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Abstract
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AIM: Widespread access to illicit fentanyl has contributed to an ongoing epidemic of fatal drug overdoses in the United States. The incidence of fatal overdoses in the United States accelerated during the COVID-19 pandemic, with over 100,000 deaths recorded by April 2021. Fentanyl-specific monoclonal antibodies (mAb) offer a prophylactic and therapeutic intervention against opioid overdose by binding and sequestering fentanyl in serum, and reducing distribution to the brain. Here, the kinetics of overdose reversal by anti-fentanyl mAb alone or in combination with naloxone were explored, and the dose-response relationship between naloxone and high doses of fentanyl in the presence of mAb was evaluated.
METHODS: To evaluate the kinetics of fentanyl reversal, fentanyl 0.1 mg/kg was administered to male Sprague-Dawley rats, and mAb or naloxone was administered fifteen minutes after exposure. Oxygen saturation was monitored constantly for ten minutes following administration of reversal agent. To evaluate duration and extent of protection from further fentanyl exposures, rats were pre-treated with mAb, naloxone, or a combination, and challenged with increasing doses of fentanyl up to 0.5 mg/kg. Finally, to determine whether the presence of mAb would increase efficacy of naloxone against a lethal dose of fentanyl, 2.25 mg/kg fentanyl was administered, followed by naloxone 0.01 to 1.0 mg/kg.
RESULTS: The most rapid reversal of fentanyl toxicity was achieved by intravenous administration of a combination of anti-fentanyl mAb and naloxone (<1 min). Intravenous naloxone reversed fentanyl toxicity more quickly than subcutaneous naloxone, and intravenous mAb was effective against fentanyl within 4 minutes, similar to subcutaneous NLX. Against further challenges of fentanyl, both mAb and 0.1 mg/kg naloxone were effective against 0.1-0.2 mg/kg fentanyl, and the combination of mAb and naloxone was effective against doses of 0.5 mg/kg fentanyl or higher. Prophylactic administration of mAb enhanced efficacy of naloxone in reversing a potentially lethal challenge of 2.25 mg/kg fentanyl. Finally, mAb sequestered high concentrations of both fentanyl and its metabolite norfentanyl in serum, and reduced brain concentrations of fentanyl in pre-exposure scenarios.
CONCLUSIONS: These results support translation of mAb as medical countermeasures to prevent and reverse opioid overdose related to fentanyl and its analogs.
Language: en |