Pharmacokinetic studies have shown that body size and hepatic function have a significant influence on the pharmacokinetic profile of dexmedetomidine. Plasma albumin and cardiac output are suggested to have an impact on the apparent volume of distribution and clearance. Studies of the influence of other patient characteristics have produced inconclusive results. |
Unlike sedative drugs such as propofol and the benzodiazepines, dexmedetomidine does not act at the gamma-aminobutyric acid (GABA) receptors. It induces sedation through activation of α2-receptors in the locus coeruleus and induces a state mimicking natural sleep. Whilst sedated, respiration is minimally affected and patients remain rousable. Side effects are mainly hemodynamic and include hypertension, hypotension, and bradycardia as a result of vasoconstriction, sympatholysis, and baroreflex-mediated parasympathetic activation. |
Further research is needed to investigate the clinical feasibility of different promising off-label indications, such as use in the pediatric and geriatric population, intranasal dexmedetomidine administration, its use as an adjuvant to prolong peripheral or spinal nerve blocks, and the potential of dexmedetomidine to reduce opioid consumption. |
1 Introduction
2 Methods
3 Drug Formulations and Dosing Regimens
4 Pharmacokinetics
4.1 Absorption
4.2 Distribution
4.3 Metabolism and Elimination
4.4 Dose Proportionality and Inter-Individual Variability
5 Population Pharmacokinetic Modeling
5.1 Adult Population
Study (year) | Population |
N
| Blood PK samples | Patient characteristics | Drug administration | Tested covariates | Covariate models | Remarks | |
---|---|---|---|---|---|---|---|---|---|
No. of samples a (arterial) v (venous) | Last sample (time after termination of infusion) | Age/WGT/HGT average (range) | |||||||
Male HV | 10 + 6 | 14 a samples after different target plasma concentrations | 120 min | 31.5 years (27–40) 82 kg (71–98) | TCI (based on PK parameters from first 10 subjects) targeting 0.49, 0.65, 0.81, and 0.97 ng/mL | Age, WGT, HGT | 3-compartment model with HGT as a covariate on CL | Data were pooled and fitted using ELS non-linear regression; the authors suggest DMED-induced changes in SVR and CO, leading to a non-linearity in DMED PK (with higher CL at lower DMED targets) | |
Talke (1997) [38] | Female postoperative patients | 8 | 14 a samples during (n = 4) and after (n = 10) DMED infusion | 180 min | 36 years (23–44) 69 kg (62–79) 166 cm (157–178) | TCI (based on a combination of previously published PK data) targeting 0.60 ng/mL for 60 min | Age, WGT, HGT | 2-compartment model with no significant influence of tested covariates | A general overshoot of the DMED target. This is likely owing to the concomitant intra-operative use of other anesthetics |
Dutta (2000) [26] | Male HV | 10 | 22 v samples during (n = 14) and after (n = 8) DMED infusion | 240 min | 24 years (20–27) 78 kg (68–89) 177 cm (170–185) | CCIP (based on an unpublished two-compartment PK model) targeting 7 different plasma DMED target concentrations, resulting in measured DMED concentrations from 0.7 to 14.7 ng/mL | CO | 2-compartment model with CO as covariate on CL | CO and DMED clearance were found to decrease with increasing DMED concentrations. An estimated reduction in CO and DMED CL of 19 and 12% was found at 1.2 vs. 0.3 ng/mL. The I
max, IC50, and gamma of this inhibition were estimated separately as 0.34, 1.3 ng/mL, and 3.0, respectively. The authors found no statistically significant difference in the weighted sum of squares between a CO-dependent and a CO-independent model. The former was parameterized according to the well-stirred liver model |
Venn (2002) [22] | Postoperative ICU patients | 10 | 25 a samples during (n = 13) and after (n = 12) DMED infusion | 720 min | 68 years (35–80) | 2.5 µg/kg/h for 10 min followed by a 0.7 µg/kg/h for 660 min (median) Average measured C
max is 1.12 ng/mL | 2-compartment model with no tested covariates reported | ||
Lin (2011) [39] | Chinese postoperative patients | 22 | 24 v samples during (n = 10) and after (n = 14) DMED infusion | 720 min | 46 years (22–69) 60 kg (46–78) 165 cm (155–178) 13 were male, 9 were female | 6 µg/kg/h loading dose for 10 min followed by 0.4 µg/kg/h maintenance dose for 350 min. Highest measured DMED concentration is approximately 1.7 ng/mL | Age, WGT, HGT, sex, BSA, BMI, LBM | 3-compartment model with HGT as a covariate on CL | The authors hypothesize that the difference in V
1 with respect to the Dyck model might be owing to the venous blood sampling in this study (as compared with the arterial blood sampling in the Dyck model) Furthermore, the authors suggest that ethnic differences might be responsible for the discrepancy with earlier published PK models (no evidence/specific rational is provided for this hypothesis) |
Iirola (2012) [32] | ICU patients | 21 | a samples during loading dose (n = 10) and during (every 6–8 h) DMED maintenance infusion | 0 min | 60 years (22–85) 85 kg (53–120) 174 cm (160–181) ALB: 13.5 (6.6–30.3) | 3–6 µg/kg/h for 10 min followed by 0.1–2.5 µg/kg/h for 96 h (median in study; range: 20–571). Highest measured DMED concentration is approximately 7 ng/mL | Age, WGT, HGT, sex, BMI, LBM | 2-compartment model with age as a covariate on CL and ALB on V
2
| Lack of identification of “third” compartment likely owing to limited availability of samples after termination of the DMED infusion Authors warn for potential confounding by the large number of concomitant drugs that were used throughout the study |
Lee (2012) [29] | Korean HV | 24 | 13 a/v samples during (n = 4) and after (n = 9) DMED infusion | 720 min | 27 years (median) 71 kg (median) 174 cm (median) | 3 µg/kg/h for 10 min followed by 0.17 µg/kg/h for 50 min 6 µg/kg/h for 10 min followed by 0.34 µg/kg/h for 50 min 3.7 µg/kg/h for 35 min followed by 0.7 µg/kg/h for 25 min Average measured C
max 1.08 and 3.3 ng/mL for lowest and highest dose group, respectively | Age, WGT, HGT, serum creatinine, AST, ALT, ALB | 2-compartment model with ALB as a covariate on clearance and age on V
1
| Very similar to other HV data. Authors suggest that there is little evidence to support an ethnic difference in pharmacokinetics for DMED |
Välitalo (2013) [24] | Critically ill patients (3 phase III trials) | 527 | a/v samples taken during (every 24 h) and after (n = 2) DMED infusion | 48 h | 62 years 80 kg 65% were male ALB: 23.4 g/L | 0.7 µg/kg/h infusion for 1 h; afterwards titration to RASS 0 to −3 (dose levels ranging from 0.2 to 1.4 µg/kg/h) Average treatment duration: 2 days 14 h. Most measured DMED concentrations <5 ng/mL | Age, WGT, creatinine clearance, bilirubin, AST, ALT, ALB | 1-compartment model with weight as a covariate on clearance and ALB on V
1
| Most/all patients were mechanically ventilated. The analysis found no relationship between C
ss and CL. Sparse sampling could have precluded the identification of the non-linearity in DMED clearance as a function of DMED concentrations (C
ss at the highest DMED infusion was well below the IC50 reported by Dutta et al.; 2.3 vs. 1.3 ng/mL) |
Cortínez (2015) [40] | Obese and non-obese laparoscopic surgery patients | 20 obese/20 non-obese | 21 v samples during (n = 10) and after (n = 11) DMED infusion | 360 min | 34/40 years 115/75 kg 165/166 cm | 0.5 µg/kg/h for 10 minutes followed by 0.25 µg/kg/h or 0.5 µg/kg/h | Age, WGT, FFM, normal fat mass, intra-operative | 2-compartment model with FFM as a covariate on clearance, Q
2, V
1 and V
2. With FAT as a covariate on clearance and intra-operative state as a covariate on V
1 and V
2
| DMED was administered at the same time as propofol and remifentanil. According to the authors, TBW-based dosing is responsible for an overshoot in the obese. This is because of a lack of an effect of TBW on V
1 and V
2 and an inhibition of DMED CL as a function of fat mass. However, the authors found that during surgery the DMED V1 is significantly lower (20.8%) which, according to the authors, is likely the result of the concomitant use of other anesthetics |
Hannivoort (2015) [42] | HV | 18 × 2 sessions | 14 a samples during (n = 7) and after (n = 7) DMED infusion | 300 min | 20–70 years (range) 51–110 kg (range) 9 were male, 9 were female Age-stratified cohorts (18–34/35–54/55–72 years) | TCI (based on the model from Dyck et al.) targeting 1, 2, 3, 4, 6, and 8 ng/mL 10 min after a short (20 s) bolus infusion at 6 µg/kg/h | Age, WGT, HGT, BMI, sex | 3-compartment model with weight as a covariate on clearance, Q
2, Q
3, V
1, V
2, and V
3
| The authors found no systematic difference in V
1 between a volunteer’s first or second session. Nevertheless, the magnitude of the IOV far exceeds the magnitude of the IIV for DMED V
1
|
Kuang (2016) [41] | Chinese patients under spinal anesthesia | 19 young/16 elderly | 15 a/v during (n = 5) and after (n = 10) DMED infusion | 600 min | 33 vs. 69 years 71 vs. 54 kg 172 vs. 158 cm ALT 49 vs.20 U/L Male:female 7:12 vs. 15:1 | 3.0 µg/kg/h for 10 min followed by 0.5 µg/kg/h for 50 min Maximum measured DMED concentration is approximately 1.7 ng/mL | Age, WGT, HGT, sex, BMI, AST, ALT, creatinine clearance | 3-compartment model with ALT as a covariate on clearance, age on V
1 and weight on V
2
|
5.2 Pediatric Population
Population |
N
| Blood PK samples | Patient characteristics | Drug administration | Tested covariates | Covariate models | Remarks | ||
---|---|---|---|---|---|---|---|---|---|
No. of samples a (arterial) v (venous) | Last sample (time after termination of infusion) | Age/WGT/HGT average (range) | |||||||
Potts (2009) [43] | Pediatric ICU patients | 95a
| a (1 trial) and v (3 trials) samples during and after DMED infusion | 8 h | 3.83 years (0.01–14.4) 16.0 kg (3.1–58.9) | 1–6 µg/kg over 5 or 10 min or 0.2-µg/kg/h infusion | Age, WGT, cardiac surgery, arterial/venous sampling, study site | 2-compartment model with age, WGT (allometry) and post-cardiac surgery state as covariates on CL and WGT (allometry) as a covariate on Q
2, V
1, and V
2
| IIV is almost twofold higher than the effect of maturation (30.9% vs. approximately 20%). Clearance in post-operative cardiac pediatric patients was approximately 27% reduced compared with other pediatric patients |
Su (2010) [45] | Pediatric cardiac post-operative patients | 36 | a/v samples obtained during (n = 5) and after (n = 8) DMED infusion | 24 h | 7.8 months (2.6–20.4) 7.0 kg (5.1–11.9) 20 were male, 16 were female | 0.35–1 µg/kg over 10 min followed by 0.25–0.75 µg/kg/h for 2–24 hours | Age, WGT, total cardiopulmonary bypass time, ventricular physiology | 2-compartment model with age and ventricular physiology as covariates on CL | A full covariate model was reported. Nevertheless, only the covariate for ventricular physiology on CL had acceptable precision (i.e., RSE <50%). BSV is higher than the effect of maturation |
Liu (2016) [47] | Chinese pediatric general surgery patients | 39 | v samples obtained during (n = 1) and after (n = 12) DMED infusion | 8 h | 3.0 years (1–9) 14.5 kg (10–27) 20 were male, 19 were female | 1.0–2.0 µg/kg over 10 min | Age, WGT, BMI, sex, lean body mass | 2-compartment model with WGT (allometry) as a covariate on CL, Q
2, V
1, and V
2
| During surgery patients were maintained under anesthesia with sevoflurane, which might have caused a shift in plasma protein binding of DMED resulting in a higher distribution volume |
Su (2016) [45] | Neonatal and pediatric post-operative patients | 23 + 36 | a/v samples obtained during and after DMED infusionb
| 18 hb
| 4.3 months (0.03–20.4) 5.9 kg (2.3–11.9) 32 were male, 27 were female | 0.25–1 µg/kg over 10 min followed by 0.20–0.75 µg/kg/h for 2–24 h | Age, WGT, total cardiopulmonary bypass time, ventricular physiology | 2-compartment model with age, WGT (allometry), total bypass time, and ventricular physiology as covariates on CL and WGT (allometry) as a covariate on Q
2, V
1, and V
2
| WGT-corrected CL increases with age until approximately 1 month. A linearly scaled version of the model performs slightly better, probably owing to the limited WGT range of the included subjects |
Wiczling (2016) [44] | Critically ill pediatric patients | 38 | a samples obtained during (n = 8) and after (n = 7) long-term DMED infusion | 6 h | 5.8 years (0.12–15.7) 18.5 kg (4.7–60) 23 were male, 15 were female | Initiation of 0.8 µg/kg/h with titration to effect for ventilated patients with maximum of 1.4 µg/kg/h | cfr. Potts | 2-compartment model with age, WGT (allometry), and fractional increase in the 2nd session as covariates on CL and with WGT (allometry) and fractional increase in the 2nd session as covariates on Q
2, V
1, and V
2
| Results might be confounded by concomitant use of sufentanil and midazolam. No population PK model was developed, the parameter estimates were obtained by a Bayesian fit of the Potts model to these data. The posterior distribution for the parameters closely resembles the prior distributions |