-effect curve 24 hours post-treatment. A 13.6-fold rightward shift was observed in the fifth monkey, who was the most sensitive to fentanyl prior to treatment (ED₇₀ = 0.91 μg/kg). The post-treatment ED₇₀ values slowly decreased over time; taking approximately four weeks to return to baseline in one monkey, and three weeks in the others. These findings support the potential clinical utility of the mAb as a reversal agent and long-acting preventative medication for fentanyl-induced hypoventilation. These studies are supported by USPHS grants U01DA051658 (MP), T32DA031115 (CPF), and the Welch Foundation (AQ-0039 [CPF]).