J. vet. Pharmacol. Therap. doi: 10.1111/jvp.12172
SHORT COMMUNICATION
Pharmacokinetics of oral transmucosal and intramuscular dexmedetomidine combined with buprenorphine in cats N. PORTERS* H. DE ROOSTER* T. BOSMANS* K. BAERT † M. CHERLET † S. CROUBELS ‡ P. DE BACKER ‡ & I. POLIS* *Department of Medicine and Clinical Biology of Small Animals, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium; †Medicem NV, Sint Niklaas, Belgium; ‡Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
Porters, N., de Rooster, H., Bosmans, T., Baert, K., Cherlet, M., Croubels, S., De Backer, P., Polis, I. Pharmacokinetics of oral transmucosal and intramuscular dexmedetomidine combined with buprenorphine in cats. J. vet. Pharmacol. Therap. doi: 10.1111/jvp.12172. Plasma concentrations and pharmacokinetics of dexmedetomidine and buprenorphine after oral transmucosal (OTM) and intramuscular (i.m.) administration of their combination in healthy adult cats were compared. According to a crossover protocol (1-month washout), a combination of dexmedetomidine (40 lg/kg) and buprenorphine (20 lg/kg) was given OTM (buccal cavity) or i.m. (quadriceps muscle) in six female neutered cats. Plasma samples were collected through a jugular catheter during a 24-h period. Plasma dexmedetomidine and buprenorphine concentrations were determined by liquid chromatography–tandem mass spectrometry. Plasma concentration–time data were fitted to compartmental models. For dexmedetomidine and buprenorphine, the area under the plasma concentration–time curve (AUC) and the maximum plasma concentrations (Cmax) were significantly lower following OTM than following i.m. administration. For buprenorphine, time to reach Cmax was also significantly longer after OTM administration than after i.m. injection. Data suggested that dexmedetomidine (40 lg/kg) combined with buprenorphine (20 lg/kg) is not as well absorbed from the buccal mucosa site as from the intramuscular injection site. (Paper received 13 March 2014; accepted for publication 8 September 2014) Ingeborgh Polis, Department of Medicine and Clinical Biology of Small Animals, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium. E-mail: [email protected]
Oral transmucosal (OTM) drug delivery refers to the local and systemic delivery of drugs to or via any oral cavity membrane (Rathbone et al., 1994). In the current study, OTM administration refers to the administration of drugs via the buccal mucosa. It is a painless and often more practical alternative compared with the conventional gastrointestinal and parenteral routes of administration (Rathbone et al., 1994). Recently, there is growing interest in the clinical use of OTM administration of dexmedetomidine (Slingsby et al., 2006, 2009), buprenorphine (Robertson et al., 2003, 2005; Giordano et al., 2010; Catbagan et al., 2011; Bortolami et al., 2012) and the combination of dexmedetomidine and buprenorphine (Santos et al., 2010) in cats. Therefore, our group investigated the sedative, analgesic and adverse effects of the i.m. vs. OTM administration of a dexmedetomidine–buprenorphine combination as premedication for early age neutering in cats (Porters et al., 2014b). To facilitate clinical interpretation of differences in sedative and analgesic effects of this combination following OTM and i.m. administration, a pharmacodynamic (PD) study (Porters et al., 2014a) and the present © 2014 John Wiley & Sons Ltd
pharmacokinetic (PK) study were performed in adult experimental cats. In this study, the pharmacokinetics of the combination of dexmedetomidine (40 lg/kg) and buprenorphine (20 lg/kg) after a single OTM or i.m. administration in healthy adult cats were determined and compared. The study was approved by the Ethical Committee of the Faculty of Veterinary Medicine, Ghent University, Belgium (licence number EC 54/2011). Six purpose-bred neutered female cats with a weight of 5.7 0.4 kg (mean SD) and age of 7.3 0.015 years were used in this study. Cats were considered healthy based on a general physical examination. Food, but not water, was withheld for 12 h before treatment. Seventeen hours prior to treatment, the cats were anesthetized with propofol (4–6 mg/kg Propoflo Plusâ; Abbott Laboratories, Ltd, Queenborough, UK) for placement of a jugular catheter. Treatments were administered in a randomized crossover design with a washout period of 1 month between treatments. The combination of dexmedetomidine hydrochloride (Dexdomitorâ, 0.5 mg/mL; Orion Corporation, Espoo, Finland) 1
2 N. Porters et al.
1
Qiaozhen G., Zhenxia D. (2011). Development of a rapid and simultaneous detection method for buprenorphine, norbuprenorphine and naloxone in human plasma using ultra-high performance liquid chromatography tandem mass spectrometer with solid-phase extraction. Chin. J. Chem., 29, 1922–1926.
2
Commission Decision 2002/657/EC implementing council Directive 96/23/EC concerning the performances of analytical methods and the interpretation of results. Official Journal of the European Communities, No L221, 17.8.2002, Decision of 12 August 2002, European Commission, Directorate General for Public Health and Consumers Protection, 2002/657/EC, 17-08-2002 (SANCO).
the PK analysis. The following PK parameters were calculated: the area under the concentration–time curve (AUC0–t), time to maximal plasma concentration (Tmax), maximal plasma concentration (Cmax), absorption rate constant (Ka), elimination rate constant (K10), rate constant from central to peripheral compartment and peripheral to central compartment (K12 and K21, respectively), absorption half-life (t1/2a), elimination half-life (t1/2e for one-compartmental model, t1/2a and t1/2b for two-compartmental model) and mean residence time (MRT). Descriptive statistical parameters were calculated as mean standard deviation (SD). A Wilcoxon signed-rank test was performed to examine significant differences between the two routes of administration. Values of P < 0.05 were considered significant. Statistical software SPSSâ (SPSS Statistics, Version 20; IBM Corp., Armonk, NY, USA) was used. Cats resisted OTM administration of the dexmedetomidine– buprenorphine combination. Vomiting and salivation were also observed, but not recorded in this study. Observed adverse reactions were comparable to the ones reported in the PD study on the identical drug combination (Porters et al., 2014a). For dexmedetomidine, the mean estimated plasma profiles obtained over time from OTM and i.m. administration are depicted in Fig. 1. After both treatments, plasma dexmedetomidine concentrations were quantified until 12 h in all cats. Pharmacokinetic parameters for dexmedetomidine in cats are summarized in Table 1. For buprenorphine, the mean plasma concentration vs. time curves following OTM and i.m. administration are shown in Fig. 2. Following OTM administration, plasma buprenorphine concentration was first detected at 5 min and remained detectable until 6 h in 5, and until 24 h in 3 of 6 cats. In one cat, however, buprenorphine was first measured at 20 min only and, at 6 h after OTM administration, its concentration fell below the detection threshold. On the
100 IM
Dexmedetomidine (ng/mL)
at 40 lg/kg and buprenorphine hydrochloride (Vetergesic Multidoseâ, 0.3 mg/mL; Alstoe Animal Health Ltd., Hull, UK) at 20 lg/kg was mixed in a syringe immediately before OTM or i.m. administration. Cats were manually restrained while the drugs were administered. OTM administration was performed by inserting the nozzle of a 1-mL syringe into the buccal cavity of the cat’s mouth. Afterwards, the content (volume range from 0.77 to 0.91 mL) was gently squirted into the cheek area. For the i.m. route, a 25-gauge needle was used to inject the drugs (volume range from 0.75 to 0.88 mL) into the quadriceps muscle. Blood samples (2 mL) were collected from the jugular catheter before and at 1, 5, 10, 20, 30 and 60 min, and at 2, 4, 6, 12 and 24 h after drug administration. After each sample, an equal volume of 0.9% saline was injected through the jugular catheter (Robertson et al., 2005). Blood was transferred into heparinized tubes (Vacuetteâ 2 mL Lithium Heparine; Greiner bio one, Kremsmu¨nster, Austria), enrolled in aluminium foil and centrifuged (2000 g) for 10 min within 2 h after sampling (Robertson et al., 2005). Plasma was separated and stored at 80 °C until analysed. Plasma concentrations of dexmedetomidine, buprenorphine and norbuprenorphine, the primary active N-dealkylated metabolite of buprenorphine, were determined using an ultrahigh performance liquid chromatography (UPLC) method combined with tandem mass spectrometric detection. The extraction procedure was adapted from the method described by Qiaozhen and Zhenxia.1 The analytical method was inhouse validated according to criteria given in the EC guidelines.2 For dexmedetomidine, the limit of quantification (LOQ) was 0.025 ng/mL, while for buprenorphine and norbuprenorphine, the LOQ was 0.05 ng/mL. A limit of detection (LOD) of 0.012, 0.016 and 0.023 ng/mL was determined for dexmedetomidine, buprenorphine and norbuprenorphine, respectively. Pharmacokinetic parameters were calculated on an individual basis for each cat following OTM and i.m. treatment. Pharmacokinetic analysis was performed by use of a computer program (MW/PHARM 3.15) (Proost & Meijer, 1992). The individual plasma drug concentration–time data were fitted to a one- or two-compartmental open model. The appropriate model was selected by evaluating correlation of the observed and predicted plasma concentrations and by visual examination of the line fits and the residual plots. Values below the LOQ of the method were not taken into account in
OTM
10
1
0.1
0.01
0
1
2
3
4
5
6
7
8
9
10 11 12
Time (h) Fig. 1. Plasma dexmedetomidine concentration over time (mean SD) following oral transmucosal (OTM) and intramuscular (i.m.) administration of dexmedetomidine (40 µg/kg) plus buprenorphine (20 µg/kg) in 6 healthy adult cats. © 2014 John Wiley & Sons Ltd
© 2014 John Wiley & Sons Ltd
0.76 9 10 1.10
1.58
3.10
0.01 26.30 909.60 0.63
0.72 3.07 3.70 0.32
0.19 2.15
6.0 0.24 1 41.78
i.m.
6.2 0.25 1 11.95
OTM
1
3
0.24 28.68 10.36 0.83 0.31 0.82 0.07 0.46 1.53 1.65
0.26 2.06 2.00
5.5 0.22 2 45.56
i.m.
0.44 5.61 2.65 1.20 1.04 0.74 0.26
5.5 0.22 2 11.41
OTM
2
0.36 2.23 1.91
0.59 6.51 1.91 1.08 0.58 0.55 0.36
5.3 0.21 2 14.92
OTM
3
0.40 1.63 1.81
0.74 15.88 1.72 0.82 0.43 0.88 0.40
5.1 0.20 2 42.85
i.m.
2.81
0.05 1.95
0.27 2.86 14.0 0.36
5.3 0.21 1 8.73
OTM
4
2.18
0.05 1.51
0.27 8.67 12.8 0.46
5.3 0.21 1 21.53
i.m.
1.12
0.77 0.78
1.12 1.64 0.89 0.89
6.1 0.24 1 5.11
OTM
5
0.10 1.38 1.61
0.17 32.73 7.09 1.84 3.80 1.93 0.10
6.0 0.24 2 41.24
i.m.
0.49 2.68 2.32
0.80 1.83 1.40 0.82 0.40 0.44 0.49
5.9 0.24 2 5.42
OTM
6
0.21 1.51 1.72
0.38 20.14 3.35 1.18 1.32 1.31 0.21
5.8 0.23 2 38.41
i.m.
0.75
0.30 22.07 157.49 0.96 1.47 1.24 0.14 1.27† 0.21† 1.51† 1.76
0.22
0.25 8.91 368.5 0.49 1.62 0.51 0.15
38.56 8.66
9.59 3.88* 0.30 2.02* 4.95 0.36 0.33 0.15 0.26
5.6 0.4 0.23 0.02
5.7 0.4 0.23 0.02
0.66 3.59 4.09 0.78 0.67 0.58 0.36 1.33† 0.30† 2.29† 2.21
i.m.
OTM
Mean SD
CA, one- or two-compartmental analysis; AUC0–12, area under the plasma concentration–time curve from 0 to 12 h (time of last quantified point); Tmax, time to maximum plasma concentration; Cmax, maximum plasma concentration; Ka, absorption rate constant; K10, K12, K21, elimination rate constant, rate constant from central to peripheral compartment, and from peripheral to central compartment; t1/2a, absorption half-life; t1/2e, elimination half-life for one-compartmental model; t1/2a, t1/2b, elimination half-life for first and second slope; MRT, mean residence time; *significantly different from i.m. (P < 0.05); †harmonic mean.
Weight (kg) Dose (mg) CA AUC0–12 (ngh/mL) Tmax (h) Cmax (ng/mL) Ka (1/h) K10 (1/h) K12 (1/h) K21 (1/h) t1/2a (h) t1/2e (h) t1/2a (h) t1/2b (h) MRT (h)
Cat Treatment
Table 1. Pharmacokinetic parameters of dexmedetomidine after OTM (oral transmucosal) and i.m. (intramuscular) administration of dexmedetomidine (40 lg/kg) plus buprenorphine (20 lg/kg) in 6 healthy adult cats (individual cats 1–6 and mean SD)
PK dexmedetomidine/buprenorphine in cats 3
4 N. Porters et al.
Buprenorphine (ng/mL)
100
IM OTM
10
1
0.1
0.01
0
3
6
9
12
15
18
21
24
Time (h) Fig. 2. Plasma buprenorphine concentration over time (mean SD) following oral transmucosal (OTM) and intramuscular (i.m.) administration of dexmedetomidine (40 µg/kg) plus buprenorphine (20 µg/kg) in 6 healthy adult cats.
other hand, plasma buprenorphine concentrations following i.m. administration were detected in all cats throughout the whole study. The PK parameters obtained for buprenorphine are shown in Table 2. Norbuprenorphine was not detected in any cat at concentrations above the LOD at any time point. The results show that the PK profile of OTM administration of dexmedetomidine (40 lg/kg)/buprenorphine (20 lg/ kg) in cats is different from the i.m. PK profile of the identical drug combination. The lower AUC, the lower Cmax and the longer Tmax after OTM administration compared with i.m. injection are most likely the result of a combination of a lesser absorption, a loss of drugs by resistance to and/or salivation during OTM administration, and a hepatic firstpass effect of eventually swallowed drugs. Also, a slower absorption of these drugs from the site of OTM administration might be expected due to the vasoconstriction caused by dexmedetomidine, a finding reported previously for medetomidine (Ansah, 2004). In the PD study (Porters et al., 2014a) using the same cats and an identical drug combination, statistical analysis failed to pick up a difference in sedative and analgesic effects between OTM and i.m. administration of dexmedetomidine combined with buprenorphine. Yet, the sedative effect was more distinct after i.m. injection than OTM administration of the premedication in our largescale clinical study in kittens (Porters et al., 2014b). In general, our clinical impression is in accordance with the findings published by Santos et al. (2010), who described a less sedative effect following OTM administration compared with i.m. injection of dexmedetomidine (20 lg/kg) plus buprenorphine (20 lg/kg), and by Giordano et al. (2010), who observed a lower quality postoperative analgesia following OTM administration of buprenorphine (10 lg/kg) compared with i.m. administration.
The results of this PK study should be interpreted in view of strengths and limitations. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to determine plasma concentrations as it selectively distinguishes the parent buprenorphine compound from its metabolites, in contrast to radioimmunoassays (RIA) with cross-reactivity between buprenorphine and its phase I metabolite norbuprenorphine and phase II glucuronide metabolites (Kuhlman et al., 1996). This might partially explain why in the present study different pharmacokinetics was observed after OTM and i.m. administration of buprenorphine, whereas previous studies (in which data were obtained with RIA) (Robertson et al., 2003, 2005) reported similar pharmacokinetics after OTM, i.m. and i.v. administration of buprenorphine. In agreement with our results, a comparable low bioavailability of buprenorphine following OTM administration was observed in a previous study in cats that also used LC-MS/MS to analyse buprenorphine (Hedges et al., 2013a). Besides the use of different analytical methods, the concomitant use of dexmedetomidine may also explain why the PK profile of buprenorphine following OTM administration is not in accordance with the findings of Robertson et al. (2003, 2005). Despite the finding that dexmedetomidine combined with buprenorphine has no influence on the concentration of each drug separately (data not published), the low pH of the combination of the pharmaceutical drug formulations of dexmedetomidine hydrochloride and buprenorphine hydrochloride (pH = 4.383) may have enhanced drug ionization and therefore decreased drug absorption by passive diffusion through lipid membranes. The taste of OTM administered drugs will also influence the degree of absorption. Adverse effects (resentment to administration and salivation) observed in the PD study (Porters et al., 2014a) and the present study are likely to be caused by the preservative 0.135% chlorocresol in Vetergesic Multidoseâ. Hence, preservative-free buprenorphine is preferable for OTM administration to prevent adverse reactions (Bortolami et al., 2012). Careful application is absolutely warranted to minimize the degree of wasting drugs during OTM administration. If drugs are administered via the OTM route to cats, more attention should be paid to the formulation (with or without conservative) and to the tastefulness of the drug candidate. Furthermore, only six experimental cats were involved, but the study design was set up as a crossover trial to filter out cat variation and increase the power of the study. It should also be noticed that jugular venous blood samples were used as well after i.m. as after OTM drug administration. Recently, it has been claimed that arterial blood samples should be used for time–concentration drug profiles after OTM drug administration because blood perfusing the buccal mucosa drains in the jugular vein (Hedges et al., 2013b). Based on this knowledge, our results of the PK profile of dexmedetomidine and buprenorphine following OTM administration may be overestimated, suggesting the real difference between the PK profiles following OTM and i.m. administration to be even more distinct.
© 2014 John Wiley & Sons Ltd
© 2014 John Wiley & Sons Ltd
1.83
1.27 1.27
1.83 0.33 0.55 0.55
6.2 0.12 1 1.61
OTM
i.m.
1.12 77.13 44.51
6.0 0.12 2 27.05 30.34 0.04 1 16.20 21.83 0.38 0.23 0.01 0.32 9 10
1
3
1.83
0.32 1.26
0.85 1.05 2.16 0.55
5.5 0.11 1 2.97
OTM
2
0.91 13.87 6.29
5.5 0.11 2 23.73 27.7 0.13 15.76 31.57 0.57 0.17 0.07 0.02
i.m.
1.48
0.50 1.02
1.01 0.63 1.40 0.68
5.3 0.11 1 1.91
OTM
3
1.36 14.60 13.52
5.1 0.10 2 11.25 17.54 0.44 4.07 6.54 0.23 0.22 0.11 0.11
i.m.
1.84
0.46 1.27
1.06 0.59 1.50 0.54
5.3 0.11 1 1.83
OTM
4
0.81 12.34 12.56
5.3 0.11 2 9.41 15.04 0.09 5.15 45.69 0.31 0.45 0.16 0.02
i.m.
3.28
0.40 2.27
1.21 0.18 1.75 0.31
6.1 0.12 1 0.74
OTM
5
1.14 15.19 9.78
6.0 0.12 2 21.15 27.78 0.09 12.28 48.14 0.38 0.20 0.07 0.01
i.m.
2.36
0.41 1.63
1.09 0.31 1.69 0.42
5.9 0.12 1 1.10
OTM
6
0.80 7.16 4.94
5.8 0.12 2 14.59 18.24 0.16 9.13 21.43 0.55 0.26 0.15 0.03
i.m.
0.34* 0.31* 0.54* 0.13
2.10 0.64*
0.56 0.35* 1.36*,†
1.18 0.52 1.51 0.51
1.69 0.77*
0.99† 13.63*,† 15.27 14.72
7.15 6.55 0.15 5.20 15.90 0.13 0.10 0.05 0.04
5.6 0.4 0.11 0.01
5.7 0.4 0.11 0.01
17.86 22.77 0.15 10.43 29.2 0.40 0.26 0.10 0.03
i.m.
OTM
Mean SD
CA, one- or two-compartmental analysis; AUC0–6/24, area under the plasma concentration–time curve from 0 to 6 h and 24 h (time of last quantified point after OTM and i.m. administration respectively); Tmax, time to maximum plasma concentration; Cmax, maximum plasma concentration; Ka, absorption rate constant; K10, K12, K21, elimination rate constant, rate constant from central to peripheral compartment, and from peripheral to central compartment; t1/2a, absorption half-life; t1/2e, elimination half-life for one-compartmental model; t1/2a, t1/2b, elimination halflife for first and second slope; MRT, mean residence time; *significantly difference between OTM and i.m. (P < 0.05); †harmonic mean.
Weight (kg) Dose (mg) CA AUC0–6 (ngh/mL) AUC0–24 (ngh/mL) Tmax (h) Cmax (ng/mL) Ka (L/h) K10 (L/h) K12 (L/h) K21 (L/h) t1/2a (h) t1/2e (h) t1/2a (h) t1/2b (h) MRT (h)
Cat Treatment
Table 2. Pharmacokinetic parameters of buprenorphine after OTM (oral transmucosal) and (i.m.) intramuscular administration of dexmedetomidine (40 lg/kg) plus buprenorphine (20 lg/kg) in 6 healthy adult cats (individual cats 1–6 and mean SD)
PK dexmedetomidine/buprenorphine in cats 5
6 N. Porters et al.
ACKNOWLEDGMENT The authors thank DoCoLab for providing norbuprenorphine. This research received no grant from any funding agency in the public, commercial or not-for-profit sectors.
REFERENCES Ansah, O.B. (2004) Use of the Alpha-2-Adrenoceptor Agonists Medetomidine and Dexmedetomidine in the Sedation of Analgesia of Domestic Cats, pp. 1–93. Department of Veterinary Clinical Sciences, Clinical Pharmacology – Anaesthesia, University of Helsinki, Helsinki, Finland. Bortolami, E., Slingsby, L. & Love, E.J. (2012) Comparison of two formulations of buprenorphine in cats administered by the oral transmucosal route. Journal of Feline Medicine and Surgery, 14, 534–539. Catbagan, D.L., Quimby, J.M., Mama, K.R., Rychel, J.K. & Mich, P.M. (2011) Comparison of the efficacy and adverse effects of sustainedrelease buprenorphine hydrochloride following subcutaneous administration and buprenorphine hydrochloride following oral transmucosal administration in cats undergoing ovariohysterectomy. American Journal of Veterinary Research, 72, 461–466. Giordano, T., Steagall, P.V., Ferreira, T.H., Minto, B.W., de Sa Lorena, S.E., Brondani, J. & Luna, S.P. (2010) Postoperative analgesic effects of intravenous, intramuscular, subcutaneous or oral transmucosal buprenorphine administered to cats undergoing ovariohysterectomy. Veterinary Anaesthesia and Analgesia, 37, 357–366. Hedges, A.R., Pypendop, B.H., Shilo-Benjamini, Y., Stanley, S.D. & Ilkiw, J.E. (2013a) Pharmacokinetics of buprenorphine following intravenous and buccal administration in cats, and effects on thermal threshold. Journal of Veterinary Pharmacology and Therapeutics, 37, 252–259. Hedges, A.R., Pypendop, B.H., Shilo, Y., Stanley, S.D. & Ilkiw, J.E. (2013b) Impact of the blood sampling site on time–concentration drug profiles following intravenous or buccal drug administration. Journal of Veterinary Pharmacology and Therapeutics, 37, 145–150. Kuhlman, J.J. Jr, Lalani, S., Magluilo, J. Jr, Levine, B. & Darwin, W.D. (1996) Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. Journal of Analytical Toxicology, 20, 369–378.
Porters, N., Bosmans, T., Debille, M., de Rooster, H., Duchateau, L. & Polis, I. (2014a) Sedative and antinociceptive effects of dexmedetomidine and buprenorphine after oral transmucosal or intramuscular administration in cats. Veterinary Anaesthesia and Analgesia, 41, 90– 96. Porters, N., de Rooster, H., Moons, C.P.H., Duchateau, L., Goethals, K., Bosmans, T. & Polis, I. (2014b) Prepubertal gonadectomy in cats: different injectable anaesthetic combinations and comparison with gonadectomy at traditional age. Journal of Feline Medicine and Surgery, 28, pii: 1098612X14546919. [Epub ahead of print]. Proost, J.H. & Meijer, D.K. (1992) MW/Pharm, an integrated software package for drug dosage regimen calculation and therapeutic drug monitoring. Computers in Biology and Medicine, 22, 155–163. Rathbone, M.J., Drummond, B.K. & Tucker, I.G. (1994) The oral cavity as a site for systemic drug delivery. Advanced Drug Delivery Reviews, 13, 1–22. Robertson, S.A., Taylor, P.M. & Sear, J.W. (2003) Systemic uptake of buprenorphine by cats after oral mucosal administration. The Veterinary Record, 152, 675–678. Robertson, S.A., Lascelles, B.D., Taylor, P.M. & Sear, J.W. (2005) PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration. Journal of Veterinary Pharmacology and Therapeutics, 28, 453–460. Santos, L.C., Ludders, J.W., Erb, H.N., Basher, K.L., Kirch, P. & Gleed, R.D. (2010) Sedative and cardiorespiratory effects of dexmedetomidine and buprenorphine administered to cats via oral transmucosal or intramuscular routes. Veterinary Anaesthesia and Analgesia, 37, 417–424. Slingsby, L.S., Taylor, P.M. & Waterman Pearson, A.E. (2006) Efficacy of buccal compared to intramuscular dexmedetomidine for antinociception to a thermal nociceptive stimulus in the cat. Proceedings of the 9th World Congress of Veterinary Anaesthesia, pp. 163, Santos, Brazil. Slingsby, L.S., Taylor, P.M. & Monroe, T. (2009) Thermal antinociception after dexmedetomidine administration in cats: a comparison between intramuscular and oral transmucosal administration. Journal of Feline Medicine and Surgery, 11, 829–834.
© 2014 John Wiley & Sons Ltd
SHORT COMMUNICATION
Pharmacokinetics of oral transmucosal and intramuscular dexmedetomidine combined with buprenorphine in cats N. PORTERS* H. DE ROOSTER* T. BOSMANS* K. BAERT † M. CHERLET † S. CROUBELS ‡ P. DE BACKER ‡ & I. POLIS* *Department of Medicine and Clinical Biology of Small Animals, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium; †Medicem NV, Sint Niklaas, Belgium; ‡Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
Porters, N., de Rooster, H., Bosmans, T., Baert, K., Cherlet, M., Croubels, S., De Backer, P., Polis, I. Pharmacokinetics of oral transmucosal and intramuscular dexmedetomidine combined with buprenorphine in cats. J. vet. Pharmacol. Therap. doi: 10.1111/jvp.12172. Plasma concentrations and pharmacokinetics of dexmedetomidine and buprenorphine after oral transmucosal (OTM) and intramuscular (i.m.) administration of their combination in healthy adult cats were compared. According to a crossover protocol (1-month washout), a combination of dexmedetomidine (40 lg/kg) and buprenorphine (20 lg/kg) was given OTM (buccal cavity) or i.m. (quadriceps muscle) in six female neutered cats. Plasma samples were collected through a jugular catheter during a 24-h period. Plasma dexmedetomidine and buprenorphine concentrations were determined by liquid chromatography–tandem mass spectrometry. Plasma concentration–time data were fitted to compartmental models. For dexmedetomidine and buprenorphine, the area under the plasma concentration–time curve (AUC) and the maximum plasma concentrations (Cmax) were significantly lower following OTM than following i.m. administration. For buprenorphine, time to reach Cmax was also significantly longer after OTM administration than after i.m. injection. Data suggested that dexmedetomidine (40 lg/kg) combined with buprenorphine (20 lg/kg) is not as well absorbed from the buccal mucosa site as from the intramuscular injection site. (Paper received 13 March 2014; accepted for publication 8 September 2014) Ingeborgh Polis, Department of Medicine and Clinical Biology of Small Animals, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium. E-mail: [email protected]
Oral transmucosal (OTM) drug delivery refers to the local and systemic delivery of drugs to or via any oral cavity membrane (Rathbone et al., 1994). In the current study, OTM administration refers to the administration of drugs via the buccal mucosa. It is a painless and often more practical alternative compared with the conventional gastrointestinal and parenteral routes of administration (Rathbone et al., 1994). Recently, there is growing interest in the clinical use of OTM administration of dexmedetomidine (Slingsby et al., 2006, 2009), buprenorphine (Robertson et al., 2003, 2005; Giordano et al., 2010; Catbagan et al., 2011; Bortolami et al., 2012) and the combination of dexmedetomidine and buprenorphine (Santos et al., 2010) in cats. Therefore, our group investigated the sedative, analgesic and adverse effects of the i.m. vs. OTM administration of a dexmedetomidine–buprenorphine combination as premedication for early age neutering in cats (Porters et al., 2014b). To facilitate clinical interpretation of differences in sedative and analgesic effects of this combination following OTM and i.m. administration, a pharmacodynamic (PD) study (Porters et al., 2014a) and the present © 2014 John Wiley & Sons Ltd
pharmacokinetic (PK) study were performed in adult experimental cats. In this study, the pharmacokinetics of the combination of dexmedetomidine (40 lg/kg) and buprenorphine (20 lg/kg) after a single OTM or i.m. administration in healthy adult cats were determined and compared. The study was approved by the Ethical Committee of the Faculty of Veterinary Medicine, Ghent University, Belgium (licence number EC 54/2011). Six purpose-bred neutered female cats with a weight of 5.7 0.4 kg (mean SD) and age of 7.3 0.015 years were used in this study. Cats were considered healthy based on a general physical examination. Food, but not water, was withheld for 12 h before treatment. Seventeen hours prior to treatment, the cats were anesthetized with propofol (4–6 mg/kg Propoflo Plusâ; Abbott Laboratories, Ltd, Queenborough, UK) for placement of a jugular catheter. Treatments were administered in a randomized crossover design with a washout period of 1 month between treatments. The combination of dexmedetomidine hydrochloride (Dexdomitorâ, 0.5 mg/mL; Orion Corporation, Espoo, Finland) 1
2 N. Porters et al.
1
Qiaozhen G., Zhenxia D. (2011). Development of a rapid and simultaneous detection method for buprenorphine, norbuprenorphine and naloxone in human plasma using ultra-high performance liquid chromatography tandem mass spectrometer with solid-phase extraction. Chin. J. Chem., 29, 1922–1926.
2
Commission Decision 2002/657/EC implementing council Directive 96/23/EC concerning the performances of analytical methods and the interpretation of results. Official Journal of the European Communities, No L221, 17.8.2002, Decision of 12 August 2002, European Commission, Directorate General for Public Health and Consumers Protection, 2002/657/EC, 17-08-2002 (SANCO).
the PK analysis. The following PK parameters were calculated: the area under the concentration–time curve (AUC0–t), time to maximal plasma concentration (Tmax), maximal plasma concentration (Cmax), absorption rate constant (Ka), elimination rate constant (K10), rate constant from central to peripheral compartment and peripheral to central compartment (K12 and K21, respectively), absorption half-life (t1/2a), elimination half-life (t1/2e for one-compartmental model, t1/2a and t1/2b for two-compartmental model) and mean residence time (MRT). Descriptive statistical parameters were calculated as mean standard deviation (SD). A Wilcoxon signed-rank test was performed to examine significant differences between the two routes of administration. Values of P < 0.05 were considered significant. Statistical software SPSSâ (SPSS Statistics, Version 20; IBM Corp., Armonk, NY, USA) was used. Cats resisted OTM administration of the dexmedetomidine– buprenorphine combination. Vomiting and salivation were also observed, but not recorded in this study. Observed adverse reactions were comparable to the ones reported in the PD study on the identical drug combination (Porters et al., 2014a). For dexmedetomidine, the mean estimated plasma profiles obtained over time from OTM and i.m. administration are depicted in Fig. 1. After both treatments, plasma dexmedetomidine concentrations were quantified until 12 h in all cats. Pharmacokinetic parameters for dexmedetomidine in cats are summarized in Table 1. For buprenorphine, the mean plasma concentration vs. time curves following OTM and i.m. administration are shown in Fig. 2. Following OTM administration, plasma buprenorphine concentration was first detected at 5 min and remained detectable until 6 h in 5, and until 24 h in 3 of 6 cats. In one cat, however, buprenorphine was first measured at 20 min only and, at 6 h after OTM administration, its concentration fell below the detection threshold. On the
100 IM
Dexmedetomidine (ng/mL)
at 40 lg/kg and buprenorphine hydrochloride (Vetergesic Multidoseâ, 0.3 mg/mL; Alstoe Animal Health Ltd., Hull, UK) at 20 lg/kg was mixed in a syringe immediately before OTM or i.m. administration. Cats were manually restrained while the drugs were administered. OTM administration was performed by inserting the nozzle of a 1-mL syringe into the buccal cavity of the cat’s mouth. Afterwards, the content (volume range from 0.77 to 0.91 mL) was gently squirted into the cheek area. For the i.m. route, a 25-gauge needle was used to inject the drugs (volume range from 0.75 to 0.88 mL) into the quadriceps muscle. Blood samples (2 mL) were collected from the jugular catheter before and at 1, 5, 10, 20, 30 and 60 min, and at 2, 4, 6, 12 and 24 h after drug administration. After each sample, an equal volume of 0.9% saline was injected through the jugular catheter (Robertson et al., 2005). Blood was transferred into heparinized tubes (Vacuetteâ 2 mL Lithium Heparine; Greiner bio one, Kremsmu¨nster, Austria), enrolled in aluminium foil and centrifuged (2000 g) for 10 min within 2 h after sampling (Robertson et al., 2005). Plasma was separated and stored at 80 °C until analysed. Plasma concentrations of dexmedetomidine, buprenorphine and norbuprenorphine, the primary active N-dealkylated metabolite of buprenorphine, were determined using an ultrahigh performance liquid chromatography (UPLC) method combined with tandem mass spectrometric detection. The extraction procedure was adapted from the method described by Qiaozhen and Zhenxia.1 The analytical method was inhouse validated according to criteria given in the EC guidelines.2 For dexmedetomidine, the limit of quantification (LOQ) was 0.025 ng/mL, while for buprenorphine and norbuprenorphine, the LOQ was 0.05 ng/mL. A limit of detection (LOD) of 0.012, 0.016 and 0.023 ng/mL was determined for dexmedetomidine, buprenorphine and norbuprenorphine, respectively. Pharmacokinetic parameters were calculated on an individual basis for each cat following OTM and i.m. treatment. Pharmacokinetic analysis was performed by use of a computer program (MW/PHARM 3.15) (Proost & Meijer, 1992). The individual plasma drug concentration–time data were fitted to a one- or two-compartmental open model. The appropriate model was selected by evaluating correlation of the observed and predicted plasma concentrations and by visual examination of the line fits and the residual plots. Values below the LOQ of the method were not taken into account in
OTM
10
1
0.1
0.01
0
1
2
3
4
5
6
7
8
9
10 11 12
Time (h) Fig. 1. Plasma dexmedetomidine concentration over time (mean SD) following oral transmucosal (OTM) and intramuscular (i.m.) administration of dexmedetomidine (40 µg/kg) plus buprenorphine (20 µg/kg) in 6 healthy adult cats. © 2014 John Wiley & Sons Ltd
© 2014 John Wiley & Sons Ltd
0.76 9 10 1.10
1.58
3.10
0.01 26.30 909.60 0.63
0.72 3.07 3.70 0.32
0.19 2.15
6.0 0.24 1 41.78
i.m.
6.2 0.25 1 11.95
OTM
1
3
0.24 28.68 10.36 0.83 0.31 0.82 0.07 0.46 1.53 1.65
0.26 2.06 2.00
5.5 0.22 2 45.56
i.m.
0.44 5.61 2.65 1.20 1.04 0.74 0.26
5.5 0.22 2 11.41
OTM
2
0.36 2.23 1.91
0.59 6.51 1.91 1.08 0.58 0.55 0.36
5.3 0.21 2 14.92
OTM
3
0.40 1.63 1.81
0.74 15.88 1.72 0.82 0.43 0.88 0.40
5.1 0.20 2 42.85
i.m.
2.81
0.05 1.95
0.27 2.86 14.0 0.36
5.3 0.21 1 8.73
OTM
4
2.18
0.05 1.51
0.27 8.67 12.8 0.46
5.3 0.21 1 21.53
i.m.
1.12
0.77 0.78
1.12 1.64 0.89 0.89
6.1 0.24 1 5.11
OTM
5
0.10 1.38 1.61
0.17 32.73 7.09 1.84 3.80 1.93 0.10
6.0 0.24 2 41.24
i.m.
0.49 2.68 2.32
0.80 1.83 1.40 0.82 0.40 0.44 0.49
5.9 0.24 2 5.42
OTM
6
0.21 1.51 1.72
0.38 20.14 3.35 1.18 1.32 1.31 0.21
5.8 0.23 2 38.41
i.m.
0.75
0.30 22.07 157.49 0.96 1.47 1.24 0.14 1.27† 0.21† 1.51† 1.76
0.22
0.25 8.91 368.5 0.49 1.62 0.51 0.15
38.56 8.66
9.59 3.88* 0.30 2.02* 4.95 0.36 0.33 0.15 0.26
5.6 0.4 0.23 0.02
5.7 0.4 0.23 0.02
0.66 3.59 4.09 0.78 0.67 0.58 0.36 1.33† 0.30† 2.29† 2.21
i.m.
OTM
Mean SD
CA, one- or two-compartmental analysis; AUC0–12, area under the plasma concentration–time curve from 0 to 12 h (time of last quantified point); Tmax, time to maximum plasma concentration; Cmax, maximum plasma concentration; Ka, absorption rate constant; K10, K12, K21, elimination rate constant, rate constant from central to peripheral compartment, and from peripheral to central compartment; t1/2a, absorption half-life; t1/2e, elimination half-life for one-compartmental model; t1/2a, t1/2b, elimination half-life for first and second slope; MRT, mean residence time; *significantly different from i.m. (P < 0.05); †harmonic mean.
Weight (kg) Dose (mg) CA AUC0–12 (ngh/mL) Tmax (h) Cmax (ng/mL) Ka (1/h) K10 (1/h) K12 (1/h) K21 (1/h) t1/2a (h) t1/2e (h) t1/2a (h) t1/2b (h) MRT (h)
Cat Treatment
Table 1. Pharmacokinetic parameters of dexmedetomidine after OTM (oral transmucosal) and i.m. (intramuscular) administration of dexmedetomidine (40 lg/kg) plus buprenorphine (20 lg/kg) in 6 healthy adult cats (individual cats 1–6 and mean SD)
PK dexmedetomidine/buprenorphine in cats 3
4 N. Porters et al.
Buprenorphine (ng/mL)
100
IM OTM
10
1
0.1
0.01
0
3
6
9
12
15
18
21
24
Time (h) Fig. 2. Plasma buprenorphine concentration over time (mean SD) following oral transmucosal (OTM) and intramuscular (i.m.) administration of dexmedetomidine (40 µg/kg) plus buprenorphine (20 µg/kg) in 6 healthy adult cats.
other hand, plasma buprenorphine concentrations following i.m. administration were detected in all cats throughout the whole study. The PK parameters obtained for buprenorphine are shown in Table 2. Norbuprenorphine was not detected in any cat at concentrations above the LOD at any time point. The results show that the PK profile of OTM administration of dexmedetomidine (40 lg/kg)/buprenorphine (20 lg/ kg) in cats is different from the i.m. PK profile of the identical drug combination. The lower AUC, the lower Cmax and the longer Tmax after OTM administration compared with i.m. injection are most likely the result of a combination of a lesser absorption, a loss of drugs by resistance to and/or salivation during OTM administration, and a hepatic firstpass effect of eventually swallowed drugs. Also, a slower absorption of these drugs from the site of OTM administration might be expected due to the vasoconstriction caused by dexmedetomidine, a finding reported previously for medetomidine (Ansah, 2004). In the PD study (Porters et al., 2014a) using the same cats and an identical drug combination, statistical analysis failed to pick up a difference in sedative and analgesic effects between OTM and i.m. administration of dexmedetomidine combined with buprenorphine. Yet, the sedative effect was more distinct after i.m. injection than OTM administration of the premedication in our largescale clinical study in kittens (Porters et al., 2014b). In general, our clinical impression is in accordance with the findings published by Santos et al. (2010), who described a less sedative effect following OTM administration compared with i.m. injection of dexmedetomidine (20 lg/kg) plus buprenorphine (20 lg/kg), and by Giordano et al. (2010), who observed a lower quality postoperative analgesia following OTM administration of buprenorphine (10 lg/kg) compared with i.m. administration.
The results of this PK study should be interpreted in view of strengths and limitations. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to determine plasma concentrations as it selectively distinguishes the parent buprenorphine compound from its metabolites, in contrast to radioimmunoassays (RIA) with cross-reactivity between buprenorphine and its phase I metabolite norbuprenorphine and phase II glucuronide metabolites (Kuhlman et al., 1996). This might partially explain why in the present study different pharmacokinetics was observed after OTM and i.m. administration of buprenorphine, whereas previous studies (in which data were obtained with RIA) (Robertson et al., 2003, 2005) reported similar pharmacokinetics after OTM, i.m. and i.v. administration of buprenorphine. In agreement with our results, a comparable low bioavailability of buprenorphine following OTM administration was observed in a previous study in cats that also used LC-MS/MS to analyse buprenorphine (Hedges et al., 2013a). Besides the use of different analytical methods, the concomitant use of dexmedetomidine may also explain why the PK profile of buprenorphine following OTM administration is not in accordance with the findings of Robertson et al. (2003, 2005). Despite the finding that dexmedetomidine combined with buprenorphine has no influence on the concentration of each drug separately (data not published), the low pH of the combination of the pharmaceutical drug formulations of dexmedetomidine hydrochloride and buprenorphine hydrochloride (pH = 4.383) may have enhanced drug ionization and therefore decreased drug absorption by passive diffusion through lipid membranes. The taste of OTM administered drugs will also influence the degree of absorption. Adverse effects (resentment to administration and salivation) observed in the PD study (Porters et al., 2014a) and the present study are likely to be caused by the preservative 0.135% chlorocresol in Vetergesic Multidoseâ. Hence, preservative-free buprenorphine is preferable for OTM administration to prevent adverse reactions (Bortolami et al., 2012). Careful application is absolutely warranted to minimize the degree of wasting drugs during OTM administration. If drugs are administered via the OTM route to cats, more attention should be paid to the formulation (with or without conservative) and to the tastefulness of the drug candidate. Furthermore, only six experimental cats were involved, but the study design was set up as a crossover trial to filter out cat variation and increase the power of the study. It should also be noticed that jugular venous blood samples were used as well after i.m. as after OTM drug administration. Recently, it has been claimed that arterial blood samples should be used for time–concentration drug profiles after OTM drug administration because blood perfusing the buccal mucosa drains in the jugular vein (Hedges et al., 2013b). Based on this knowledge, our results of the PK profile of dexmedetomidine and buprenorphine following OTM administration may be overestimated, suggesting the real difference between the PK profiles following OTM and i.m. administration to be even more distinct.
© 2014 John Wiley & Sons Ltd
© 2014 John Wiley & Sons Ltd
1.83
1.27 1.27
1.83 0.33 0.55 0.55
6.2 0.12 1 1.61
OTM
i.m.
1.12 77.13 44.51
6.0 0.12 2 27.05 30.34 0.04 1 16.20 21.83 0.38 0.23 0.01 0.32 9 10
1
3
1.83
0.32 1.26
0.85 1.05 2.16 0.55
5.5 0.11 1 2.97
OTM
2
0.91 13.87 6.29
5.5 0.11 2 23.73 27.7 0.13 15.76 31.57 0.57 0.17 0.07 0.02
i.m.
1.48
0.50 1.02
1.01 0.63 1.40 0.68
5.3 0.11 1 1.91
OTM
3
1.36 14.60 13.52
5.1 0.10 2 11.25 17.54 0.44 4.07 6.54 0.23 0.22 0.11 0.11
i.m.
1.84
0.46 1.27
1.06 0.59 1.50 0.54
5.3 0.11 1 1.83
OTM
4
0.81 12.34 12.56
5.3 0.11 2 9.41 15.04 0.09 5.15 45.69 0.31 0.45 0.16 0.02
i.m.
3.28
0.40 2.27
1.21 0.18 1.75 0.31
6.1 0.12 1 0.74
OTM
5
1.14 15.19 9.78
6.0 0.12 2 21.15 27.78 0.09 12.28 48.14 0.38 0.20 0.07 0.01
i.m.
2.36
0.41 1.63
1.09 0.31 1.69 0.42
5.9 0.12 1 1.10
OTM
6
0.80 7.16 4.94
5.8 0.12 2 14.59 18.24 0.16 9.13 21.43 0.55 0.26 0.15 0.03
i.m.
0.34* 0.31* 0.54* 0.13
2.10 0.64*
0.56 0.35* 1.36*,†
1.18 0.52 1.51 0.51
1.69 0.77*
0.99† 13.63*,† 15.27 14.72
7.15 6.55 0.15 5.20 15.90 0.13 0.10 0.05 0.04
5.6 0.4 0.11 0.01
5.7 0.4 0.11 0.01
17.86 22.77 0.15 10.43 29.2 0.40 0.26 0.10 0.03
i.m.
OTM
Mean SD
CA, one- or two-compartmental analysis; AUC0–6/24, area under the plasma concentration–time curve from 0 to 6 h and 24 h (time of last quantified point after OTM and i.m. administration respectively); Tmax, time to maximum plasma concentration; Cmax, maximum plasma concentration; Ka, absorption rate constant; K10, K12, K21, elimination rate constant, rate constant from central to peripheral compartment, and from peripheral to central compartment; t1/2a, absorption half-life; t1/2e, elimination half-life for one-compartmental model; t1/2a, t1/2b, elimination halflife for first and second slope; MRT, mean residence time; *significantly difference between OTM and i.m. (P < 0.05); †harmonic mean.
Weight (kg) Dose (mg) CA AUC0–6 (ngh/mL) AUC0–24 (ngh/mL) Tmax (h) Cmax (ng/mL) Ka (L/h) K10 (L/h) K12 (L/h) K21 (L/h) t1/2a (h) t1/2e (h) t1/2a (h) t1/2b (h) MRT (h)
Cat Treatment
Table 2. Pharmacokinetic parameters of buprenorphine after OTM (oral transmucosal) and (i.m.) intramuscular administration of dexmedetomidine (40 lg/kg) plus buprenorphine (20 lg/kg) in 6 healthy adult cats (individual cats 1–6 and mean SD)
PK dexmedetomidine/buprenorphine in cats 5
6 N. Porters et al.
ACKNOWLEDGMENT The authors thank DoCoLab for providing norbuprenorphine. This research received no grant from any funding agency in the public, commercial or not-for-profit sectors.
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