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Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane
Veterinary Anaesthesia and Analgesia xxxx, xxx, xxx
RESEARCH PAPER
Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane Bruno H Pypendopa, Hanna Ahokoivua & Juhana Honkavaarab a
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA,
USA b
Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA, USA
Correspondence: Bruno Pypendop, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, One Shields Avenue, Davis, CA, 95616, USA. E-mail: [email protected]
Abstract Objective To characterize the pharmacokinetics of vatinoxan in isoflurane-anesthetized cats. Study design Prospective experimental study.
cardiovascular effects of dexmedetomidine (25 mg kge1) in conscious cats. Keywords a2-antagonist, cats, isoflurane, pharmacokinetics.
Animals A group of six adult healthy male neutered cats. Methods Cats were anesthetized using isoflurane in oxygen. Venous catheters were placed to administer the drug and sample blood. Vatinoxan, 1 mg kge1, was administered intravenously over 5 minutes. Blood was sampled before and at various times during and up to 8 hours after vatinoxan administration. Plasma vatinoxan concentration was measured using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the timeeconcentration data using population methods and nonlinear mixed effect modeling. Results A three-compartment model best fitted the data. Typical value (% interindividual variability) for the three volumes (mL kge1), the metabolic clearance and two distribution clearances (mL minutee1 kge1) were 34 (55), 151 (35), 306 (18), 2.3 (34), 42.6 (25) and 5.6 (0), respectively. Hypotension increased the second distribution clearance to 10.6. Conclusion and clinical relevance The pharmacokinetics of vatinoxan in anesthetized cats were characterized by a small volume of distribution and a low clearance. An intravenous bolus of 100 mg kge1 of vatinoxan followed by constant rate infusions of 55 mg kge1 minutee1 for 20 minutes, then 22 mg kge1 minutee1 for 60 minutes and finally 10 mg kge1 minutee1 for the remainder of the infusion time is expected to maintain the plasma concentration within 90%e110% of the plasma vatinoxan concentration previously shown to attenuate the
Introduction Vatinoxan (formerly known as MK-467 and L-659,066) is an a2-adrenoceptor antagonist believed to poorly cross the mammalian bloodebrain barrier (Clineschmidt et al. 1988). When combined with an a2-adrenoceptor agonist, it will attenuate the agonist-induced cardiovascular effects while preserving the sedative effect in several species, including cats (Honkavaara et al. 2011, 2017; Vainionpaa et al. 2013; Kaartinen et al. 2014; de Vries et al. 2016; Pypendop et al. 2017a; Restitutti et al. 2017). The pharmacokinetics of vatinoxan in conscious cats has been previously reported (Pypendop et al. 2016, 2017b). Inhaled anesthetics will influence the disposition of drugs administered concurrently (Thomasy et al. 2005; Pypendop et al. 2008). The use of vatinoxan in anesthetized cats may be of interest as the a2-adrenoceptor agonist, dexmedetomidine, has been reported to decrease anesthetic requirements but worsen cardiovascular performance because of its own effects on hemodynamics (Pypendop et al. 2011; Escobar et al. 2012). Therefore, it is possible that combining dexmedetomidine with vatinoxan would result in improved cardiovascular performance in cats anesthetized with an inhaled anesthetic. Characterization of the pharmacokinetics of vatinoxan in cats during anesthesia is necessary to the rational dosing of the drug, particularly if a desired plasma drug concentration is known. The aim of this study was to characterize the pharmacokinetics of vatinoxan in cats anesthetized with isoflurane.
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Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
Pharmacokinetics vatinoxaneisoflurane cats BH Pypendop et al.
Materials and methods Animals A group of six male neutered cats, aged 1 year, weighing 5.5 ± 0.5 kg (mean ± standard deviation) and deemed healthy based on history and physical examination, were used. Husbandry conditions have been previously reported for this facility (Honkavaara et al. 2017). The study was approved by the University of California, Davis, USA Institutional Animal Care and Use Committee (no. 19114). Instrumentation Cats were anesthetized with isoflurane in oxygen, delivered in an acrylic chamber. After the cat had lost its righting reflex, it was removed from the chamber and the trachea was intubated with a cuffed endotracheal tube. Anesthesia was maintained with isoflurane in oxygen delivered via a Bain circuit, with a fresh gas flow of 1.5e2.0 L minutee1. A 20 gauge, 5 cm catheter (Insyte; Becton Dickinson, CA, USA) was inserted in a medial saphenous vein for drug administration and administration of lactated Ringer’s solution (Baxter Healthcare Corp., IL, USA) at 3 mL kge1 houre1. A 19 gauge, 15 cm catheter (Central Venous Catheter; MILA International Inc., KY, USA) was inserted in a jugular vein for blood sampling. Intermittent positive pressure ventilation was provided to maintain endtidal partial pressure of carbon dioxide (PE0 CO2) at 35e40 mmHg (4.7e5.3 kPa). A Doppler flow detector (Model 811; Parks Medical Electronics Inc., OR, USA) probe was placed over the palmar aspect of the metacarpus, and an occluding cuff was placed dorsal to the ipsilateral carpus for the measurement of systolic arterial pressure (SAP). A pulse oximeter probe was placed over the tongue and connected to a monitor (S/5 Compact; GE Healthcare, WI, USA) for the measurement of hemoglobin oxygen saturation (SpO2) and pulse rate (PR). A thermistor, calibrated daily against a certified thermometer, was positioned in the thoracic esophagus and connected to a data acquisition system (Ponemah; DSI, MN, USA) for the measurement of body temperature. Esophageal temperature was maintained at 38.5e39.5 C by providing external heat (HotDog Patient Warming System; Augustine Temperature Management LLC, MN, USA) as needed. A catheter placed into the lumen of the endotracheal tube so that its tip was close to the distal (tracheal) end of the tube was connected to an infrared spectrometer (S/5 Compact; GE Healthcare) for the continuous measurement of PE0 CO2 and end-tidal isoflurane concentration (FE0 Iso). Variables were recorded every 15 minutes. In addition, at the time of recording, approximately 5 mL of gas was sampled by hand from the endotracheal catheter into a glass syringe. Isoflurane concentration in these samples was measured using a second infrared spectrometer (LB2; Beckman Instruments, CA, USA) calibrated daily using four 2
secondary standards of known isoflurane concentrations (0.51%, 2.04%, 2.38% and 3.33%), and considered the actual isoflurane concentration. Drug administration and blood sampling Following instrumentation, the FE0 Iso was set at the cat’s minimum alveolar concentration (MAC) previously determined in duplicate using the bracketing technique and tail clamping. After a minimum of 15 minutes at a constant FE0 Iso, vatinoxan (1 mg kge1) was administered intravenously (IV) via the medial saphenous catheter over 5 minutes (i.e. 0.2 mg kge1 minutee1) using a syringe pump (PHD2000; Harvard Apparatus, MA, USA). Vatinoxan powder was dissolved in sterile isotonic saline to a concentration of 1 mg mLe1 and filtered through a sterile 0.22 mm filter (Fisherbrand Syringe Filter; Fisher Scientific, MA, USA). Blood samples (2 mL) were collected from the jugular catheter prior to vatinoxan administration and 2, 5, 6, 7, 9, 13, 20, 35, 65, 125, 245 and 485 minutes after the beginning of the vatinoxan IV infusion. Samples were transferred into tubes containing ethylenediaminetetracetic acid (Vacuette; Greiner Bio-One, NC, USA), placed on ice and centrifuged at 4 C within 15 minutes of collection. The plasma was separated, transferred to cryotubes and frozen at e80 C until analysis for vatinoxan concentrations. After the last sample had been collected, catheters and monitoring instruments were removed, meloxicam (0.1 mg kge1; Loxicom; Norbrook Inc. USA, KS, USA) was administered subcutaneously, and the cat was allowed to recover from anesthesia. Plasma vatinoxan concentration analysis Vatinoxan concentration was measured in protein-precipitated plasma samples using liquid chromatography/tandem mass spectrometry according to methods previously described (Honkavaara et al. 2012). Calibrator and quality control stock solutions of vatinoxan were prepared in water and acetonitrile (ACN) at 1 mg mLe1. Calibration curves and negative control samples were prepared fresh for each quantitative assay. Quality control samples (feline plasma with added analyte at three concentrations within the standard curve) were included with each sample set as an additional check of accuracy. All plasma samples were diluted with 100 mL of internal standard 2-(1-hydroxyethyl) promazine sulfoxide (HEPS; Frontier BioPharm, KY, USA) HEPS at 100 ng mLe1 in water prior to sample analysis. The injection volume was 30 mL. The concentration of vatinoxan was measured in plasma by liquid chromatography/tandem mass spectrometry with positive heated electrospray ionization [HESI(þ)]. Quantitative analysis of plasma vatinoxan was conducted on a TSQ Vantage triple quadrupole mass spectrometer (Thermo Scientific, CA, USA) combined with a turbulent flow chromatography system (TFC
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., xxx, xxx
Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
Pharmacokinetics vatinoxaneisoflurane cats BH Pypendop et al.
TLX2; Thermo Scientific) with LC-10ADvp liquid chromatography systems (Shimadzu, Japan) and operated in laminar flow mode. Product masses and collision energies of each analyte were optimized by infusing the analytes into the mass spectrometer. The chromatography column was an ACE 3 C18 10 cm 2.1 mm 3 mm (MAC-MOD Analytical Inc., PA, USA), and a linear gradient of ACN in water with a constant 0.2% formic acid at a flow rate of 0.35 mL minutee1 was used. The initial ACN concentration was held at 10% for 0.50 minutes, ramped to 90% over 5 minutes and held at that concentration for 0.33 minute, before re-equilibrating for 4.17 minutes at initial conditions. Detection and quantification were performed using selective reaction monitoring of initial precursor ion for vatinoxan (m ze1 419.18) and the internal standard (HEPS; m ze1 345.15). The response for the product ions for vatinoxan (m ze1 199.9, 237.9, 281.0) and internal standard (m ze1 58.1, 86.0, 242.9) were graphed and peaks integrated at the proper retention time using Quanbrowser software (Thermo Scientific). Calibration curves were generated, and vatinoxan concentration quantitated in all samples using the Quanbrowser software. A weighting factor of 1/X was applied to all calibration curves. The response for vatinoxan was linear between 0.1 and 500 ng mLe1, and between 500 and 5000 ng mLe1 (two calibration curves were generated and vatinoxan concentration in the samples was quantified according to the corresponding curve) and gave a coefficient of determination of 0.99. Samples with a vatinoxan concentration above 5000 ng mLe1 were reanalyzed after dilution, and the measured concentration was corrected accordingly. The limit of quantitation was 0.1 ng mLe1, and the limit of detection was 0.02 ng mLe1. Accuracy (% nominal concentration) and imprecision (coefficient of variation) were verified at 0.3, 300 and 4000 ng mLe1 and ranged from 88% to 111% and 6% to 11%, respectively. Pharmacokinetic analysis Two- and three-compartment models with zero-order input in, and first-order elimination from the central compartment were fitted to the timeeconcentration data using nonlinear mixed effect modeling in Phoenix NLME 8.1 (Certara, NJ, USA). The models were fitted to the data from all cats simultaneously using population methods and the first-order conditional estimation-extended least squares algorithm. Different error and covariance structure were tested. The parameters estimated by the model were volumes and clearances. Additional parameters were calculated from these estimates. The best fitting model was selected based on precision of the parameters, observation of residuals plots, the e2 log likelihood (e2LL), and Akaike’s information criterion. In addition, SAP and hypotension (defined as SAP < 80 mmHg) were tested as possible continuous and categorical covariate, respectively. The decision to add either covariate to one or more of the structural
parameters was based on a stepwise covariate search with the threshold for forward addition set at 0.05 (i.e. an improvement in e2LL by a minimum of 3.84) and that for backward deletion set at 0.01 (i.e. a worsening in e2LL by a minimum of 6.64). Typical values (tv) of the parameters and random effects (h) to account for interindividual variability were estimated. The parameter (P) in the ith individual was calculated as Pi ¼ tvPi ehi and a different h was estimated for each P. When hypotension was added as a categorical covariate, the calculation was adjusted to Pi ¼ tvPi ð1 þdPidHypoÞ ehi with dPidHypo an additional parameter estimated by the model, and applied when hypotension was observed. The random effects (h) were assumed to have a normal distribution with a mean of 0 and a variance of u2. The interindividual variability p is ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi calculated as a coefficient of variation (%) acffi 2 cording to eu 1 100 (Mould & Upton 2013). Pharmacokinetic simulation using the best model and Phoenix NLME 8.1 was used to design a dosing regimen to rapidly achieve and maintain plasma vatinoxan concentration within 10% of a desired concentration. The desired plasma vatinoxan concentration was considered to correspond to 4169 ng mLe1, the peak plasma concentration observed after bolus IV administration of 600 mg kge1, the dose previously reported to optimally attenuate the bradycardia induced by 25 mg kge1 of dexmedetomidine in conscious cats (Pypendop et al. 2016). Pharmacokinetic parameters are presented as typical value (% interindividual variability). Other data are presented as mean ± standard deviation. Results The previously measured MAC of isoflurane was 2.09 ± 0.20%. A three-compartment model best fitted the plasma vatinoxan concentrationetime data (Fig. 1). A multiplicative error and diagonal covariance structures resulted in the best fit. Hypotension as a categorical covariate applied to the second distribution clearance improved the model. Pharmacokinetic parameters are presented in Table 1. PR, SAP, SpO2, esophageal temperature and PE0 CO2 (data pooled for all cats at all time points) were 156 ± 30 beats minutee1, 91 ± 20 mmHg, 96 ± 1%, 39.2 ± 0.2 C and 31 ± 3 mmHg (4.1 ± 0.4 kPa). SAP was 80 mmHg in 80 out of 194 (41%) measurements. Cats maintained spontaneous ventilation in addition to the intermittent positive pressure ventilation provided. FE0 Iso (data pooled for all cats at all time points) corresponded to 1.02 ± 0.05 times the MAC previously determined in each cat. Based on the typical values of the pharmacokinetic parameters, an IV bolus of 100 mg kge1 of vatinoxan followed by constant rate infusions (CRIs) of 55 mg kge1 minutee1 for 20 minutes, then 22 mg kge1 minutee1 for 60 minutes and finally 10 mg kge1 minutee1 for the remainder of the infusion time (regardless of the total duration of infusion) would be expected
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., xxx, xxx
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Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
Pharmacokinetics vatinoxaneisoflurane cats BH Pypendop et al.
Figure 1 Observed (circles) and predicted (line) plasma vatinoxan concentrations in six cats anesthetized with isoflurane, during and after a 5 minute intravenous infusion of vatinoxan (1 mg kge1; 0.2 mg kg minutee1) started at time 0. Predicted concentrations were obtained by fitting a three-compartment model to the time-plasma vatinoxan concentration data using population methods. The typical values of the parameters are adjusted using random effects to account for the interindividual variability. The dashed line represents the predicted concentrations obtained from the typical values of the parameters (i.e. the population model).
Table 1 Typical value (% interindividual variability) for the pharmacokinetic parameters for vatinoxan in cats (n ¼ 6) anesthetized with isoflurane Parameter
Value
V1 (mL kge1) V2 (mL kge1) V3 (mL kge1) CL (mL minutee1 kge1) CL2 (mL minutee1 kge1) CL3 (mL minutee1 kge1) dCL3dHypo* Vss (mL kge1)y T½ a (minutes)y T½ b (minutes)y T½ g (minutes)y
34 (55) 151 (35) 306 (18) 2.3 (34) 42.6 (25) 5.6 (0) 0.9 491 0.4 14 174
V1, volume of the central compartment; V2, volume of the first peripheral compartment; V3, volume of the second peripheral compartment; CL, metabolic clearance; CL2, first distribution clearance; CL3, second distribution clearance; dCL3dHypo, correction factor (covariate) for CL3 when hypotension (systolic arterial pressure < 80 mmHg) is present; Vss, volume of distribution at steady-state; T½ a, half-life of the fast distribution phase; T½ b, half-life of the slow distribution phase; T½ g, elimination half-life. *No interindividual variability calculated for covariates. yNo interindividual variability estimated because the parameter was calculated from typical values of other parameters.
to achieve 90% of the desired plasma vatinoxan concentration within 14 minutes of starting the administration, and to maintain the plasma concentration within 90e110% of the desired concentration thereafter (Fig. 2). 4
Discussion In this study, the pharmacokinetics of vatinoxan in isofluraneanesthetized cats was characterized by a small volume of distribution and low metabolic clearance. This is in agreement with previous studies in conscious cats (Pypendop et al. 2016, 2017b). In the previous studies, a two-compartment model best fitted the data, whereas a three-compartment model best fitted the data in the current study. This may result from differences in study design (e.g. bolus administration in the previous studies versus short infusion in the current study; differences in doses, modeling of each individual dataset separately versus population approach), or to an effect of isoflurane anesthesia. The volume of distribution at steady state appeared similar in conscious and isoflurane-anesthetized cats, whereas the clearance was lower in the anesthetized cats. Previous studies have shown that dexmedetomidine did not markedly affect the disposition of vatinoxan in conscious cats, likely because the latter prevents the agonist-induced decrease in cardiac output (Pypendop et al. 2016, 2017a). Nevertheless, the possible impact of dexmedetomidine on vatinoxan clearance in isoflurane-anesthetized cats would need to be investigated separately. In contrast, the decrease in cardiac output produced by isoflurane would be less likely to be attenuated by vatinoxan, resulting in decreased liver blood flow and clearance (Steffey & Howland 1977). This lower clearance in anesthetized cats compared with conscious cats results in longer terminal half-life of close to 3 hours.
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., xxx, xxx
Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
Pharmacokinetics vatinoxaneisoflurane cats BH Pypendop et al.
Figure 2 Plasma vatinoxan concentration following a simulated intravenous bolus of 100 mg kge1 of vatinoxan followed by constant rate infusions of 55 mg kge1 minutee1 for 20 minutes, then 22 mg kge1 minutee1 for 60 minutes and finally 10 mg kge1 minutee1 for the remainder of the infusion time. This simulation used the typical value of the pharmacokinetic parameters and a desired concentration of 4169 ng mLe1 (dashed line). The continuous horizontal lines show 90% and 110% of the desired concentration.
In this study, the use of a short infusion was selected in part to avoid the physiologically incorrect assumption of instantaneous drug mixing within the central compartment following bolus IV administration (Avram & Krejcie 2003; Henthorn et al. 2008). This may have contributed to the small estimate of the volume of the central compartment. In addition, isoflurane anesthesia may also have limited the initial distribution of the drug to highly perfused organs through the aforementioned cardiovascular effects. Nevertheless, the estimate of the volume of the central compartment is very small and variable among individuals. The estimate of the volume of distribution at steady state is small, probably a result of the low lipid solubility (log P of 1.3) (Clineschmidt et al. 1988). The relatively long terminal half-life is expected to result in difficulties in maintaining stable plasma drug concentrations if using a single CRI, with or without a loading dose. Indeed, steady state would be approached after approximately 9 hours with a CRI. The pharmacokinetic simulation shows that this time can be considerably shortened with the use of a loading dose and a ‘three-step’ infusion consisting of two higher infusion rates for a predetermined duration prior to the ‘maintenance’ CRI. It should be noted that the desired concentration was chosen as the peak plasma vatinoxan concentration following IV bolus administration of 600 mg kge1 in conscious cats. However, assuming doseindependent pharmacokinetics, different concentrations could be achieved by proportionally changing the loading dose and infusion rates, without adjusting the predetermined duration (e.g. if the desired concentration is half that used in
the simulation, the corresponding dosing regimen would consist of half the IV bolus dose and half the administration rate at each step, with the duration of each step remaining the same. Although the goal of this study was not to assess the cardiovascular effects of vatinoxan in isoflurane-anesthetized cats, hypotension was frequently observed, suggesting that vatinoxan may promote hypotension in anesthetized cats. Hypotension was also observed with much lower doses of vatinoxan in isoflurane-anesthetized cats concurrently administered dexmedetomidine (Martin-Flores et al. 2018). Concurrent administration of dexmedetomidine may partially counteract vatinoxan-induced hypotension by causing vasoconstriction. Moreover, in a recent study, severe hypotension was observed during vatinoxan administration in cats anesthetized with 1.25 MAC isoflurane, with or without dexmedetomidine, except at the highest plasma dexmedetomidine concentration studied (Jaeger et al. 2019). Together, these results suggest that caution may be needed when administering vatinoxan in anesthetized cats. The results of this study should be interpreted in view of several limitations. The study sample was small and included healthy young adult neutered male cats. This homogeneity is not representative of the larger cat population and the pharmacokinetic parameters should be interpreted in this context. Venous sampling was used for logistical reasons, although arterial drug concentrations may be more useful for the prediction of drug effects (Jacobs & Nath 1995). The isoflurane concentration maintained during the study was lower than would be necessary for surgery. In addition, the use of isoflurane alone is not representative of clinical practice. Hypotension was observed in some cats and left untreated; the model predicts that the influence of hypotension on the disposition of vatinoxan is minimal. Finally, it is unlikely that the administration of vatinoxan alone would be desirable in clinical patients. As previously mentioned, it is possible that combining vatinoxan with an a2-agonist would influence the pharmacokinetics of vatinoxan, and the results of this study should be confirmed with concurrent a2-agonist administration. However, in previous studies in conscious dogs and cats, dexmedetomidine did not affect the disposition of vatinoxan (Honkavaara et al. 2012; Pypendop et al. 2016). Conclusion The pharmacokinetics of vatinoxan in isoflurane-anesthetized cats was characterized by a small volume of distribution and low clearance. Acknowledgements This study was funded by the Winn Feline Foundation, the Miller Trust, San Francisco Foundation, and the Center for
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., xxx, xxx
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Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
Pharmacokinetics vatinoxaneisoflurane cats BH Pypendop et al.
Companion Animal Health, School of Veterinary Medicine, University of California. Vatinoxan was provided free of charge by Vetcare Ltd. Authors' contributions BHP: study design, conducted experiments, data analysis, manuscript preparation. HA: conducted experiments, manuscript review. JH: study design, manuscript review. Conflict of interest statement Vetcare Ltd provided vatinoxan for free. Dr Honkavaara has received funding from Vetcare Ltd. References Avram MJ, Krejcie TC (2003) Using front-end kinetics to optimize target-controlled drug infusions. Anesthesiology 99, 1078e1086. Clineschmidt BV, Pettibone DJ, Lotti VJ et al. (1988) A peripherally acting alpha-2 adrenoceptor antagonist: L-659,066. J Pharmacol Exp Ther 245, 32e40. de Vries A, Pakkanen SA, Raekallio MR et al. (2016) Clinical effects and pharmacokinetic variables of romifidine and the peripheral a2-adrenoceptor antagonist MK-467 in horses. Vet Anaesth Analg 43, 599e610. Escobar A, Pypendop BH, Siao KT et al. (2012) Effect of dexmedetomidine on the minimum alveolar concentration of isoflurane in cats. J Vet Pharmacol Ther 35, 163e168. Henthorn TK, Krejcie TC, Avram MJ (2008) Early drug distribution: a generally neglected aspect of pharmacokinetics of particular relevance to intravenously administered anesthetic agents. Clin Pharmacol Ther 84, 18e22. Honkavaara J, Pypendop B, Turunen H, Ilkiw J (2017) The effect of MK467, a peripheral a2-adrenoceptor antagonist, on dexmedetomidineinduced sedation and bradycardia after intravenous administration in conscious cats. Vet Anaesth Analg 44, 42e51. Honkavaara JM, Restitutti F, Raekallio MR et al. (2011) The effects of increasing doses of MK-467, a peripheral alpha2-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs. J Vet Pharmacol Ther 34, 332e337. Honkavaara J, Restitutti F, Raekallio M et al. (2012) Influence of MK-467, a peripherally acting a2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs. Drug Metab Dispos 40, 445e449. Jacobs JR, Nath PA (1995) Compartment model to describe peripheral arterial-venous drug concentration gradients with drug elimination from the venous sampling compartment. J Pharm Sci 84, 370e375. Jaeger AT, Pypendop BH, Ahokoivu H, Honkavaara J (2019) Cardiopulmonary effects of dexmedetomidine, with and without
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vatinoxan, in isoflurane-anesthetized cats. Vet Anaesth Analg 46, 753e764. Kaartinen J, del Castillo JR, Salla K et al. (2014) Haemodynamic interactions of medetomidine and the peripheral alpha-2 antagonist MK-467 during step infusions in isoflurane-anaesthetised dogs. Vet J 202, 353e360. Martin-Flores M, Sakai DM, Honkavaara J et al. (2018) Hemodynamic effects of MK-467 following intravenous administration to isoflurane-anesthetized cats concurrently receiving dexmedetomidine. Am J Vet Res 79, 711e717. Mould DR, Upton RN (2013) Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacometrics Syst Pharmacol 2, e38. Pypendop BH, Honkavaara J, Ilkiw JE (2016) Pharmacokinetics of dexmedetomidine, MK-467, and their combination following intravenous administration in male cats. J Vet Pharmacol Ther 39, 460e468. Pypendop BH, Honkavaara J, Ilkiw JE (2017a) Cardiovascular effects of dexmedetomidine, with or without MK-467, following intravenous administration in cats. Vet Anaesth Analg 44, 52e62. Pypendop BH, Honkavaara J, Ilkiw JE (2017b) Pharmacokinetics of dexmedetomidine, MK-467 and their combination following intramuscular administration in male cats. Vet Anaesth Analg 44, 823e831. Pypendop BH, Brosnan RJ, Siao KT, Stanley SD (2008) Pharmacokinetics of remifentanil in conscious cats and cats anesthetized with isoflurane. Am J Vet Res 69, 531e536. Pypendop BH, Barter LS, Stanley SD, Ilkiw JE (2011) Hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats. Vet Anaesth Analg 38, 555e567. Restitutti F, Kaartinen MJ, Raekallio MR et al. (2017) Plasma concentration and cardiovascular effects of intramuscular medetomidine combined with three doses of the peripheral alpha2-antagonist MK-467 in dogs. Vet Anaesth Analg 44, 417e426. Steffey EP, Howland D Jr (1977) Isoflurane potency in the dog and cat. Am J Vet Res 38, 1833e1836. Thomasy SM, Pypendop BH, Ilkiw JE et al. (2005) Pharmacokinetics of lidocaine and its active metabolite, monoethylglycinexylidide, after intravenous administration of lidocaine to awake and isoflurane-anesthetized cats. Am J Vet Res 66, 1162e1166. Vainionpaa MH, Raekallio MR, Pakkanen SA et al. (2013) Plasma drug concentrations and clinical effects of a peripheral alpha-2adrenoceptor antagonist, MK-467, in horses sedated with detomidine. Vet Anaesth Analg 40, 257e264. Received 23 April 2019; accepted 5 October 2019. Available online xxx
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Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
RESEARCH PAPER
Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane Bruno H Pypendopa, Hanna Ahokoivua & Juhana Honkavaarab a
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA,
USA b
Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA, USA
Correspondence: Bruno Pypendop, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, One Shields Avenue, Davis, CA, 95616, USA. E-mail: [email protected]
Abstract Objective To characterize the pharmacokinetics of vatinoxan in isoflurane-anesthetized cats. Study design Prospective experimental study.
cardiovascular effects of dexmedetomidine (25 mg kge1) in conscious cats. Keywords a2-antagonist, cats, isoflurane, pharmacokinetics.
Animals A group of six adult healthy male neutered cats. Methods Cats were anesthetized using isoflurane in oxygen. Venous catheters were placed to administer the drug and sample blood. Vatinoxan, 1 mg kge1, was administered intravenously over 5 minutes. Blood was sampled before and at various times during and up to 8 hours after vatinoxan administration. Plasma vatinoxan concentration was measured using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the timeeconcentration data using population methods and nonlinear mixed effect modeling. Results A three-compartment model best fitted the data. Typical value (% interindividual variability) for the three volumes (mL kge1), the metabolic clearance and two distribution clearances (mL minutee1 kge1) were 34 (55), 151 (35), 306 (18), 2.3 (34), 42.6 (25) and 5.6 (0), respectively. Hypotension increased the second distribution clearance to 10.6. Conclusion and clinical relevance The pharmacokinetics of vatinoxan in anesthetized cats were characterized by a small volume of distribution and a low clearance. An intravenous bolus of 100 mg kge1 of vatinoxan followed by constant rate infusions of 55 mg kge1 minutee1 for 20 minutes, then 22 mg kge1 minutee1 for 60 minutes and finally 10 mg kge1 minutee1 for the remainder of the infusion time is expected to maintain the plasma concentration within 90%e110% of the plasma vatinoxan concentration previously shown to attenuate the
Introduction Vatinoxan (formerly known as MK-467 and L-659,066) is an a2-adrenoceptor antagonist believed to poorly cross the mammalian bloodebrain barrier (Clineschmidt et al. 1988). When combined with an a2-adrenoceptor agonist, it will attenuate the agonist-induced cardiovascular effects while preserving the sedative effect in several species, including cats (Honkavaara et al. 2011, 2017; Vainionpaa et al. 2013; Kaartinen et al. 2014; de Vries et al. 2016; Pypendop et al. 2017a; Restitutti et al. 2017). The pharmacokinetics of vatinoxan in conscious cats has been previously reported (Pypendop et al. 2016, 2017b). Inhaled anesthetics will influence the disposition of drugs administered concurrently (Thomasy et al. 2005; Pypendop et al. 2008). The use of vatinoxan in anesthetized cats may be of interest as the a2-adrenoceptor agonist, dexmedetomidine, has been reported to decrease anesthetic requirements but worsen cardiovascular performance because of its own effects on hemodynamics (Pypendop et al. 2011; Escobar et al. 2012). Therefore, it is possible that combining dexmedetomidine with vatinoxan would result in improved cardiovascular performance in cats anesthetized with an inhaled anesthetic. Characterization of the pharmacokinetics of vatinoxan in cats during anesthesia is necessary to the rational dosing of the drug, particularly if a desired plasma drug concentration is known. The aim of this study was to characterize the pharmacokinetics of vatinoxan in cats anesthetized with isoflurane.
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Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
Pharmacokinetics vatinoxaneisoflurane cats BH Pypendop et al.
Materials and methods Animals A group of six male neutered cats, aged 1 year, weighing 5.5 ± 0.5 kg (mean ± standard deviation) and deemed healthy based on history and physical examination, were used. Husbandry conditions have been previously reported for this facility (Honkavaara et al. 2017). The study was approved by the University of California, Davis, USA Institutional Animal Care and Use Committee (no. 19114). Instrumentation Cats were anesthetized with isoflurane in oxygen, delivered in an acrylic chamber. After the cat had lost its righting reflex, it was removed from the chamber and the trachea was intubated with a cuffed endotracheal tube. Anesthesia was maintained with isoflurane in oxygen delivered via a Bain circuit, with a fresh gas flow of 1.5e2.0 L minutee1. A 20 gauge, 5 cm catheter (Insyte; Becton Dickinson, CA, USA) was inserted in a medial saphenous vein for drug administration and administration of lactated Ringer’s solution (Baxter Healthcare Corp., IL, USA) at 3 mL kge1 houre1. A 19 gauge, 15 cm catheter (Central Venous Catheter; MILA International Inc., KY, USA) was inserted in a jugular vein for blood sampling. Intermittent positive pressure ventilation was provided to maintain endtidal partial pressure of carbon dioxide (PE0 CO2) at 35e40 mmHg (4.7e5.3 kPa). A Doppler flow detector (Model 811; Parks Medical Electronics Inc., OR, USA) probe was placed over the palmar aspect of the metacarpus, and an occluding cuff was placed dorsal to the ipsilateral carpus for the measurement of systolic arterial pressure (SAP). A pulse oximeter probe was placed over the tongue and connected to a monitor (S/5 Compact; GE Healthcare, WI, USA) for the measurement of hemoglobin oxygen saturation (SpO2) and pulse rate (PR). A thermistor, calibrated daily against a certified thermometer, was positioned in the thoracic esophagus and connected to a data acquisition system (Ponemah; DSI, MN, USA) for the measurement of body temperature. Esophageal temperature was maintained at 38.5e39.5 C by providing external heat (HotDog Patient Warming System; Augustine Temperature Management LLC, MN, USA) as needed. A catheter placed into the lumen of the endotracheal tube so that its tip was close to the distal (tracheal) end of the tube was connected to an infrared spectrometer (S/5 Compact; GE Healthcare) for the continuous measurement of PE0 CO2 and end-tidal isoflurane concentration (FE0 Iso). Variables were recorded every 15 minutes. In addition, at the time of recording, approximately 5 mL of gas was sampled by hand from the endotracheal catheter into a glass syringe. Isoflurane concentration in these samples was measured using a second infrared spectrometer (LB2; Beckman Instruments, CA, USA) calibrated daily using four 2
secondary standards of known isoflurane concentrations (0.51%, 2.04%, 2.38% and 3.33%), and considered the actual isoflurane concentration. Drug administration and blood sampling Following instrumentation, the FE0 Iso was set at the cat’s minimum alveolar concentration (MAC) previously determined in duplicate using the bracketing technique and tail clamping. After a minimum of 15 minutes at a constant FE0 Iso, vatinoxan (1 mg kge1) was administered intravenously (IV) via the medial saphenous catheter over 5 minutes (i.e. 0.2 mg kge1 minutee1) using a syringe pump (PHD2000; Harvard Apparatus, MA, USA). Vatinoxan powder was dissolved in sterile isotonic saline to a concentration of 1 mg mLe1 and filtered through a sterile 0.22 mm filter (Fisherbrand Syringe Filter; Fisher Scientific, MA, USA). Blood samples (2 mL) were collected from the jugular catheter prior to vatinoxan administration and 2, 5, 6, 7, 9, 13, 20, 35, 65, 125, 245 and 485 minutes after the beginning of the vatinoxan IV infusion. Samples were transferred into tubes containing ethylenediaminetetracetic acid (Vacuette; Greiner Bio-One, NC, USA), placed on ice and centrifuged at 4 C within 15 minutes of collection. The plasma was separated, transferred to cryotubes and frozen at e80 C until analysis for vatinoxan concentrations. After the last sample had been collected, catheters and monitoring instruments were removed, meloxicam (0.1 mg kge1; Loxicom; Norbrook Inc. USA, KS, USA) was administered subcutaneously, and the cat was allowed to recover from anesthesia. Plasma vatinoxan concentration analysis Vatinoxan concentration was measured in protein-precipitated plasma samples using liquid chromatography/tandem mass spectrometry according to methods previously described (Honkavaara et al. 2012). Calibrator and quality control stock solutions of vatinoxan were prepared in water and acetonitrile (ACN) at 1 mg mLe1. Calibration curves and negative control samples were prepared fresh for each quantitative assay. Quality control samples (feline plasma with added analyte at three concentrations within the standard curve) were included with each sample set as an additional check of accuracy. All plasma samples were diluted with 100 mL of internal standard 2-(1-hydroxyethyl) promazine sulfoxide (HEPS; Frontier BioPharm, KY, USA) HEPS at 100 ng mLe1 in water prior to sample analysis. The injection volume was 30 mL. The concentration of vatinoxan was measured in plasma by liquid chromatography/tandem mass spectrometry with positive heated electrospray ionization [HESI(þ)]. Quantitative analysis of plasma vatinoxan was conducted on a TSQ Vantage triple quadrupole mass spectrometer (Thermo Scientific, CA, USA) combined with a turbulent flow chromatography system (TFC
© 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., xxx, xxx
Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
Pharmacokinetics vatinoxaneisoflurane cats BH Pypendop et al.
TLX2; Thermo Scientific) with LC-10ADvp liquid chromatography systems (Shimadzu, Japan) and operated in laminar flow mode. Product masses and collision energies of each analyte were optimized by infusing the analytes into the mass spectrometer. The chromatography column was an ACE 3 C18 10 cm 2.1 mm 3 mm (MAC-MOD Analytical Inc., PA, USA), and a linear gradient of ACN in water with a constant 0.2% formic acid at a flow rate of 0.35 mL minutee1 was used. The initial ACN concentration was held at 10% for 0.50 minutes, ramped to 90% over 5 minutes and held at that concentration for 0.33 minute, before re-equilibrating for 4.17 minutes at initial conditions. Detection and quantification were performed using selective reaction monitoring of initial precursor ion for vatinoxan (m ze1 419.18) and the internal standard (HEPS; m ze1 345.15). The response for the product ions for vatinoxan (m ze1 199.9, 237.9, 281.0) and internal standard (m ze1 58.1, 86.0, 242.9) were graphed and peaks integrated at the proper retention time using Quanbrowser software (Thermo Scientific). Calibration curves were generated, and vatinoxan concentration quantitated in all samples using the Quanbrowser software. A weighting factor of 1/X was applied to all calibration curves. The response for vatinoxan was linear between 0.1 and 500 ng mLe1, and between 500 and 5000 ng mLe1 (two calibration curves were generated and vatinoxan concentration in the samples was quantified according to the corresponding curve) and gave a coefficient of determination of 0.99. Samples with a vatinoxan concentration above 5000 ng mLe1 were reanalyzed after dilution, and the measured concentration was corrected accordingly. The limit of quantitation was 0.1 ng mLe1, and the limit of detection was 0.02 ng mLe1. Accuracy (% nominal concentration) and imprecision (coefficient of variation) were verified at 0.3, 300 and 4000 ng mLe1 and ranged from 88% to 111% and 6% to 11%, respectively. Pharmacokinetic analysis Two- and three-compartment models with zero-order input in, and first-order elimination from the central compartment were fitted to the timeeconcentration data using nonlinear mixed effect modeling in Phoenix NLME 8.1 (Certara, NJ, USA). The models were fitted to the data from all cats simultaneously using population methods and the first-order conditional estimation-extended least squares algorithm. Different error and covariance structure were tested. The parameters estimated by the model were volumes and clearances. Additional parameters were calculated from these estimates. The best fitting model was selected based on precision of the parameters, observation of residuals plots, the e2 log likelihood (e2LL), and Akaike’s information criterion. In addition, SAP and hypotension (defined as SAP < 80 mmHg) were tested as possible continuous and categorical covariate, respectively. The decision to add either covariate to one or more of the structural
parameters was based on a stepwise covariate search with the threshold for forward addition set at 0.05 (i.e. an improvement in e2LL by a minimum of 3.84) and that for backward deletion set at 0.01 (i.e. a worsening in e2LL by a minimum of 6.64). Typical values (tv) of the parameters and random effects (h) to account for interindividual variability were estimated. The parameter (P) in the ith individual was calculated as Pi ¼ tvPi ehi and a different h was estimated for each P. When hypotension was added as a categorical covariate, the calculation was adjusted to Pi ¼ tvPi ð1 þdPidHypoÞ ehi with dPidHypo an additional parameter estimated by the model, and applied when hypotension was observed. The random effects (h) were assumed to have a normal distribution with a mean of 0 and a variance of u2. The interindividual variability p is ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi calculated as a coefficient of variation (%) acffi 2 cording to eu 1 100 (Mould & Upton 2013). Pharmacokinetic simulation using the best model and Phoenix NLME 8.1 was used to design a dosing regimen to rapidly achieve and maintain plasma vatinoxan concentration within 10% of a desired concentration. The desired plasma vatinoxan concentration was considered to correspond to 4169 ng mLe1, the peak plasma concentration observed after bolus IV administration of 600 mg kge1, the dose previously reported to optimally attenuate the bradycardia induced by 25 mg kge1 of dexmedetomidine in conscious cats (Pypendop et al. 2016). Pharmacokinetic parameters are presented as typical value (% interindividual variability). Other data are presented as mean ± standard deviation. Results The previously measured MAC of isoflurane was 2.09 ± 0.20%. A three-compartment model best fitted the plasma vatinoxan concentrationetime data (Fig. 1). A multiplicative error and diagonal covariance structures resulted in the best fit. Hypotension as a categorical covariate applied to the second distribution clearance improved the model. Pharmacokinetic parameters are presented in Table 1. PR, SAP, SpO2, esophageal temperature and PE0 CO2 (data pooled for all cats at all time points) were 156 ± 30 beats minutee1, 91 ± 20 mmHg, 96 ± 1%, 39.2 ± 0.2 C and 31 ± 3 mmHg (4.1 ± 0.4 kPa). SAP was 80 mmHg in 80 out of 194 (41%) measurements. Cats maintained spontaneous ventilation in addition to the intermittent positive pressure ventilation provided. FE0 Iso (data pooled for all cats at all time points) corresponded to 1.02 ± 0.05 times the MAC previously determined in each cat. Based on the typical values of the pharmacokinetic parameters, an IV bolus of 100 mg kge1 of vatinoxan followed by constant rate infusions (CRIs) of 55 mg kge1 minutee1 for 20 minutes, then 22 mg kge1 minutee1 for 60 minutes and finally 10 mg kge1 minutee1 for the remainder of the infusion time (regardless of the total duration of infusion) would be expected
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Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
Pharmacokinetics vatinoxaneisoflurane cats BH Pypendop et al.
Figure 1 Observed (circles) and predicted (line) plasma vatinoxan concentrations in six cats anesthetized with isoflurane, during and after a 5 minute intravenous infusion of vatinoxan (1 mg kge1; 0.2 mg kg minutee1) started at time 0. Predicted concentrations were obtained by fitting a three-compartment model to the time-plasma vatinoxan concentration data using population methods. The typical values of the parameters are adjusted using random effects to account for the interindividual variability. The dashed line represents the predicted concentrations obtained from the typical values of the parameters (i.e. the population model).
Table 1 Typical value (% interindividual variability) for the pharmacokinetic parameters for vatinoxan in cats (n ¼ 6) anesthetized with isoflurane Parameter
Value
V1 (mL kge1) V2 (mL kge1) V3 (mL kge1) CL (mL minutee1 kge1) CL2 (mL minutee1 kge1) CL3 (mL minutee1 kge1) dCL3dHypo* Vss (mL kge1)y T½ a (minutes)y T½ b (minutes)y T½ g (minutes)y
34 (55) 151 (35) 306 (18) 2.3 (34) 42.6 (25) 5.6 (0) 0.9 491 0.4 14 174
V1, volume of the central compartment; V2, volume of the first peripheral compartment; V3, volume of the second peripheral compartment; CL, metabolic clearance; CL2, first distribution clearance; CL3, second distribution clearance; dCL3dHypo, correction factor (covariate) for CL3 when hypotension (systolic arterial pressure < 80 mmHg) is present; Vss, volume of distribution at steady-state; T½ a, half-life of the fast distribution phase; T½ b, half-life of the slow distribution phase; T½ g, elimination half-life. *No interindividual variability calculated for covariates. yNo interindividual variability estimated because the parameter was calculated from typical values of other parameters.
to achieve 90% of the desired plasma vatinoxan concentration within 14 minutes of starting the administration, and to maintain the plasma concentration within 90e110% of the desired concentration thereafter (Fig. 2). 4
Discussion In this study, the pharmacokinetics of vatinoxan in isofluraneanesthetized cats was characterized by a small volume of distribution and low metabolic clearance. This is in agreement with previous studies in conscious cats (Pypendop et al. 2016, 2017b). In the previous studies, a two-compartment model best fitted the data, whereas a three-compartment model best fitted the data in the current study. This may result from differences in study design (e.g. bolus administration in the previous studies versus short infusion in the current study; differences in doses, modeling of each individual dataset separately versus population approach), or to an effect of isoflurane anesthesia. The volume of distribution at steady state appeared similar in conscious and isoflurane-anesthetized cats, whereas the clearance was lower in the anesthetized cats. Previous studies have shown that dexmedetomidine did not markedly affect the disposition of vatinoxan in conscious cats, likely because the latter prevents the agonist-induced decrease in cardiac output (Pypendop et al. 2016, 2017a). Nevertheless, the possible impact of dexmedetomidine on vatinoxan clearance in isoflurane-anesthetized cats would need to be investigated separately. In contrast, the decrease in cardiac output produced by isoflurane would be less likely to be attenuated by vatinoxan, resulting in decreased liver blood flow and clearance (Steffey & Howland 1977). This lower clearance in anesthetized cats compared with conscious cats results in longer terminal half-life of close to 3 hours.
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Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
Pharmacokinetics vatinoxaneisoflurane cats BH Pypendop et al.
Figure 2 Plasma vatinoxan concentration following a simulated intravenous bolus of 100 mg kge1 of vatinoxan followed by constant rate infusions of 55 mg kge1 minutee1 for 20 minutes, then 22 mg kge1 minutee1 for 60 minutes and finally 10 mg kge1 minutee1 for the remainder of the infusion time. This simulation used the typical value of the pharmacokinetic parameters and a desired concentration of 4169 ng mLe1 (dashed line). The continuous horizontal lines show 90% and 110% of the desired concentration.
In this study, the use of a short infusion was selected in part to avoid the physiologically incorrect assumption of instantaneous drug mixing within the central compartment following bolus IV administration (Avram & Krejcie 2003; Henthorn et al. 2008). This may have contributed to the small estimate of the volume of the central compartment. In addition, isoflurane anesthesia may also have limited the initial distribution of the drug to highly perfused organs through the aforementioned cardiovascular effects. Nevertheless, the estimate of the volume of the central compartment is very small and variable among individuals. The estimate of the volume of distribution at steady state is small, probably a result of the low lipid solubility (log P of 1.3) (Clineschmidt et al. 1988). The relatively long terminal half-life is expected to result in difficulties in maintaining stable plasma drug concentrations if using a single CRI, with or without a loading dose. Indeed, steady state would be approached after approximately 9 hours with a CRI. The pharmacokinetic simulation shows that this time can be considerably shortened with the use of a loading dose and a ‘three-step’ infusion consisting of two higher infusion rates for a predetermined duration prior to the ‘maintenance’ CRI. It should be noted that the desired concentration was chosen as the peak plasma vatinoxan concentration following IV bolus administration of 600 mg kge1 in conscious cats. However, assuming doseindependent pharmacokinetics, different concentrations could be achieved by proportionally changing the loading dose and infusion rates, without adjusting the predetermined duration (e.g. if the desired concentration is half that used in
the simulation, the corresponding dosing regimen would consist of half the IV bolus dose and half the administration rate at each step, with the duration of each step remaining the same. Although the goal of this study was not to assess the cardiovascular effects of vatinoxan in isoflurane-anesthetized cats, hypotension was frequently observed, suggesting that vatinoxan may promote hypotension in anesthetized cats. Hypotension was also observed with much lower doses of vatinoxan in isoflurane-anesthetized cats concurrently administered dexmedetomidine (Martin-Flores et al. 2018). Concurrent administration of dexmedetomidine may partially counteract vatinoxan-induced hypotension by causing vasoconstriction. Moreover, in a recent study, severe hypotension was observed during vatinoxan administration in cats anesthetized with 1.25 MAC isoflurane, with or without dexmedetomidine, except at the highest plasma dexmedetomidine concentration studied (Jaeger et al. 2019). Together, these results suggest that caution may be needed when administering vatinoxan in anesthetized cats. The results of this study should be interpreted in view of several limitations. The study sample was small and included healthy young adult neutered male cats. This homogeneity is not representative of the larger cat population and the pharmacokinetic parameters should be interpreted in this context. Venous sampling was used for logistical reasons, although arterial drug concentrations may be more useful for the prediction of drug effects (Jacobs & Nath 1995). The isoflurane concentration maintained during the study was lower than would be necessary for surgery. In addition, the use of isoflurane alone is not representative of clinical practice. Hypotension was observed in some cats and left untreated; the model predicts that the influence of hypotension on the disposition of vatinoxan is minimal. Finally, it is unlikely that the administration of vatinoxan alone would be desirable in clinical patients. As previously mentioned, it is possible that combining vatinoxan with an a2-agonist would influence the pharmacokinetics of vatinoxan, and the results of this study should be confirmed with concurrent a2-agonist administration. However, in previous studies in conscious dogs and cats, dexmedetomidine did not affect the disposition of vatinoxan (Honkavaara et al. 2012; Pypendop et al. 2016). Conclusion The pharmacokinetics of vatinoxan in isoflurane-anesthetized cats was characterized by a small volume of distribution and low clearance. Acknowledgements This study was funded by the Winn Feline Foundation, the Miller Trust, San Francisco Foundation, and the Center for
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Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004
Pharmacokinetics vatinoxaneisoflurane cats BH Pypendop et al.
Companion Animal Health, School of Veterinary Medicine, University of California. Vatinoxan was provided free of charge by Vetcare Ltd. Authors' contributions BHP: study design, conducted experiments, data analysis, manuscript preparation. HA: conducted experiments, manuscript review. JH: study design, manuscript review. Conflict of interest statement Vetcare Ltd provided vatinoxan for free. Dr Honkavaara has received funding from Vetcare Ltd. References Avram MJ, Krejcie TC (2003) Using front-end kinetics to optimize target-controlled drug infusions. Anesthesiology 99, 1078e1086. Clineschmidt BV, Pettibone DJ, Lotti VJ et al. (1988) A peripherally acting alpha-2 adrenoceptor antagonist: L-659,066. J Pharmacol Exp Ther 245, 32e40. de Vries A, Pakkanen SA, Raekallio MR et al. (2016) Clinical effects and pharmacokinetic variables of romifidine and the peripheral a2-adrenoceptor antagonist MK-467 in horses. Vet Anaesth Analg 43, 599e610. Escobar A, Pypendop BH, Siao KT et al. (2012) Effect of dexmedetomidine on the minimum alveolar concentration of isoflurane in cats. J Vet Pharmacol Ther 35, 163e168. Henthorn TK, Krejcie TC, Avram MJ (2008) Early drug distribution: a generally neglected aspect of pharmacokinetics of particular relevance to intravenously administered anesthetic agents. Clin Pharmacol Ther 84, 18e22. Honkavaara J, Pypendop B, Turunen H, Ilkiw J (2017) The effect of MK467, a peripheral a2-adrenoceptor antagonist, on dexmedetomidineinduced sedation and bradycardia after intravenous administration in conscious cats. Vet Anaesth Analg 44, 42e51. Honkavaara JM, Restitutti F, Raekallio MR et al. (2011) The effects of increasing doses of MK-467, a peripheral alpha2-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs. J Vet Pharmacol Ther 34, 332e337. Honkavaara J, Restitutti F, Raekallio M et al. (2012) Influence of MK-467, a peripherally acting a2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs. Drug Metab Dispos 40, 445e449. Jacobs JR, Nath PA (1995) Compartment model to describe peripheral arterial-venous drug concentration gradients with drug elimination from the venous sampling compartment. J Pharm Sci 84, 370e375. Jaeger AT, Pypendop BH, Ahokoivu H, Honkavaara J (2019) Cardiopulmonary effects of dexmedetomidine, with and without
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vatinoxan, in isoflurane-anesthetized cats. Vet Anaesth Analg 46, 753e764. Kaartinen J, del Castillo JR, Salla K et al. (2014) Haemodynamic interactions of medetomidine and the peripheral alpha-2 antagonist MK-467 during step infusions in isoflurane-anaesthetised dogs. Vet J 202, 353e360. Martin-Flores M, Sakai DM, Honkavaara J et al. (2018) Hemodynamic effects of MK-467 following intravenous administration to isoflurane-anesthetized cats concurrently receiving dexmedetomidine. Am J Vet Res 79, 711e717. Mould DR, Upton RN (2013) Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacometrics Syst Pharmacol 2, e38. Pypendop BH, Honkavaara J, Ilkiw JE (2016) Pharmacokinetics of dexmedetomidine, MK-467, and their combination following intravenous administration in male cats. J Vet Pharmacol Ther 39, 460e468. Pypendop BH, Honkavaara J, Ilkiw JE (2017a) Cardiovascular effects of dexmedetomidine, with or without MK-467, following intravenous administration in cats. Vet Anaesth Analg 44, 52e62. Pypendop BH, Honkavaara J, Ilkiw JE (2017b) Pharmacokinetics of dexmedetomidine, MK-467 and their combination following intramuscular administration in male cats. Vet Anaesth Analg 44, 823e831. Pypendop BH, Brosnan RJ, Siao KT, Stanley SD (2008) Pharmacokinetics of remifentanil in conscious cats and cats anesthetized with isoflurane. Am J Vet Res 69, 531e536. Pypendop BH, Barter LS, Stanley SD, Ilkiw JE (2011) Hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats. Vet Anaesth Analg 38, 555e567. Restitutti F, Kaartinen MJ, Raekallio MR et al. (2017) Plasma concentration and cardiovascular effects of intramuscular medetomidine combined with three doses of the peripheral alpha2-antagonist MK-467 in dogs. Vet Anaesth Analg 44, 417e426. Steffey EP, Howland D Jr (1977) Isoflurane potency in the dog and cat. Am J Vet Res 38, 1833e1836. Thomasy SM, Pypendop BH, Ilkiw JE et al. (2005) Pharmacokinetics of lidocaine and its active metabolite, monoethylglycinexylidide, after intravenous administration of lidocaine to awake and isoflurane-anesthetized cats. Am J Vet Res 66, 1162e1166. Vainionpaa MH, Raekallio MR, Pakkanen SA et al. (2013) Plasma drug concentrations and clinical effects of a peripheral alpha-2adrenoceptor antagonist, MK-467, in horses sedated with detomidine. Vet Anaesth Analg 40, 257e264. Received 23 April 2019; accepted 5 October 2019. Available online xxx
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Please cite this article as: Pypendop BH, Ahokoivu H, Honkavaara J Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia, https://doi.org/10.1016/j.vaa.2019.10.004