Preclinical Assessment of Naloxone Adequacy to Reverse Polysubstance Use-Induced Respiratory Depression — In Vivo Validation

Title: Preclinical Assessment of Naloxone Adequacy to Reverse Polysubstance Use-Induced Respiratory Depression — In Vivo Validation Agency: U.S. Food and Drug Administration (FDA) Notice Type: Presolicitation: Firm-Fixed Price DEA surveillance data show that street fentanyl is frequently adulterated with xylazine, d-methamphetamine, or alprazolam — each of which induces respiratory depression through a distinct mechanism. Approximately 80% of opioid overdose cases involve multiple drugs, yet naloxone — the primary FDA-approved reversal agent — was developed and tested for opioid-only scenarios. This mechanistic complexity creates uncertainty about naloxone's efficacy in polysubstance overdose and raises the question of what alternative or adjunct therapies may be needed. Drug-induced respiratory changes are closely linked to cardiovascular (CV) changes. When a drug disrupts respiration, the heart alters its function to compensate for failing oxygen delivery; however, the same drugs may also impair CV function, reducing that compensatory drive. Simultaneous measurement of both systems is therefore essential. The U.S. Food and Drug Administration (FDA) intends to solicit a period of performance of (12) months from the date of award. Study initiation is anticipated within two (2) months of award, subject to research animal availability., sole source (in accordance with FAR 6.103-1), firm-fixed-price purchase order from Charles River Laboratories (CRL) 54943 N Main St, Mattawan, MI 49071. The North American Industry Classification System (NAICS) code is 541714 - Research and Development in Biotechnology (except Nanobiotechnology), anticipated period of performance consists of a 1-year base purchase order. This notice is not a request for competitive proposals. Objectives: This purchase order directs contractor to conduct a 4-phase in vivo study in male rats to accomplish the following: Simultaneously measure drug-induced changes in respiratory and cardiovascular parameters. Evaluate the ability of naloxone and alternative reversal agents to restore respiratory and CV function following polysubstance-induced full respiratory depression. Collect blood samples at five (5) prespecified time points per animal for pharmacokinetic (PK) analysis to be conducted at the FDA. Scope: Contractor shall conduct four (4) sequential study phases in male CD rats. Each phase uses a parallel group design with n=4 animals per treatment group. All drug combinations shall be administered via intravenous (IV) bolus injection. Animals shall be on day 1 and day 8. Respiratory and CV measurements shall be collected simultaneously. Blood samples shall be collected at five (5) prespecified time points on day 8 and shipped to the FDA for bioanalysis. Animal Instrumentation (All Phases) Tasks: All animals shall be surgically instrumented with the following: Vascular access buttons for IV bolus drug administration. Telemetry implants for continuous cardiovascular data collection. Respiratory Monitoring (All Phases) Respiratory data shall be collected using whole body plethysmography (WBP) chambers. Animals shall be acclimated to the WBP apparatus prior to dosing. Data collection shall begin at least 1 hour prior to dosing and continue for up to 5 hours post-dose. The following respiratory parameters shall be measured: Respiratory frequency Tidal volume Minute volume Peak inspiratory flow Peak expiratory flow Inspiratory time Expiratory time Cardiovascular Monitoring (All Phases) Cardiovascular data shall be collected via continuous implanted telemetry. Animals shall be conscious and unrestrained. Data shall be collected from at least 1 hour prior to each dose through approximately 24 hours following each dose (25-hour total duration per dosing occasion). The following CV parameters shall be quantitatively evaluated: Heart rate Systolic blood pressure Diastolic blood pressure Mean arterial blood pressure Body temperature Statistical analysis shall use ANOVA. Bioanalysis — Blood Sample Collection (All Phases) Whole blood shall be collected at five (5) prespecified time points on day 8 per animal. Plasma shall be prepared and aliquoted into two (2) aliquots per sample, both shipped to the FDA-specified destination for bioanalysis. Fasting is not required prior to sample collection. An AAALAC-accredited animal facility with applicable Animal Welfare Assurance and IACUC approval. The study will be conducted under non-GLP conditions.

• NAICS541714
• PSCAN12

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• Kimberly Pennix
  kimberly.pennix@fda.hhs.gov2404029703
• Ian Weiss
  ian.weiss@fda.hhs.gov3017965728