Pharmacokinetic Modeling

Pharmacokinetic Modeling of Fentanyl Citrate and Norfentanyl Using a Nonlinear Mixed-Effects Approach

Fentanyl NLME EAVPT2018 JMochel

While cattle are commonly subjected to potentially painful production and surgical procedures, practitioners have limited options for pain management, as in the U.S there are currently no drugs labelled for surgical analgesia in this species. With a pharmacological efficacy equivalent to that of morphine but a potency ~ 100 times greater and a rapid onset of action, fentanyl is an ideal clinical analgesic in veterinary medicine. The aim of this study was to characterize the disposition kinetics of fentanyl citrate and its primary metabolite norfentanyl in Holstein calves using a nonlinear mixed-effects (NLME) modeling approach.

Materials and Methods
Eight female calves (58.6 +/- 2.2 kg), aged 3-4 weeks, were administered fentanyl citrate at a single dose of 5.0 µg/kg IV. Blood samples (N=14) were collected at serial timepoints for 24 hours. Plasma (nor)fentanyl concentrations were determined using LC/MS and a LLOQ of 0.03 ng/mL. (Nor)fentanyl concentration time-courses were analyzed simultaneously using the stochastic approximation expectation maximization algorithm implemented in Monolix v4.3.2. 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 and the precision of parameter estimates.

Dosing with fentanyl was well tolerated by all calves. A 3-compartment disposition model with 1-order elimination and biotransformation to norfentanyl best described the disposition of fentanyl in plasma. Structural identifiability of the model parameters was further confirmed using the sensitivity package implemented in R v3.3.2, the estimated low correlation of the random effects (<0.10 for most parameters) and the accurate precision of model parameters (RSE<20%). The systemic CL on fentanyl was estimated to be moderate (typical value: 0.6 L/kg/h) with a population steady-state volume of distribution of 27 L/kg. This is the first report of the pharmacokinetics of (nor)fentanyl in calves using an NLME modeling approach. Fentanyl citrate administered IV at 5.0 µg/kg appears to be safely tolerated in calves and reaches systemic concentrations associated with analgesia in other veterinary species.