PII-092 - THE EFFECT OF POLYDRUG USE AND FENTANYL VACCINE ON THE PHARMACOKINETICS OF FENTANYL

D. Song¹, J. Barry², J. Vigliaturo¹, A. Gebo¹, D. Burroughs³, M. Pravetoni⁴, A. Birnbaum²; ¹Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA, ²Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA, ³Advanced Preclinical Imaging Center, Lillehei Heart Institute, Minneapolis, MN, USA, ⁴Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.

Background: Individuals with opioid use disorder often administer polydrug street mixtures containing highly potent fentanyl with other opioids (e.g., oxycodone and heroin), resulting in poor survival outcomes. Despite the prevalence of polydrug use, pharmacokinetic (PK) analyses of fentanyl in such scenarios are lacking, limiting our understanding of the synergistic effects seen when fentanyl is part of these mixtures. In response, our group developed a quadrivalent opioid vaccine targeting fentanyl, carfentanil, oxycodone, and heroin to counter polydrug mixtures in preclinical models. Among these, the oxycodone vaccine is currently in a clinical trial (NCT04458545), while the fentanyl vaccine is being prepared for an upcoming clinical trial.

Methods: This study tested the effects of polydrug use and vaccination on fentanyl PK. Sprague Dawley rats (n=5-6 per group) were surgically implanted with jugular vein catheters and immunized with either saline (control group) or a fentanyl vaccine (monovalent fentanyl vaccine or a quadrivalent vaccine targeting fentanyl, carfentanil, oxycodone, and heroin). Each rat was administered fentanyl alone in week 1, followed by a polydrug mixture containing fentanyl, carfentanil, oxycodone, and heroin in week 2. Blood samples were collected over 8 hours post-drug administration and drug concentrations were measured for fentanyl. PK parameters such as clearance (CL) and volume of distribution (V) were estimated using population PK modeling in Phoenix NLME (Certara, Princeton, NJ).

Results: A two-compartment, extravascular PK model with a combined error model for residual variability was selected as the best fit for fentanyl PK. Covariate selection via forward-selection and backward-elimination [based on changes in the objective function value (-2log likelihood, p< 0.01)] identified polydrug use and vaccination as significant covariates impacting CL. While the mean fentanyl CL was 1115 mL/hr, polydrug use reduced it to 425.8 mL/hr, and vaccination further decreased it to 51 mL/hr.

Conclusion: The lower CL of fentanyl in a polydrug mixture suggests that its potency may be synergistically enhanced due to increased total exposure in the system. The findings regarding drug PK response to vaccination also offer valuable insights for ongoing and future clinical trials involving fentanyl and oxycodone vaccines.