Pharmacokinetic Modeling of Fentanyl Citrate and Norfentanyl in Calves Using a Nonlinear Mixed-Effects Approach
Joe Smith [2,3]*, Claude Magnard [1]*, Yeon-Jung Seo [2,4], Pauline Traynard [1], Jonathan P. Mochel [2]
[1] Simulations Plus, Lixoft division, Antony, France, [2] Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, [3] Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, [4] Department of Statistics, University of Pittsburgh, PA, *: co-lead authors.
Objectives: Fentanyl citrate is a potent opioid agonist commonly used as an analgesic in animal studies, providing several hours of pain relief during surgical and other medical procedures [1]. Plasma fentanyl and norfentanyl pharmacokinetic data were previously analyzed using a noncompartmental approach [2]. This study aimed to characterize the kinetics of fentanyl citrate and norfentanyl using a nonlinear mixed‐effects (NLME) modeling approach. This model will be used to compare competing dosing regimens that achieve therapeutic steady-state concentrations of fentanyl and norfentanyl, while minimizing systemic toxicity in calves.
Methods: Sixteen calves (58.6 +/- 2.2 kg), ranging from 23 to 30 days, were administered fentanyl citrate at a single intravenous dose of either 2.5 µg/kg or 5.0 µg/kg. The parent drug and metabolite plasma concentration-time data were analyzed using a NLME approach in Monolix 2021. Candidate dosing regimens were simulated with Simulx 2021. Standard goodness-of-fit (GOF) diagnostics, including population and individual predictions vs. observations, and the distributions of weighted residuals were used to evaluate the performances of the final model. Model selection was based on statistical significance between competing models using the objective function value and the Bayesian information criteria, together with the evaluation of GOFs. Residual error estimates from the mathematical models were used as supportive information for evaluation of lack of fit.
Results: A four-compartment parent-metabolite model (three compartments for the parent, one for the metabolite) with first‐order elimination best described the pharmacokinetics of fentanyl and its metabolite, norfentanyl, in plasma. Structural identifiability of the model parameters was confirmed using sensitivity analyses, the estimated correlation of the random effects (<0.10 for most parameters) and the accuracy of the final model parameters (RSE<30%). The validity of final model parameter estimates was further confirmed through visual predictive checks using 500 Monte-Carlo simulations. Overall, our simulation framework comparing several scenarios suggests that combining a loading dose of fentanyl with a continuous intravenous infusion would provide the best therapeutic efficacy and safety profile.
Conclusions: This modeling and simulation platform can be used to assess various dosing scenarios for fentanyl administrations in calves. Moving forward, the optimal dosing schedule (amount, route, frequency) will be evaluated in a prospective study aiming to relieve pain during surgery and other medical procedures in calves.
Citations:
[1] Smith JS, Schleining J, Plummer P. Pain Management in Small Ruminants and Camelids: Applications and Strategies. Vet Clin North Am Food Anim Pract. 2021;37(1):17-31. doi:10.1016/j.cvfa.2020.12.005
[2] Smith JS, Coetzee JF, Fisher IWG, Borts DJ, Mochel JP. Pharmacokinetics of fentanyl citrate and norfentanyl in Holstein calves and effect of analytical performances on fentanyl parameter estimation. J Vet Pharmacol Ther. 2018;41(4):555-561. doi:10.1111/jvp.12501
