Pharmacokinetics and pharmacodynamics of intramuscular dexmedetomidine in dogs

Turi K. Aarnes Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH

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Brian T. Dent Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH

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Jeffrey Lakritz Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH

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Butch KuKanich Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS

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Vincent A. Wavreille Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH

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Phillip Lerche Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH

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Carolina H. Ricco Pereira Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH

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Richard M. Bednarski Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH

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Abstract

OBJECTIVE

To determine the pharmacokinetics and pharmacodynamics of dexmedetomidine after IM administration in dogs.

ANIMALS

6 healthy adult purpose-bred dogs (3 males, 3 females) with a mean ± SD body weight of 25.2 ± 1.8 kg.

PROCEDURES

Each dog received 10 µg/kg dexmedetomidine, IM. Heart rate and respiratory rate were counted via cardiac auscultation and visual assessment of chest excursions. Sedation was assessed utilizing 2 sedation scoring systems. Plasma concentrations were determined using ultra performance liquid chromatography–mass spectrometry. Plasma concentrations versus time data after IM dexmedetomidine were analyzed using noncompartmental analysis for extravascular administration.

RESULTS

Over the first 2 hours following IM injection of dexmedetomidine, plasma concentrations fluctuated in each dog. The geometric mean (range) maximum plasma concentration was 109.2 (22.4 to 211.5) ng/mL occurring at 20.5 (5 to 75) minutes, and the mean half-life was 25.5 (11.5 to 41.5) minutes. Heart rate was significantly lower than baseline from 30 minutes to 2 hours postdexmedetomidine administration, and respiratory rate was significantly lower than baseline from 45 minutes to 1.75 hours. Dogs were significantly more sedated from 30 minutes to 1.5 hours postdexmedetomidine administration. Median time to onset of sedation was 7.5 minutes (range, 2 to 10 minutes), and median time to peak sedation was 30 minutes (range, 15 to 60 minutes).

CLINICAL RELEVANCE

Variations in plasma concentrations occurred in all dogs for the 2 hours postinjection of dexmedetomidine at 10 µg/kg, IM. This was likely due to alterations in absorption due to dexmedetomidine-induced local vasoconstriction. Despite variable plasma concentrations, all dogs were sedated following IM dexmedetomidine administration.

Abstract

OBJECTIVE

To determine the pharmacokinetics and pharmacodynamics of dexmedetomidine after IM administration in dogs.

ANIMALS

6 healthy adult purpose-bred dogs (3 males, 3 females) with a mean ± SD body weight of 25.2 ± 1.8 kg.

PROCEDURES

Each dog received 10 µg/kg dexmedetomidine, IM. Heart rate and respiratory rate were counted via cardiac auscultation and visual assessment of chest excursions. Sedation was assessed utilizing 2 sedation scoring systems. Plasma concentrations were determined using ultra performance liquid chromatography–mass spectrometry. Plasma concentrations versus time data after IM dexmedetomidine were analyzed using noncompartmental analysis for extravascular administration.

RESULTS

Over the first 2 hours following IM injection of dexmedetomidine, plasma concentrations fluctuated in each dog. The geometric mean (range) maximum plasma concentration was 109.2 (22.4 to 211.5) ng/mL occurring at 20.5 (5 to 75) minutes, and the mean half-life was 25.5 (11.5 to 41.5) minutes. Heart rate was significantly lower than baseline from 30 minutes to 2 hours postdexmedetomidine administration, and respiratory rate was significantly lower than baseline from 45 minutes to 1.75 hours. Dogs were significantly more sedated from 30 minutes to 1.5 hours postdexmedetomidine administration. Median time to onset of sedation was 7.5 minutes (range, 2 to 10 minutes), and median time to peak sedation was 30 minutes (range, 15 to 60 minutes).

CLINICAL RELEVANCE

Variations in plasma concentrations occurred in all dogs for the 2 hours postinjection of dexmedetomidine at 10 µg/kg, IM. This was likely due to alterations in absorption due to dexmedetomidine-induced local vasoconstriction. Despite variable plasma concentrations, all dogs were sedated following IM dexmedetomidine administration.

Dexmedetomidine is an α2-adrenergic agonist commonly used to provide sedation and analgesia in dogs and cats. It has been evaluated in other veterinary species, and it is also used in human medicine for anxiolysis, sedation, sympatholytic, and analgesic effects.1 The sedative effects are dose dependent, and onset has been reported as a median of 1 minute following IV administration and a median of 30 minutes following oral transmucosal administration in dogs.2 Dexmedetomidine administration results in peripheral vasoconstriction due to its effects on the α2-receptor and bradycardia due to a centrally mediated effect and a baroreceptor reflex.3

Intramuscular administration of dexmedetomidine has been investigated in humans and resulted in pharmacodynamics that were linearly correlated to plasma concentrations based on dosage, while dosage had no effect on absorption and elimination.4 Pharmacokinetics of dexmedetomidine in dogs following IM administration have been determined but only in conjunction with other drugs such as methadone, morphine, and maropitant.5,6 To the authors’ knowledge, the pharmacokinetics of IM dexmedetomidine alone in dogs have not been reported.

The objective of our study was to evaluate the pharmacokinetics of dexmedetomidine in dogs following IM administration of 10 µg/kg and to determine its effects on heart rate, respiratory rate, and sedation. Our hypothesis was that the pharmacokinetics of IM dexmedetomidine would be characterized by a rapid absorption phase and a short elimination phase. Additionally, we expected that heart rate and respiratory rate would decrease, and sedation would increase with increasing plasma concentrations of dexmedetomidine.

Materials and Methods

Animals

Six adult purpose-bred dogs (3 females and 3 males) with a mean age of 9.2 ± 1.5 months and a mean body weight of 25.2 ± 1.8 kg were housed individually or in group housing by sex. Food was withheld approximately 12 hours prior to drug administration. A physical examination, complete blood cell count, serum biochemistry profile, and fecal analysis were evaluated prior to the start of the study. The study was approved by the Institutional Animal Care and Use Committee of The Ohio State University (2017A00000039).

Drug administration and sample collection

At least 2 hours prior to drug administration, a 20-gauge 20-cm catheter (Mila International, Inc) was placed aseptically in a lateral saphenous vein for collection of blood samples. Catheters were flushed with heparinized saline to maintain patency. Catheters were capped and covered with a bandage until just prior to dexmedetomidine administration. Drug administration was performed by the same investigator (TKA).

This study was completed in conjunction with another study2 evaluating dexmedetomidine administered intravenously or oral transmucosal. Seven milliliters of blood were collected prior to (baseline, t = 0) and at 5, 10, 15, 30, 45, 60, 75, 90, and 105 minutes and 2, 4, 8, 12, and 24 hours after administration of 10 µg/kg dexmedetomidine (Dexdomitor; Zoetis Inc) into the epaxial muscle on the side opposite of the leg in which the catheter had been placed. Blood samples were placed in evacuated glass tubes containing heparin, stored on ice, and centrifuged within 1 hour of collection at 4,000 X g for 10 minutes. Plasma was separated and frozen at −70°C until analysis.

Pharmacodynamic evaluations were recorded prior to dexmedetomidine administration and immediately prior to each sampling time point in the same order by the same investigator (BTD). First, sedation was evaluated using the Vettorato Sedation Score, which evaluates response to physical and auditory stimuli, and the Composite Sedation Score, which evaluates body position and responses to auditory stimuli.7,8 Second, respiratory rate was evaluated by counting chest excursion over a 15-second period. Finally, the heart rate was determined by cardiac auscultation over a 15-second period. During the first 12 hours, dogs were allowed free access to a room supervised by the investigators, at which point they returned to individual or group housing.

Drug analysis

Plasma concentrations of dexmedetomidine were determined using ultraperformance liquid chromatography–mass spectrometry as previously described.2 The samples were analyzed in conjunction with another study. As previously reported, the accuracy and precision of the assay were determined on replicates of 5 at each concentration. The accuracy at 10, 25, and 50 ng/mL was 9.8, 5.4, and 1.1%, respectively. The precision (coefficient of variation) at 10, 25, and 50 ng/mL was 2, 2, and 1%, respectively. The level of detection was < 0.1 ng/mL (signal/noise = 47 at 1 ng/mL), but the accuracy was greater than ± 20%. The level of quantification was 0.25 ng/mL (signal/noise = 96) with accuracy less than or equal to ± 15%.

Data analysis

Plasma concentration versus time data after IM dexmedetomidine were analyzed using noncompartmental analysis for extravascular administration (Phoenix-WinNonlin version 6.4; Certara). Plasma concentration data were weighted 1/C where C is the actual plasma dexmedetomidine concentration. Peak plasma dexmedetomidine (Cmax) and time of maximum concentration (tmax) were taken from the individual animal’s concentration versus time data. The AUC from time = 0 to infinity with extrapolation of the terminal phase was calculated using the log-linear trapezoidal method (AUCINFobs). The rate constant associated with the terminal portion of the concentration versus time curve (λz) was estimated by log-linear regression of time versus log concentration using the last 3 plasma concentrations above the lower limit of quantitation for each animal. The terminal phase half-life (HLz) was calculated by ln2/λz. The percentage of the AUC after IM dexmedetomidine administration extrapolated to infinity was estimated by dividing the last quantifiable drug concentration by λz (AUC%Extrapobs). The area under the moment curve from time = 0 to the time of the last quantifiable drug concentration and extrapolated to infinity and the mean residence time of dexmedetomidine were also calculated. Pharmacokinetic parameters were tabulated for each animal and are reported as geometric mean and range.

Statistical analysis

Heart rate and respiratory rate were examined for normal distribution using the D’Agostino-Pearson test; the data were not normally distributed and were analyzed using the Kruskal Wallis test with a Dunn posttest comparing each time point to baseline. Sedation scores were also analyzed using the Kruskal-Wallis test with a Dunn posttest comparing each time point to baseline. P values < 0.05 were considered statistically significant.

Results

Dexmedetomidine was detectable in plasma 5 minutes after injection of a 10-µg/kg dosage into the epaxial muscles. Individual variations in plasma concentrations in each dog occurred, with plasma concentrations higher at the 5-minute time point followed by a decreased plasma concentration 5 minutes later in one dog compared with other dogs with increasing plasma concentrations at each timepoint up to 30 minutes followed by variable plasma concentrations up to the 2-hour time point (Figure 1).

Figure 1
Figure 1

Plasma concentrations of dexmedetomidine versus time after IM administration of dexmedetomidine at a dosage of 10 µg/kg to 6 healthy dogs.

Citation: American Journal of Veterinary Research 84, 4; 10.2460/ajvr.22.10.0184

The geometric mean (range) maximum plasma concentration (Cmax) was 109.2 (22.4 to 211.5) ng/mL occurring at 20.5 (5.0 to 75.0) minutes (tmax). The last quantifiable concentration was 5.5 (0.6 to 26.3) ng/mL, which occurred at 4 hours in 5 of the 6 dogs; the last quantifiable concentration in the sixth dog occurred at the 2-hour time point. The half-life was 25.5 (11.5 to 41.5) minutes (Table 1).

Table 1

Geometric mean (range) results of noncompartmental analysis of plasma concentrations of dexmedetomidine after IM administration of 10 µg/kg to 6 healthy dogs.

Parameter
Rsq 0.954 (0.954–0.996)
λz (1/min) 0.027 (0.016–0.06)
HLz (min) 25.5 (11.5–41.5)
tmax (min) 20.5 (5.0–75.0)
Cmax (ng/mL) 109.2 (22.4–211.5)
tlast (min) 220 (120–240)
Clast (ng/mL) 5.5 (0.6–26.3)
AUCINFobs (min·ng/mL) 5,720 (1,569–11,752)
AUC%Extrapobs (%) 1.2 (0.4–4.8)
AUMCINFobs (min·min·ng/mL) 402,838 (135,218–794,127)
MRTINFobs (min) 70.4 (54.4–86.2)

λz = Elimination rate constant. AUC% Extrapobs = Percentage of the AUC that was extrapolated. AUCINFobs = Area under the concentration-time curve from time zero to ∞, with extrapolation of the terminal phase; time 0 was the time at which dexmedetomidine was administered; AUMCINFobs = Area under the moment curve from time 0 to ∞, with extrapolation of the terminal phase; time 0 was the time at which dexmedetomidine was administered. Clast = Last observed quantifiable concentration. Cmax = Maximum plasma concentration. HLz = Half-life of the terminal phase. MRTINFobs = Mean residence time of dexmedetomidine molecules. Rsq = Coefficient of determination. tlast = Time postadministration of the last analytically quantifiable concentration. tmax = Time of the maximum plasma concentration.

Heart rate was significantly lower than baseline from 30 minutes to 2 hours postdexmedetomidine administration and respiratory rate was significantly lower than baseline from 45 minutes to 1.75 hours (Table 2). Dogs were significantly more sedate using both sedation-scoring systems from 30 minutes to 1.5 hours postdexmedetomidine administration. Initial signs of sedation occurred within 10 minutes in all dogs, with a median time to onset of sedation of 7.5 minutes (range, 2.0 to 10.0 minutes) and median time to peak sedation of 30 minutes (range, 15 to 60 minutes).

Table 2

Median (range) values for cardiopulmonary variables and sedation scores before and after IM administration of dexmedetomidine at a dosage of 10 µg/kg to 6 healthy dogs.

Time Heart rate (beats/min) Respiratory rate (beats/min) Vettorato sedation score Composite sedation score
0 min 92 (92–100) 24 (20–28) 0 (0–0) 0 (0–0)
5 min 58 (44–64) 20 (16–24) 1 (0–3) 1 (0–8)
10 min 48 (40–52) 16 (12–20) 1 (1–3) 2 (1–10)
15 min 45 (40–52) 16 (12–20) 3 (2–3) 6 (3–11)
30 min 36 (32–40)* 14 (12–16) 3 (3–3)* 9 (7–11)*
45 min 34 (32–40)* 12 (8–16)* 3 (3–3)* 9 (8–11)*
1 h 34 (32–40)* 12 (12–12)* 3 (3–3)* 10 (8–11)*
1.25 h 38 (36–40)* 14 (8–16)* 3 (3–3)* 9 (7–11)*
1.5 h 36 (32–40)* 12 (8–16)* 3 (3–3)* 9 (8–10)*
1.75 h 38 (32–44)* 12 (12–20)* 3 (1–3) 7 (2–9)
2 h 38 (32–44)* 12 (12–20) 3 (2–3) 8 (3–9)
4 h 48 (40–64) 18 (12–20) 1 (0–1) 1 (0–2)
8 h 64 (52–84) 20 (12–24) 0 (0–0) 0 (0–0)
12 h 70 (52–80) 22 (16–24) 0 (0–0) 0 (0–0)
24 h 80 (72–92) 20 (16–24) 0 (0–0) 0 (0–0)
*

Value is significantly (P < 0.05) different from the baseline value for the same variable.

Discussion

Dexmedetomidine absorption after IM administration of 10 µg/kg demonstrated rapid absorption and a short half-life, consistent with other studies4,6,913 in dogs, cats, and humans at dosages between 0.5 and 40 µg/kg IM. The Cmax in our study is more than 10 times that in the study of DiCesare et al6 despite administration of the same dosage of dexmedetomidine, and the half-life in our study was more than 50% shorter than the study of DiCesare et al. Coadministration of methadone would not be expected to impact absorption following IM administration unless the combination impacted the vasoconstrictive effect of dexmedetomidine. In the study of DiCesare et al, the half-life may have been prolonged due to the effects of general anesthesia, but the tmax in our study was 20.5 minutes compared with 20 minutes in the study of DiCesare et al,6 which occurred prior to anesthetic induction. Additionally, in the study of DiCesare et al, dexmedetomidine and methadone were mixed in the same syringe, which affected the concentration of dexmedetomidine and could have affected other properties of the solution such as pH or tonicity, which may have affected drug absorption. It is also possible the differences may be due to random variability. A crossover study assessing the pharmacokinetics of dexmedetomidine alone and in combination with methadone, along with the effects of concentration, pH, and tonicity, would need to be performed to tease out the potential differences.

The assay only measured the plasma concentrations of dexmedetomidine but did not measure whole blood concentrations. It is possible that dexmedetomidine may have become partitioned in red blood cells following its absorption due to the presence of α2-receptors in red blood cells, which could have affected the perceived Cmax and tmax if substantial and rapid partitioning into red blood cells occurred. Red blood cell partitioning has been demonstrated following romifidine administration in horses.14

Previous studies of α2-agonists following IM administration in other species indicated similar patterns of variable plasma concentrations in the first 60 minutes following administration. Peak plasma concentrations of detomidine occurred at 0.5 hours in the horse and 0.26 hours in the cow, with marked variation in individual animals.15 A study16 of guinea pigs and evaluation of skin blood flow demonstrated significantly decreased skin blood flow in areas injected with dexmedetomidine, likely due to α2-receptor-mediated peripheral vasoconstriction. This vasoconstriction can result in prolongation of the rate of absorption.

Since the Cmax was higher and the half-life of dexmedetomidine was shorter in this study compared to the study of DiCesare et al,6 it is possible that the volume of distribution for dexmedetomidine was smaller in the dogs in the study reported here. The Cmax is inversely proportional to the volume of distribution (eg, a higher Cmax occurs with a smaller volume of distribution), and the half-life is proportional to the volume of distribution (eg, a shorter half-life occurs with a smaller volume of distribution) and inversely proportional to clearance.

In these dogs, mean tmax and Cmax did not occur at the time of median peak sedation scores. In individual dogs, tmax and Cmax were also independent of peak sedation scores. The time to peak sedation following IM administration of 10 µg/kg was consistent with previous reports6,10 in dogs following IM administration of 5 µg/kg and IM administration of dexmedetomidine (10 µg/kg) combined with 0.4 mg/kg methadone. Similar to our findings, heart rate and respiratory rate have been reported to be inversely correlated with peak plasma concentrations similarly following oral transmucosal and IV administration in dogs.2

There are several limitations of the current study. We did not measure blood pressure or cardiac output in the study reported here, which would have elucidated the full range of cardiovascular impact of dexmedetomidine and perhaps allowed us to correlate the variable plasma concentrations with changes in vascular tone. We also did not evaluate any dexmedetomidine metabolites in plasma or urine to quantify the metabolism and excretion in temporal relation to absorption. We only examined a single dose of IM dexemedetomidine; additional investigation of other dosages would be needed to determine whether pharmacokinetics are independent of dose and a comparison to IV pharmacokinetics would allow for calculation of bioavailability. Additionally, dexmedetomidine was administered into the epaxial muscles; therefore, differences in IM injection location were not determined.

Administration of dexmedetomidine IM resulted in predictable sedation and cardiorespiratory effects despite erratic plasma concentrations.

Acknowledgments

This work was supported by a grant from Canine Research Funds of The Ohio State University.

The authors declare there were no conflicts of interest.

The authors acknowledge Dr. Michael Lovasz and Dr. John Hubbell for their assistance with the collection of pilot data that made this study possible.

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