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Pharmacokinetics and interaction pharmacodynamics of dexmedetomidine in humans
BaillieÁre's Clinical Anaesthesiology Vol. 14, No. 2, pp. 261±269, 2000
doi:10.1053/bean.2000.0081, available online at http://www.idealibrary.com on
3 Pharmacokinetics and interaction pharmacodynamics of dexmedetomidine in humans Michael D. Karol
PhD
Section Manager, Clinical Pharmacokinetics D-4PK, Ap13A-3, Abbott Laboratories, 100 Abbot Park Rd, Abbott Park, IL 60064-6104, USA
Mervyn Maze
MB, ChB, FRCP, FRCA
Magill Professor of Anaesthetics; Head, Department of Anaesthetics, and Intensive Care; Vice-Chair, Division of Surgery, Anaesthetics and Intensive Care Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
Dexmedetomidine is a potent and highly selective a2-adrenoceptor agonist with a selectivity ratio of 1600:1 (a2 :a1). Dexmedetomidine is a highly lipophylic agent that is rapidly distributed to tissues with a distribution half-life (t1/2a) of approximately 6 minutes. It is extensively distributed and rapidly eliminated, with a mean elimination half-life (t1/2) of 2±2.5 hours. This rapid distribution and short elimination kinetics makes dexmedetomidine amenable to frequent titration allowing adjustability of dosage and eects. Generally, dexmedetomidine does not exhibit pharmacokinetic-based interactions; however, dosage modi®cations of some concomitant medications may be needed to be adjusted due primarily to common pharmacological actions of the two drugs. Dexmedetomidine is eliminated by metabolism to inactive metabolites, primarily glucuronides. Eighty to ninety percent of an administered dose is excreted in the urine and 5%±13% in the faeces. Key words: dexmedetomidine; a2-adrenergic agonist; pharmacokinetics; pharmacodynamics.
Dexmedetomidine, the pharmacologically active d-enantiomer of medetomidine (Figure 1)1,2, is formulated as dexmedetomidine hydrochloride, a clear, colourless, isotonic solution with a pH of 4.5±7.0. The solution is preservative-free and contains no additives or chemical stabilizers.3 Because of its a2-adrenoceptor agonist properties, dexmedetomidine has a broad range of pharmacological properties, including sedation associated with arousability and orientation without respiratory depression. Additional properties include analgesia, anxiolysis, haemodynamic stability, anti-shivering eects, reduced nausea and vomiting, and anaesthetic-sparing eects.4,5 PHARMACOKINETICS Dexmedetomidine pharmacokinetics have been estimated following diverse intravenous administration regimens, resulting in a variety of concentration versus time 1521±6896/00/02026109 $35.00/00
c 2000 Harcourt Publishers Ltd. *
262 M. D. Karol and M. Maze
H
CH3
CH3 CH3
N
N H
3
H
Figure 1. Structure of dexmedetomidine.
Table 1. Dexmedetomidine pharmacokinetic summary.
Mean SD CV% Max. Min. n
CL (l/h)
CL (l/h/kg)
t1/2 * (h)
b (l/h)
Vss (l)
Vss (l/kg)
39.4 10.1 26 77.8 15.0 276
0.53 0.14 26 1.01 0.23 276
2.1 0.49 24 7.3 0.97 258
0.33 0.08 24 0.71 0.10 258
97.3 29.3 30 225 29.0 258
1.31 0.37 28 3.09 0.61 258
* Harmonic mean and pseudo-standard deviation presented. CL clearance; t1/2 half-life; Vss steady-state volume of distribution; CV coecient of variance.
exposure pro®les. Table 1 summarizes the pharmacokinetics of dexmedetomidine. Dexmedetomidine clearance is approximately constant within the anticipated therapeutic range, resulting in dose proportionality. However, in a maximum tolerated dose study, including concentrations 13 times the upper limit of the anticipated therapeutic range, a diminished clearance was noted of about 20% at dexmedetomidine concentrations well above the desired therapeutic range.6 Dexmedetomidine exhibits a rapid distribution phase, the central estimate of the distribution half-life (t1/2a) being about 6 minutes. The central estimate (the estimate in the central compartment) of the terminal elimination half-life (t1/2) is approximately 2.0±2.5 hours, and the central estimate of the steady-state volume of distribution (Vss) approximately 97 + 29 litres. Clearance, the pharmacokinetic parameter that relates infusion rate to steady-state concentration, has a central estimated value of about 39 + 10 litres/h. Body build description has been shown to be a signi®cant factor, and dexmedetomidine dosing in most studies has been done on a mg/kg basis. The mean body weight associated with this clearance estimate was 75 kg.7
Pharmacokinetics and pharmacodynamics of dexmedetomidine 263
Overall, the variability in dexmedetomidine clearance (CL) and t1/2 was relatively low, with a coecient of variance (CV) of only 26% and 24% respectively. Dexmedetomidine pharmacokinetics (CL, Cmax , Tmax , Vss , b and area under the curve (AUC)) were no dierent between young, middle-aged and elderly adult subjects, or between males and females. A given dexmedetomidine infusion, where dosing is per kilogram of body weight, is thus expected to produce the same dexmedetomidine concentration irrespective of age or gender.8 Pharmacokinetics in organ failure Dexmedetomidine pharmacokinetics (Tmax , Cmax , AUC, t1/2 , CL and Vss) do not dier between subjects with severe renal impairment and normal healthy subjects. The possible impact of renal impairment on the protein binding of dexmedetomidine was assessed in a separate study including plasma from normal subjects and subjects with mild, moderate and severe renal impairment. There were no signi®cant dierences in protein binding between the four renal function groups.9 Accordingly, for a given administration regimen, the pharmacokinetic pro®le of dexmedetomidine is expected to be independent of the patient's renal function.10 The eect of hepatic impairment on dexmedetomidine pharmacokinetics was assessed in a phase I, two-centre, open-label, single-period, single-dose study in which normal healthy subjects and subjects with mild, moderate and severe hepatic impairment received dexmedetomidine.11 Dexmedetomidine plasma protein binding was statistically signi®cantly decreased in subjects with hepatic impairment compared with healthy subjects. Clearance values were lower in subjects with hepatic impairment than in healthy subjects.12 The mean CL values for subjects with mild, moderate and severe hepatic impairment were 74%, 64% and 53% respectively of those observed in the normal healthy subjects. Compared with the subjects with normal hepatic function (a mean t1/2 of 2.5 hours), the mean t1/2 for the subjects with mild, moderate or severe hepatic impairment was prolonged to 3.9, 5.4 and 7.4 hours respectively. The dose of dexmedetomidine will therefore need to be reduced in subjects with hepatic impairment, depending on the degree of impairment and the pharmacodynamic response. Ethnicity Dexmedetomidine pharmacokinetics were assessed in a single-centre, open-label, randomized phase I study in which nine healthy Japanese volunteers were assigned to receive one of three doses (0.10, 0.30 and 0.60 mg/kg) of dexmedetomidine hydrochloride. Pharmacokinetic parameters obtained were comparable to those obtained from Caucasian subjects in other studies.13 Furthermore, there was no dierence in the pharmacokinetics in either Blacks or Hispanics. Eect of cardiopulmonary bypass on the pharmacokinetics of dexmedetomidine Dexmedetomidine plasma concentrations were measured before, during and after cardiopulmonary bypass (CPB) in a phase III, multicentre, double-blind, randomized, comparative study evaluating the eect of two dexmedetomidine doses versus placebo
264 M. D. Karol and M. Maze Table 2. Mean + SD dexmedetomidine concentration (ng/ml) ± summary (n 10)*. Target plasma concentration
Measured concentration (during CPB)
Measured Css (after CPB)
% Change
0.3 0.6
0.20 + 0.04 0.50 + 0.08
0.29 + 0.05 0.62 + 0.11
30.3 + 11.2 18.2 + 12.7
* Dense sampling site. Based on the multi-study dexmedetomidine clearance value of 39 l/h, steady-state concentrations of 0.3 and 0.6 ng/ml would be expected from maintenance infusions of 0.17 and 0.34 mg/kg per hour respectively. CPB cardiopulmonary bypass; Css steady-state concentration.
in adult coronary artery bypass graft (CABG) surgery.14 Sampling at one study site was, by design, more frequent than at the others, with the intent of permitting an assessment of the eect of CABG and CPB on dexmedetomidine concentration. The mean plasma concentration during CPB was approximately 30% and 18% lower than the steady-state concentrations after CPB for the regimens examined (Table 2). Upon termination of the CPB, the dexmedetomidine concentration returned to its intended values. The fact that the concentrations returned to the expected or target values after CPB indicates that the pharmacokinetics of CABG patients are similar to those of normal subjects. However, a lower concentration is expected during the bypass procedure. Metabolism Following a 10 minute 2 mg/kg intravenous infusion of [3H]dexmedetomidine to humans, 95% of the radio-active dose was excreted in the urine, whereas 4% was recovered in the faeces over 9 days.15 Unchanged dexmedetomidine was not detected in the urine, the major urinary metabolites being the N-glucuronides of dexmedetomidine (34%) and the glucuronide of the hydroxy N-methyl metabolite (14.5%).15 These results show that dexmedetomidine undergoes extensive biotransformation. In addition to direct N-glucuronidation, which accounts for about 34% of dexmedetomidine metabolism, an in vitro study showed that [3H]dexmedetomidine is metabolized to two products in both liver microsomes and human B-lymphoblastoid microsomes in the presence of NADPH16,17, the metabolites being produced by hydroxylation. Further investigation suggested that the formation of these metabolites was largely mediated by cytochrome P450 2A6 (CYP2A6).16,17 In vitro studies performed on cDNA-expressed CYPs also demonstrated that other CYP isoforms, such as CYP1A1, CYP2E1, CYP2D6 and CYP2C19, may also be capable of catalysing the metabolism of dexmedetomidine.16,17 The unchanged parent drug accounted for 15% of the plasma total radio-activity AUC0±24 h. N-glucuronides of dexmedetomidine (G-Dex-1 and G-Dex-2) were the major circulating metabolites, together accounting for 41% of the plasma AUC0±24 h radio-activity. The N-methyl O-glucuronide (G-N-Me-OH) accounted for an additional 21% of the plasma AUC0±24 h radio-activity, and the O-glucuronide metabolite (G-OH) for 3%. Thus, in total, 62% of the AUC0±24 h radio-activity was presented as glucuronides. Apart from the glucuronides, the only metabolite present in any appreciable quantity in human plasma was H-3, the result of hydroxylation at the methyl position on the methylene bridge, which accounted for 11% of the AUC0±24 h radio-activity.15
Pharmacokinetics and pharmacodynamics of dexmedetomidine 265
Chiral inversion of dexmedetomidine to its inactive l-enantiomer was found to be of minimal signi®cance in humans.18 Protein binding The average protein binding was 93.7% and was essentially constant across the concentrations tested. Binding was similar in males and females.19 There was no signi®cant dierence in protein binding between the four renal function groups examined (normal function and mild, moderate and severe impairment).9 The fraction of dexmedetomidine that was bound to plasma proteins was statistically signi®cantly decreased in subjects with hepatic impairment compared with healthy subjects.12 Binding in subjects with mild, moderate and severe impairment was 87.9%, 86.0% and 82.0% respectively, compared with 89.8% in normals. There was a negligible change in the plasma protein binding of dexmedetomidine in the presence of therapeutic concentrations of fentanyl, ketorolac, theophylline, digoxin and lidocaine. These medications are unlikely to cause a clinically signi®cant change in the plasma protein binding of dexmedetomidine.20 Displacement of other drugs The possibility of a binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine was explored in vitro. None of these compounds appeared to be signi®cantly displaced by dexmedetomidine. Thus, dexmedetomidine is unlikely to cause a clinically signi®cant change in the plasma protein binding of these medications at the concentrations observed clinically.21 Pharmacodynamics Iso¯urane Subjects receiving each of three treatments ± placebo, low and high dexmedetomidine ± were anaesthetized with iso¯urane to a level that was sucient to abolish a purposeful motor response to electric nerve stimulation.22 Thereafter, the end-tidal iso¯urane concentration was decreased by 0.2% with a 15 minute equilibration period to identify the concentration at which the motor response reappeared and the response to a verbal command occurred. A dose-dependent decrease in the end-tidal iso¯urane concentration required to elicit a positive motor response in 50% of subjects (EC50) was observed for both motor response and response to verbal command (Table 3), being 31% for the low dexmedetomidine dose and 50% for the high dose. The results of the logistic regressions performed to estimate the iso¯urane EC50 are listed in Table 3. Midazolam The pharmacokinetics of midazolam, a CYP3A4 substrate, in the presence of two concentrations of dexmedetomidine as well as for midazolam alone were assessed.23 Similarly, the dexmedetomidine pharmacokinetics were determined. The clearance, volume of distribution and t1/2 midazolam were unaected by dexmedetomidine. Pharmacodynamic measurements including the Digital Symbol Substitution Test (DSST), Visual Analogue Score for Sedation (VAS/S), Observer's Assessment of
266 M. D. Karol and M. Maze Table 3. Estimates of EC50 and 95% con®dence intervals (CI). Motor response
Response to verbal command
Treatment*
EC50 (%){
95% CI
EC50 (%){
95% CI
Placebo Low dex High dex
1.048 0.722 0.520
0.915±1.229 0.611±0.828 0.402±0.632
0.610 0.523 0.327
0.507±0.712 0.419±0.625 0.240±0.413
* Placebo (treatment C); Low dex dexmedetomidine target plasma concentration of 0.3 ng/ml (treatment A); high dex dexmedetomidine target plasma concentration of 0.6 ng/ml (treatment B). Based on the multi-study dexmedetomidine clearance value of 39 l/h, steady-state concentrations of 0.3 and 0.6 ng/ml would be expected from maintenance infusions of 0.17 and 0.34 mg/kg per hour respectively. { End-tidal iso¯urane concentration at which 50% of subjects responded.
Table 4. Predicted recall (MEM-Recall), object identi®cation (MEM-Obj.ID) and cognitive scores for combinations of dexmedetomidine and midazolam in which the midazolam dosing is adjusted to obtain a 50% probability of sedation. Midazolam concentration Dexmedetomidine to obtain 50% concentration probability of Midazolam (ng/ml) sedation (ng/ml) dose factor
Probability of Probability object of recall identi®cation (MEM-Recall) (MEM-Obj.ID)
DSST score (Emax 63.4)
0 0.2 0.4
34 10 50*
OAA/S 4 4 2% 29% 18% ± 31%{
76% 78% 72%{
39.8 48.7 43.5{
0 0.2 0.4
62 29 13
OAA/S 4 3 0% 47% 2% 21% 7%
58% 67% 64%
23.6 30.9 28.9
0 0.2 0.4
88 58 41
OAA/S 4 2 0% 66% 0% 47% 0%
39% 46% 43%
15.5 17.0 14.9
0 0.2 0.4
133 100 76
OAA/S 4 1 0% 75% 0% 57% 0%
14% 20% 21%
8.6 9.0 8.4
* At 0.4 ng/ml dexmedetomidine, the probability of Observer's Assessment of Alertness/Sedation (OAA/ S) 4 4 is 0.49; thus, the theoretical EC50m value is 50. Based on the multi-study dexmedetomidine clearance value of 39 l/h, steady-state concentrations of 0.2 and 0.4 ng/ml would be expected from maintenance infusions of 0.11 and 0.22 mg/kg per hour respectively. { Computed using a midazolam concentration of zero. { Note: pre-drug control recall probability was 61%.
Alertness/Sedation (OAA/S) and picture Recall List, which test Object Identi®cation and Memory Recall (MEM-Obj.ID and MEM-Recall), were also examined. Based on logistic regression analyses, the eect of midazolam in combination with dexmedetomidine on sedation (OAA/S) was synergistic, greater synergism occurring with less sedation (Table 4). At higher degrees of sedation, the augmentation of midazolam's
Pharmacokinetics and pharmacodynamics of dexmedetomidine 267
eect on sedation by dexmedetomidine is less. Based on the MEM-Recall test, there was an eect of dexmedetomidine and midazolam on amnesia but no synergism. The eects of dexmedetomidine and midazolam on Mem-Obj.ID and DSST were also additive. Midazolam dose modi®cation should be based on pharmacodynamic endpoints. Propofol The eect of dexmedetomidine on the pharmacokinetics and pharmacodynamics of propofol was examined.24 The propofol plasma concentration had a statistically signi®cant eect on all the sedation parameters examined. The EC50 of propofol for all the sedation parameters evaluated in the current study (except motor response) ranged between 1.14 and 1.98 mg/ml. The presence of dexmedetomidine had a statistically signi®cant eect on the ability to hold a syringe, the presence of an eyelash re¯ex and the Ramsay sedation score during propofol administration. The concentration of propofol required to achieve a 50% probability of alertness for the dierent pharmacodynamic end-points evaluated in this study for placebo (EC50) and dexmedetomidine treatment (EC50APP) are shown in Table 5. The eect of propofol in combination with dexmedetomidine on the ability to hold a syringe, the eyelash re¯ex, the motor response and the Ramsay sedation scores was greater than that for propofol alone. Only the eyelash re¯ex and mild sedation (a Ramsay score of 2) showed evidence of an interaction, which produced a total eect that was less than the sum of the eects that would be expected from the two drugs acting independently. Propofol dose modi®cation should thus be based on pharmacodynamic end-points.15 Rocuronium The eect of dexmedetomidine on the pharmacodynamics of rocuronium was investigated using the evoked mechanical response of the adductor pollicis muscle to indirect supramaximal 2 Hz, 200 ms duration, train-of-four stimulation of the ulnar nerve.25 Once the level of neuromuscular relaxation with rocuronium had been stabilized for at least 10 minutes, dexmedetomidine was administered to maintain a concentration of 0.6 ng/ml. No pharmacodynamic interaction of clinical importance was observed. Alfentanil Subjects received a logarithmically increasing concentration of alfentanil under conditions of placebo and low and high dexmedetomidine exposure26, the possible in¯uence of dexmedetomidine on alfentanil plasma concentration being examined. A small statistically signi®cant but clinically insigni®cant dierence in alfentanil concentration was observed across the dexmedetomidine treatment regimens (Table 5). The pharmacodynamic measures examined were the respiratory rate, OAA/S, VAS/ S, visual analogue scale for pain (VAS/P) and DSST. EC50 values for dexmedetomidine (EC50d) with regard to sedation were 0.17, 0.61 and 1.62 ng/ml for an OAA/S of over 4, 3 and 2 respectively. Only at the mildest degree of sedation (OAA/S 4 4) did alfentanil show statistically signi®cant sedation. With regard to pain, as assessed by the VAS/P, regression analysis indicated a statistically signi®cant eect of alfentanil and dexmedetomidine. There was no signi®cant interaction. Regarding DSST, alfentanil and
268 M. D. Karol and M. Maze Table 5. Pharmacodynamic parameters and associated propofol EC50 values with and without dexmedetomidine. Propofol Variable
EC50 *
EC50APP {
Ability to hold syringe Eyelash Re¯ex Motor Response Ramsay 4 2
1.37 1.86 6.63 1.14
0.273 ±{ 3.89** ±{
* Propofol concentration required to achieve 50% probability of alertness. { Propofol concentration required to achieve 50% probability of altertness with dexmedetomidine coadministration. { Probability of Ramsay sedation score 4 2 and eyelash re¯ex were 5 0.4. Units are g/ml. ** Dexmedetomidine did not have a statistically signi®cant eect on slope of motor response vs. propofol concentration curve.
dexmedetomidine were statistically signi®cant. Both drugs caused a decrease in DSST; however, the eect of interaction or synergism was not statistically signi®cant. Dexmedetomidine had no direct eect on respiratory rate; however, respiratory rate decreased with increasing alfentanil concentration, a greater decrease being associated with a greater dexmedetomidine concentration. The estimated mean respiratory rate dierences, upon comparison of placebo to the high-dexmedetomidine regimen (0.86 ng/ml) at an alfentanil concentration of 150 ng/ml, were approximately 3±5 breaths per minute, depending on the technique of estimation. In the presence of dexmedetomidine, less alfentanil is needed for the same degree of pain relief; thus, the impact of alfentanil±dexmedetomidine co-administration on respiratory rate can be lessened by reducing the alfentanil dose. Acknowledgements The authors gratefully acknowledge the dexmedetomidine metabolism and protein binding contributions generously provided by Joseph M. Machinist, PhD.
REFERENCES 1. Kivikoski JH, Rissanen KT & Parhi SSL. Crystal structures and absolute con®gurations of dexmedetomidine and its tosyl derivative. Tetrahedron: Asymmetry 1993; 4(1): 45±58. 2. Pelkonen O, Puurunen J, Pentti A et al. Comparative eects of medetomidine enantiomers on in vitro and in vivo microsomal drug metabolism. Pharmacology and Toxicology 1991; 69: 189±194. 3. Precedex, Dexmedetomidine Hydrochloride lnjection, Package insert, PDR, 2000. 4. Aantaa R, Kallio A & Virtanen R. Dexmedetomidine, a novel a2-adrenergic agonist. A review of its pharmacodynamic characteristics. Drugs of the Future 1993; 18(1): 49±56. 5. Aantaa R, Kanto J, Scheinin M et al. Dexmedetomidine, an a2-adrenoceptor agonist, reduces anesthetic requirements for patients undergoing minor gynecologic surgery. Anesthesiology 1990; 73(2): 230±235. 6. Dutta S, Lal R, Karol MD, Cohen T & Ebert T. In¯uence of cardiac output on dexmedetomidine pharmacokinetics. Journal of Pharmacological Science 2000; 89(4): 519±527. 7. Karol M. Overview and Summary of the Human Pharmacokinetics and Biopharmaceutics of Dexmedetomidine, 1998 Abbott Laboratories. Internal Report.
Pharmacokinetics and pharmacodynamics of dexmedetomidine 269 8. Karol MD & Rynkiewicz KE. A Phase I, Single Center, Open Label, Parallel Study to Evaluate the In¯uence of Age on the Pharmacokinetics of Dexmedetomidine in Healthy Volunteers, 1998 Abbott Laboratories. Internal Report. 9. Kukulka MJ & Machinist J. In Vitro Protein Binding of [3H] Dexmedetomidine in the Plasma of Humans with Renal Impairment, 1996 Abbott Laboratories. Internal Report. 10. Wong SL & Rynkiewicz KE. Pharmacokinetics of Dexmedetomidine in Normal Healthy Subjects and Subjects with Severe Renal Impairment, 1998 Abbott Laboratories. Internal Report. 11. Wong S & Rynkiewicz KE. Pharmacokinetics of Dexmedetomidine in Normal Healthy Subjects and Subjects with Various Degree of Hepatic Impairment, 1998 Abbott Laboratories. Internal Report. 12. Machinist JM. Protein Binding of [3H] Dexmedetomidine in the Plasma from Subjects with Various Liver Function, 1998 Abbott Laboratories. Internal Report. 13. Karol MD. Pharmacokinetics of Dexmedetomidine Hydrochloride Injection in Healthy Male Volunteers Following Administration at Three Dierent Rates, 1996 Abbott Laboratories. Internal Report. 14. Karol MD & Jennings J. A Phase III Multicenter, Double-Blind, Randomized, Comparative Study Evaluating the Eect of Two Doses of Dexmedetomidine Versus Placebo in Adult Patients Undergoing Elective Coronary Artery Bypass Graft Surgery, 1998 Abbott Laboratories. Internal Report. 15. Mayer MD & Machinist JM. Phase I Study of the Metabolism and Excretion of [3H]Dexmedetomidine . HCl in Normal Male Subjects, 1997 Abbott Laboratories. Internal Report. 16. Hickman D & Kumar GN. Identi®cation of Cytochrome P450 Isoforms Involved in the Oxidative Metabolism of Dexmedetomidine and the Eect of Dexmedetomidine on Cytochrome P450-mediated Monooxygenase Activities, 1998 Abbott Laboratories. Internal Report. 17. Rodrigues DA & Roberts EM. The in vitro interaction of dexmedetomidine with human liver microsomal cytochrome P450 2D6 (CYP2D6). Drug Metabolism and Disposition 1997; 25(5): 651±655. 18. Mayer MD & Machinist JM. Conversion of [3H]dexmedetomidine to [3H]levomedetomidine in Male Subjects Following a 2 mg/kg Infusion of [3H]dexmedetomidine HCl, 1997 Abbott Laboratories. Internal Report. 19. Kukulka MJ & Machinist JM. In Vitro Protein Binding of [3H] Dexmedetomidine in Mouse, Rat, Dog, Monkey and Human Plasma, 1996 Abbott Laboratories. Internal Report. 20. Machinist JM. Protein Binding Interactions between [3H] Dexmedetomidine and Selected Other Drugs in Human Plasma, 1997 Abbott Laboratories. Internal Report. 21. Machinist JM & Johnson MK. Eects of Dexmedetomidine on the Protein Binding of Selected other Drugs in Human Plasma, 1997 Abbott Laboratories. Internal Report. 22. Ouellet D & Karol MD. A Phase I, Single Center, Randomized Single-Blind Crossover Controlled Study to Determine the Eects of Dexmedetomidine on Iso¯urane Requirements in Healthy Volunteers, 1996 Abbott Laboratories. Internal Report. 23. Karol MD. Pharmacokinetics and Pharmacodynamics of Co-administered Dexmedetomidine and Midazolam, 1997 Abbott Laboratories. Internal Report. 24. Dutta S, Karol MD, Cohen T & Mant T. Eect of dexmedetomidine on propofol requirements in healthy subjects. Journal of Pharmacological Science (In Press). 25. Karol MD & Jennings J. Pharmacokinetics and Pharmocodynamics from a Phase I, Single Center, Open-Label Study Assessing the Interaction of Dexmedetomidine and Rocuronium, a Muscle Relaxant, in Healthy Volunteers, 1998 Abbott Laboratories. Internal Report. 26. Karol MD. Pharmacokinetics and Pharmacodynamics of Coadministered Dexmedetomidine and Alfentanil, 1989 Abbott Laboratories. Internal Report.
doi:10.1053/bean.2000.0081, available online at http://www.idealibrary.com on
3 Pharmacokinetics and interaction pharmacodynamics of dexmedetomidine in humans Michael D. Karol
PhD
Section Manager, Clinical Pharmacokinetics D-4PK, Ap13A-3, Abbott Laboratories, 100 Abbot Park Rd, Abbott Park, IL 60064-6104, USA
Mervyn Maze
MB, ChB, FRCP, FRCA
Magill Professor of Anaesthetics; Head, Department of Anaesthetics, and Intensive Care; Vice-Chair, Division of Surgery, Anaesthetics and Intensive Care Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
Dexmedetomidine is a potent and highly selective a2-adrenoceptor agonist with a selectivity ratio of 1600:1 (a2 :a1). Dexmedetomidine is a highly lipophylic agent that is rapidly distributed to tissues with a distribution half-life (t1/2a) of approximately 6 minutes. It is extensively distributed and rapidly eliminated, with a mean elimination half-life (t1/2) of 2±2.5 hours. This rapid distribution and short elimination kinetics makes dexmedetomidine amenable to frequent titration allowing adjustability of dosage and eects. Generally, dexmedetomidine does not exhibit pharmacokinetic-based interactions; however, dosage modi®cations of some concomitant medications may be needed to be adjusted due primarily to common pharmacological actions of the two drugs. Dexmedetomidine is eliminated by metabolism to inactive metabolites, primarily glucuronides. Eighty to ninety percent of an administered dose is excreted in the urine and 5%±13% in the faeces. Key words: dexmedetomidine; a2-adrenergic agonist; pharmacokinetics; pharmacodynamics.
Dexmedetomidine, the pharmacologically active d-enantiomer of medetomidine (Figure 1)1,2, is formulated as dexmedetomidine hydrochloride, a clear, colourless, isotonic solution with a pH of 4.5±7.0. The solution is preservative-free and contains no additives or chemical stabilizers.3 Because of its a2-adrenoceptor agonist properties, dexmedetomidine has a broad range of pharmacological properties, including sedation associated with arousability and orientation without respiratory depression. Additional properties include analgesia, anxiolysis, haemodynamic stability, anti-shivering eects, reduced nausea and vomiting, and anaesthetic-sparing eects.4,5 PHARMACOKINETICS Dexmedetomidine pharmacokinetics have been estimated following diverse intravenous administration regimens, resulting in a variety of concentration versus time 1521±6896/00/02026109 $35.00/00
c 2000 Harcourt Publishers Ltd. *
262 M. D. Karol and M. Maze
H
CH3
CH3 CH3
N
N H
3
H
Figure 1. Structure of dexmedetomidine.
Table 1. Dexmedetomidine pharmacokinetic summary.
Mean SD CV% Max. Min. n
CL (l/h)
CL (l/h/kg)
t1/2 * (h)
b (l/h)
Vss (l)
Vss (l/kg)
39.4 10.1 26 77.8 15.0 276
0.53 0.14 26 1.01 0.23 276
2.1 0.49 24 7.3 0.97 258
0.33 0.08 24 0.71 0.10 258
97.3 29.3 30 225 29.0 258
1.31 0.37 28 3.09 0.61 258
* Harmonic mean and pseudo-standard deviation presented. CL clearance; t1/2 half-life; Vss steady-state volume of distribution; CV coecient of variance.
exposure pro®les. Table 1 summarizes the pharmacokinetics of dexmedetomidine. Dexmedetomidine clearance is approximately constant within the anticipated therapeutic range, resulting in dose proportionality. However, in a maximum tolerated dose study, including concentrations 13 times the upper limit of the anticipated therapeutic range, a diminished clearance was noted of about 20% at dexmedetomidine concentrations well above the desired therapeutic range.6 Dexmedetomidine exhibits a rapid distribution phase, the central estimate of the distribution half-life (t1/2a) being about 6 minutes. The central estimate (the estimate in the central compartment) of the terminal elimination half-life (t1/2) is approximately 2.0±2.5 hours, and the central estimate of the steady-state volume of distribution (Vss) approximately 97 + 29 litres. Clearance, the pharmacokinetic parameter that relates infusion rate to steady-state concentration, has a central estimated value of about 39 + 10 litres/h. Body build description has been shown to be a signi®cant factor, and dexmedetomidine dosing in most studies has been done on a mg/kg basis. The mean body weight associated with this clearance estimate was 75 kg.7
Pharmacokinetics and pharmacodynamics of dexmedetomidine 263
Overall, the variability in dexmedetomidine clearance (CL) and t1/2 was relatively low, with a coecient of variance (CV) of only 26% and 24% respectively. Dexmedetomidine pharmacokinetics (CL, Cmax , Tmax , Vss , b and area under the curve (AUC)) were no dierent between young, middle-aged and elderly adult subjects, or between males and females. A given dexmedetomidine infusion, where dosing is per kilogram of body weight, is thus expected to produce the same dexmedetomidine concentration irrespective of age or gender.8 Pharmacokinetics in organ failure Dexmedetomidine pharmacokinetics (Tmax , Cmax , AUC, t1/2 , CL and Vss) do not dier between subjects with severe renal impairment and normal healthy subjects. The possible impact of renal impairment on the protein binding of dexmedetomidine was assessed in a separate study including plasma from normal subjects and subjects with mild, moderate and severe renal impairment. There were no signi®cant dierences in protein binding between the four renal function groups.9 Accordingly, for a given administration regimen, the pharmacokinetic pro®le of dexmedetomidine is expected to be independent of the patient's renal function.10 The eect of hepatic impairment on dexmedetomidine pharmacokinetics was assessed in a phase I, two-centre, open-label, single-period, single-dose study in which normal healthy subjects and subjects with mild, moderate and severe hepatic impairment received dexmedetomidine.11 Dexmedetomidine plasma protein binding was statistically signi®cantly decreased in subjects with hepatic impairment compared with healthy subjects. Clearance values were lower in subjects with hepatic impairment than in healthy subjects.12 The mean CL values for subjects with mild, moderate and severe hepatic impairment were 74%, 64% and 53% respectively of those observed in the normal healthy subjects. Compared with the subjects with normal hepatic function (a mean t1/2 of 2.5 hours), the mean t1/2 for the subjects with mild, moderate or severe hepatic impairment was prolonged to 3.9, 5.4 and 7.4 hours respectively. The dose of dexmedetomidine will therefore need to be reduced in subjects with hepatic impairment, depending on the degree of impairment and the pharmacodynamic response. Ethnicity Dexmedetomidine pharmacokinetics were assessed in a single-centre, open-label, randomized phase I study in which nine healthy Japanese volunteers were assigned to receive one of three doses (0.10, 0.30 and 0.60 mg/kg) of dexmedetomidine hydrochloride. Pharmacokinetic parameters obtained were comparable to those obtained from Caucasian subjects in other studies.13 Furthermore, there was no dierence in the pharmacokinetics in either Blacks or Hispanics. Eect of cardiopulmonary bypass on the pharmacokinetics of dexmedetomidine Dexmedetomidine plasma concentrations were measured before, during and after cardiopulmonary bypass (CPB) in a phase III, multicentre, double-blind, randomized, comparative study evaluating the eect of two dexmedetomidine doses versus placebo
264 M. D. Karol and M. Maze Table 2. Mean + SD dexmedetomidine concentration (ng/ml) ± summary (n 10)*. Target plasma concentration
Measured concentration (during CPB)
Measured Css (after CPB)
% Change
0.3 0.6
0.20 + 0.04 0.50 + 0.08
0.29 + 0.05 0.62 + 0.11
30.3 + 11.2 18.2 + 12.7
* Dense sampling site. Based on the multi-study dexmedetomidine clearance value of 39 l/h, steady-state concentrations of 0.3 and 0.6 ng/ml would be expected from maintenance infusions of 0.17 and 0.34 mg/kg per hour respectively. CPB cardiopulmonary bypass; Css steady-state concentration.
in adult coronary artery bypass graft (CABG) surgery.14 Sampling at one study site was, by design, more frequent than at the others, with the intent of permitting an assessment of the eect of CABG and CPB on dexmedetomidine concentration. The mean plasma concentration during CPB was approximately 30% and 18% lower than the steady-state concentrations after CPB for the regimens examined (Table 2). Upon termination of the CPB, the dexmedetomidine concentration returned to its intended values. The fact that the concentrations returned to the expected or target values after CPB indicates that the pharmacokinetics of CABG patients are similar to those of normal subjects. However, a lower concentration is expected during the bypass procedure. Metabolism Following a 10 minute 2 mg/kg intravenous infusion of [3H]dexmedetomidine to humans, 95% of the radio-active dose was excreted in the urine, whereas 4% was recovered in the faeces over 9 days.15 Unchanged dexmedetomidine was not detected in the urine, the major urinary metabolites being the N-glucuronides of dexmedetomidine (34%) and the glucuronide of the hydroxy N-methyl metabolite (14.5%).15 These results show that dexmedetomidine undergoes extensive biotransformation. In addition to direct N-glucuronidation, which accounts for about 34% of dexmedetomidine metabolism, an in vitro study showed that [3H]dexmedetomidine is metabolized to two products in both liver microsomes and human B-lymphoblastoid microsomes in the presence of NADPH16,17, the metabolites being produced by hydroxylation. Further investigation suggested that the formation of these metabolites was largely mediated by cytochrome P450 2A6 (CYP2A6).16,17 In vitro studies performed on cDNA-expressed CYPs also demonstrated that other CYP isoforms, such as CYP1A1, CYP2E1, CYP2D6 and CYP2C19, may also be capable of catalysing the metabolism of dexmedetomidine.16,17 The unchanged parent drug accounted for 15% of the plasma total radio-activity AUC0±24 h. N-glucuronides of dexmedetomidine (G-Dex-1 and G-Dex-2) were the major circulating metabolites, together accounting for 41% of the plasma AUC0±24 h radio-activity. The N-methyl O-glucuronide (G-N-Me-OH) accounted for an additional 21% of the plasma AUC0±24 h radio-activity, and the O-glucuronide metabolite (G-OH) for 3%. Thus, in total, 62% of the AUC0±24 h radio-activity was presented as glucuronides. Apart from the glucuronides, the only metabolite present in any appreciable quantity in human plasma was H-3, the result of hydroxylation at the methyl position on the methylene bridge, which accounted for 11% of the AUC0±24 h radio-activity.15
Pharmacokinetics and pharmacodynamics of dexmedetomidine 265
Chiral inversion of dexmedetomidine to its inactive l-enantiomer was found to be of minimal signi®cance in humans.18 Protein binding The average protein binding was 93.7% and was essentially constant across the concentrations tested. Binding was similar in males and females.19 There was no signi®cant dierence in protein binding between the four renal function groups examined (normal function and mild, moderate and severe impairment).9 The fraction of dexmedetomidine that was bound to plasma proteins was statistically signi®cantly decreased in subjects with hepatic impairment compared with healthy subjects.12 Binding in subjects with mild, moderate and severe impairment was 87.9%, 86.0% and 82.0% respectively, compared with 89.8% in normals. There was a negligible change in the plasma protein binding of dexmedetomidine in the presence of therapeutic concentrations of fentanyl, ketorolac, theophylline, digoxin and lidocaine. These medications are unlikely to cause a clinically signi®cant change in the plasma protein binding of dexmedetomidine.20 Displacement of other drugs The possibility of a binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine was explored in vitro. None of these compounds appeared to be signi®cantly displaced by dexmedetomidine. Thus, dexmedetomidine is unlikely to cause a clinically signi®cant change in the plasma protein binding of these medications at the concentrations observed clinically.21 Pharmacodynamics Iso¯urane Subjects receiving each of three treatments ± placebo, low and high dexmedetomidine ± were anaesthetized with iso¯urane to a level that was sucient to abolish a purposeful motor response to electric nerve stimulation.22 Thereafter, the end-tidal iso¯urane concentration was decreased by 0.2% with a 15 minute equilibration period to identify the concentration at which the motor response reappeared and the response to a verbal command occurred. A dose-dependent decrease in the end-tidal iso¯urane concentration required to elicit a positive motor response in 50% of subjects (EC50) was observed for both motor response and response to verbal command (Table 3), being 31% for the low dexmedetomidine dose and 50% for the high dose. The results of the logistic regressions performed to estimate the iso¯urane EC50 are listed in Table 3. Midazolam The pharmacokinetics of midazolam, a CYP3A4 substrate, in the presence of two concentrations of dexmedetomidine as well as for midazolam alone were assessed.23 Similarly, the dexmedetomidine pharmacokinetics were determined. The clearance, volume of distribution and t1/2 midazolam were unaected by dexmedetomidine. Pharmacodynamic measurements including the Digital Symbol Substitution Test (DSST), Visual Analogue Score for Sedation (VAS/S), Observer's Assessment of
266 M. D. Karol and M. Maze Table 3. Estimates of EC50 and 95% con®dence intervals (CI). Motor response
Response to verbal command
Treatment*
EC50 (%){
95% CI
EC50 (%){
95% CI
Placebo Low dex High dex
1.048 0.722 0.520
0.915±1.229 0.611±0.828 0.402±0.632
0.610 0.523 0.327
0.507±0.712 0.419±0.625 0.240±0.413
* Placebo (treatment C); Low dex dexmedetomidine target plasma concentration of 0.3 ng/ml (treatment A); high dex dexmedetomidine target plasma concentration of 0.6 ng/ml (treatment B). Based on the multi-study dexmedetomidine clearance value of 39 l/h, steady-state concentrations of 0.3 and 0.6 ng/ml would be expected from maintenance infusions of 0.17 and 0.34 mg/kg per hour respectively. { End-tidal iso¯urane concentration at which 50% of subjects responded.
Table 4. Predicted recall (MEM-Recall), object identi®cation (MEM-Obj.ID) and cognitive scores for combinations of dexmedetomidine and midazolam in which the midazolam dosing is adjusted to obtain a 50% probability of sedation. Midazolam concentration Dexmedetomidine to obtain 50% concentration probability of Midazolam (ng/ml) sedation (ng/ml) dose factor
Probability of Probability object of recall identi®cation (MEM-Recall) (MEM-Obj.ID)
DSST score (Emax 63.4)
0 0.2 0.4
34 10 50*
OAA/S 4 4 2% 29% 18% ± 31%{
76% 78% 72%{
39.8 48.7 43.5{
0 0.2 0.4
62 29 13
OAA/S 4 3 0% 47% 2% 21% 7%
58% 67% 64%
23.6 30.9 28.9
0 0.2 0.4
88 58 41
OAA/S 4 2 0% 66% 0% 47% 0%
39% 46% 43%
15.5 17.0 14.9
0 0.2 0.4
133 100 76
OAA/S 4 1 0% 75% 0% 57% 0%
14% 20% 21%
8.6 9.0 8.4
* At 0.4 ng/ml dexmedetomidine, the probability of Observer's Assessment of Alertness/Sedation (OAA/ S) 4 4 is 0.49; thus, the theoretical EC50m value is 50. Based on the multi-study dexmedetomidine clearance value of 39 l/h, steady-state concentrations of 0.2 and 0.4 ng/ml would be expected from maintenance infusions of 0.11 and 0.22 mg/kg per hour respectively. { Computed using a midazolam concentration of zero. { Note: pre-drug control recall probability was 61%.
Alertness/Sedation (OAA/S) and picture Recall List, which test Object Identi®cation and Memory Recall (MEM-Obj.ID and MEM-Recall), were also examined. Based on logistic regression analyses, the eect of midazolam in combination with dexmedetomidine on sedation (OAA/S) was synergistic, greater synergism occurring with less sedation (Table 4). At higher degrees of sedation, the augmentation of midazolam's
Pharmacokinetics and pharmacodynamics of dexmedetomidine 267
eect on sedation by dexmedetomidine is less. Based on the MEM-Recall test, there was an eect of dexmedetomidine and midazolam on amnesia but no synergism. The eects of dexmedetomidine and midazolam on Mem-Obj.ID and DSST were also additive. Midazolam dose modi®cation should be based on pharmacodynamic endpoints. Propofol The eect of dexmedetomidine on the pharmacokinetics and pharmacodynamics of propofol was examined.24 The propofol plasma concentration had a statistically signi®cant eect on all the sedation parameters examined. The EC50 of propofol for all the sedation parameters evaluated in the current study (except motor response) ranged between 1.14 and 1.98 mg/ml. The presence of dexmedetomidine had a statistically signi®cant eect on the ability to hold a syringe, the presence of an eyelash re¯ex and the Ramsay sedation score during propofol administration. The concentration of propofol required to achieve a 50% probability of alertness for the dierent pharmacodynamic end-points evaluated in this study for placebo (EC50) and dexmedetomidine treatment (EC50APP) are shown in Table 5. The eect of propofol in combination with dexmedetomidine on the ability to hold a syringe, the eyelash re¯ex, the motor response and the Ramsay sedation scores was greater than that for propofol alone. Only the eyelash re¯ex and mild sedation (a Ramsay score of 2) showed evidence of an interaction, which produced a total eect that was less than the sum of the eects that would be expected from the two drugs acting independently. Propofol dose modi®cation should thus be based on pharmacodynamic end-points.15 Rocuronium The eect of dexmedetomidine on the pharmacodynamics of rocuronium was investigated using the evoked mechanical response of the adductor pollicis muscle to indirect supramaximal 2 Hz, 200 ms duration, train-of-four stimulation of the ulnar nerve.25 Once the level of neuromuscular relaxation with rocuronium had been stabilized for at least 10 minutes, dexmedetomidine was administered to maintain a concentration of 0.6 ng/ml. No pharmacodynamic interaction of clinical importance was observed. Alfentanil Subjects received a logarithmically increasing concentration of alfentanil under conditions of placebo and low and high dexmedetomidine exposure26, the possible in¯uence of dexmedetomidine on alfentanil plasma concentration being examined. A small statistically signi®cant but clinically insigni®cant dierence in alfentanil concentration was observed across the dexmedetomidine treatment regimens (Table 5). The pharmacodynamic measures examined were the respiratory rate, OAA/S, VAS/ S, visual analogue scale for pain (VAS/P) and DSST. EC50 values for dexmedetomidine (EC50d) with regard to sedation were 0.17, 0.61 and 1.62 ng/ml for an OAA/S of over 4, 3 and 2 respectively. Only at the mildest degree of sedation (OAA/S 4 4) did alfentanil show statistically signi®cant sedation. With regard to pain, as assessed by the VAS/P, regression analysis indicated a statistically signi®cant eect of alfentanil and dexmedetomidine. There was no signi®cant interaction. Regarding DSST, alfentanil and
268 M. D. Karol and M. Maze Table 5. Pharmacodynamic parameters and associated propofol EC50 values with and without dexmedetomidine. Propofol Variable
EC50 *
EC50APP {
Ability to hold syringe Eyelash Re¯ex Motor Response Ramsay 4 2
1.37 1.86 6.63 1.14
0.273 ±{ 3.89** ±{
* Propofol concentration required to achieve 50% probability of alertness. { Propofol concentration required to achieve 50% probability of altertness with dexmedetomidine coadministration. { Probability of Ramsay sedation score 4 2 and eyelash re¯ex were 5 0.4. Units are g/ml. ** Dexmedetomidine did not have a statistically signi®cant eect on slope of motor response vs. propofol concentration curve.
dexmedetomidine were statistically signi®cant. Both drugs caused a decrease in DSST; however, the eect of interaction or synergism was not statistically signi®cant. Dexmedetomidine had no direct eect on respiratory rate; however, respiratory rate decreased with increasing alfentanil concentration, a greater decrease being associated with a greater dexmedetomidine concentration. The estimated mean respiratory rate dierences, upon comparison of placebo to the high-dexmedetomidine regimen (0.86 ng/ml) at an alfentanil concentration of 150 ng/ml, were approximately 3±5 breaths per minute, depending on the technique of estimation. In the presence of dexmedetomidine, less alfentanil is needed for the same degree of pain relief; thus, the impact of alfentanil±dexmedetomidine co-administration on respiratory rate can be lessened by reducing the alfentanil dose. Acknowledgements The authors gratefully acknowledge the dexmedetomidine metabolism and protein binding contributions generously provided by Joseph M. Machinist, PhD.
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