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Development and optimization of a fentanyl pharmacokinetic model for target-controlled infusion in anaesthetized dogs

Published:February 01, 2022DOI:https://doi.org/10.1016/j.vaa.2021.08.049

      Abstract

      Objective

      To investigate pharmacokinetics (PK) of fentanyl administered by target-controlled infusion (TCI), and to develop a PK model optimized by covariates for TCI in anaesthetized dogs.

      Study design

      Prospective clinical study.

      Animals

      A group of 20 client-owned dogs with spinal pain undergoing anaesthesia for magnetic resonance imaging.

      Methods

      Fentanyl was administered as an infusion to 20 anaesthetized dogs using a TCI system incorporating a previously described fentanyl two-compartment PK. Arterial blood samples were collected at specific time points during the infusion and over 60 minutes post-infusion for measurement of fentanyl plasma concentrations. The predictive performance of the Sano PK model was assessed by comparing predicted and measured plasma concentrations. A population PK analysis was then performed using a nonlinear mixed-effect modelling approach, allowing inter- and intra-individual variability estimation. Finally, a quantitative stepwise evaluation of the influence of various covariates such as weight, body condition score, size, size-related age, sex and type of premedication on the PK model was considered.

      Results

      Overall predictive performance of the Sano PK set of variables was not clinically acceptable in anaesthetized dogs. Fentanyl PK was best described by a three-compartment model. Weight and sex were found to affect the volume of distribution of the central compartment. Addition of these two covariate/variable associations resulted in a reduction of the objective function value (OFV) from –340.18 to –448.34, and of the median population weighted residual and the median population absolute weighted residual from 16.1% and 38.6% to 3.9% and 20.3%, respectively. Fentanyl infusions at measured concentrations up to 5.4 ng mL–1 in sevoflurane-anaesthetized dogs resulted in stable anaesthesia and smooth recoveries without complications.

      Conclusions and clinical relevance

      A population three-compartment PK model for fentanyl TCI in anaesthetized dogs was developed. Weight and sex have been detected and incorporated as significant covariates.

      Keywords

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      References

        • Ambros B.
        • Alcorn J.
        • Duke-Novakovski T.
        • et al.
        Pharmacokinetics and pharmacodynamics of a constant rate infusion of fentanyl (5 μg/kg/h) in awake cats.
        Am J Vet Res. 2014; 75: 716-721
        • Arndt J.O.
        • Mikat M.
        • Parasher C.
        Fentanyl’s analgesic, respiratory, and cardiovascular actions in relation to dose and plasma concentration in unanesthetized dogs.
        Anesthesiology. 1984; 61: 355-361
        • Beths T.
        • Reid J.
        • Monteiro A.M.
        • et al.
        Evaluation and optimisation of a targetcontrolled infusion system for administering propofol to dogs as part of a total intravenous anaesthetic technique during dental surgery.
        Vet Rec. 2001; 148: 198-203
        • Bista S.R.
        • Lobb M.
        • Haywood A.
        • et al.
        Development, validation and application of an HPLC–MS/MS method for the determination of fentanyl and nor-fentanyl in human plasma and saliva.
        J Chromatogr B. 2014; 960: 27-33
        • Cattai A.
        • Bizzotto R.
        • Cagnardi P.
        • et al.
        A pharmacokinetic model optimized by covariates for propofol target-controlled infusion in dogs.
        Vet Anaesth Analg. 2019; 46: 568-578
        • Cattai A.
        • Pilla T.
        • Cagnardi P.
        • et al.
        Evaluation and optimisation of propofol pharmacokinetic parameters in cats for target-controlled infusion.
        Vet Rec. 2016; 178: 503
        • Chang Y.W.
        • Yao H.T.
        • Chao Y.S.
        • Yeh T.K.
        Rapid and sensitive determination of fentanyl in dog plasma by on-line solid-phase extraction integrated with a hydrophilic column coupled to tandem mass spectrometry.
        J Chromatogr B Anal Technol Biomed LifeSci. 2007; 857: 195-201
        • Eleveld D.J.
        • Colin P.
        • Absalom A.R.
        • Struys M.M.
        Pharmacokinetic-pharmacodynamic model for propofol for broad application in anaesthesia and sedation.
        Br J Anaesth. 2018; 120: 942-959
        • Food and Drug Administration
        Guidance for industry: bioanalytical method validation.
        2001
        • Gutierrez-Blanco E.
        • Victoria-Mora J.M.
        • Ibancovichi-Camarillo J.A.
        • et al.
        Postoperative analgesic effects of either a constant rate infusion of fentanyl, lidocaine, ketamine, dexmedetomidine, or the combination lidocaine-ketamine-dexmedetomidine after ovariohysterectomy in dogs.
        Vet Anaesth Analg. 2015; 42: 309-318
        • Iizuka T.
        • Masui K.
        • Miyabe-Nishiwaki T.
        • et al.
        Propofol-fentanyl interaction in Beagles - Apnea, response to mechanical ventilation, endotracheal tube, and tetanic stimulation.
        Res Vet Sci. 2017; 115: 34-42
        • Ilkiw J.
        Balanced anesthetic techniques in dogs and cats.
        Clin Tech Small Anim Pract. 1999; 14: 27-37
        • Keating S.C.J.
        • Kerr C.L.
        • Valverde A.
        • et al.
        Cardiopulmonary effects of intravenous fentanyl infusion in dogs during isoflurane anesthesia and with concurrent acepromazine or dexmedetomidine administration during anesthetic recovery.
        Am J Vet Res. 2013; 74: 672-682
        • Laflamme D.
        Development and validation of a body condition score system for dogs.
        Canine Pract. 1997; 22: 10-15
        • Lee S.H.
        • Park H.W.
        • Kim M.J.
        • et al.
        External validation of pharmacokinetic and pharmacodynamic models of microemulsion and long-chain triglyceride emulsion propofol in beagle dogs.
        J Vet Pharmacol Ther. 2012; 35: 329-341
        • Levionnois O.L.
        Target-controlled infusion in small animals: improving anaesthetic safety.
        Vet Rec. 2016; 178: 501-502
        • Lindbom L.
        • Pihlgren P.
        • Jonsson E.N.
        PsN-Toolkit--a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM.
        Comput Methods Programs Biomed. 2005; 79: 241-257
        • Machado M.L.
        • Soare J.H.N.
        • Pypendop B.H.
        • et al.
        Effect of heart rate on the pharmacokinetics of fentanyl in dogs anesthetized with isoflurane and hydromorphone.
        Vet Anaesth Analg. 2019; 46: 736-744
        • Maguire P.
        • Tsai N.
        • Kamal J.
        • et al.
        Pharmacological profiles of fentanyl analogs at mu, delta and kappa opiate receptors.
        Eur J Pharmacol. 1992; 213: 219-225
        • Maitre P.O.
        • Vozeh S.
        • Heykants J.
        • et al.
        Population pharmacokinetics of alfentanil: The average dose-plasma concentration relationship and interindividual variability in patients.
        Anesthesiology. 1987; 66: 3-12
        • Peng P.W.H.
        • Sandler A.N.
        A review of the use of fentanyl analgesia in the management of acute pain in adults.
        Anesthesiology. 1999; 90: 576-599
        • Robinson T.M.
        • Kruse-Elliott K.T.
        • Markel M.D.
        • et al.
        A comparison of transdermal fentanyl versus epidural morphine for analgesia in dogs undergoing major orthopedic surgery.
        J Am Anim Hosp Assoc. 1999; 35: 95-100
        • Russell D.
        • Wilkes M.P.
        • Hunter S.C.
        • et al.
        Manual compared with target-controlled infusion of propofol.
        Br J Anaesth. 1995; 75: 562-566
        • Sano T.
        • Nishimura R.
        • Kanazawa H.
        • et al.
        Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs.
        Vet Anaesth Analg. 2006; 33: 266-273
        • Schnider T.W.
        • Minto C.F.
        • Struys M.M.R.F.
        • Absalom A.R.
        The safety of target-controlled infusions.
        Anesth Analg. 2016; 122: 79-85
        • Shafer S.L.
        • Varvel J.R.
        • Aziz N.
        • Scott J.C.
        Pharmacokinetics of fentanyl administered by computer-controlled infusion pump.
        Anesthesiology. 1990; 73: 1091-1102
        • Simon B.T.
        • Steagall P.V.
        The present and future of opioid analgesics in small animal practice.
        J Vet Pharmacol Ther. 2017; 40: 315-326
        • Steagall P.V.M.
        • Teixeira N.F.J.
        • Minto B.W.
        • et al.
        Evaluation of the isoflurane-sparing effects of lidocaine and fentanyl during surgery in dogs.
        J Am Vet Med Assoc. 2006; 229: 522-527
        • Stepien R.L.
        • Bonagura J.D.
        • Bednarski R.M.
        • Muir III, W.W.
        Cardiorespiratory effects of acepromazine maleate and buprenorphine hydrochloride in clinically normal dogs.
        Am J Vet Res. 1995; 56: 78-84
        • Varvel J.R.
        • Donoho D.L.
        • Shafer S.L.
        Measuring the predictive performance of computer-controlled infusion pumps.
        J Pharmacokinet Biopharm. 1992; 20: 63-94
        • Williamson A.J.
        • Soares J.H.N.
        • Henao-Guerrero N.
        • et al.
        Cardiovascular and respiratory effects of two doses of fentanyl in the presence or absence of bradycardia in isoflurane-anesthetized dogs.
        Vet Anaesth Analg. 2018; 45: 423-431