Etomidate is a γ-aminobutyric acid type A receptor agonist used for the induction of anesthesia and is well known for its stable cardiorespiratory profile and its adrenal toxicity. |
Recent pharmacokinetic and pharmacodynamic studies of etomidate are scarce. |
Analogs of etomidate were developed over the last decade to improve upon the pharmacokinetic and pharmacodynamic profile of etomidate. |
A recurrent side effect of etomidate and its analog ABP-700 is the occurrence of involuntary muscle movements, the origin of which requires further research. |
1 Introduction
2 Methods
3 Drug Formulation and Dosing
4 Pre-clinical Development of Etomidate Analogs
5 Adverse Effects
5.1 Adrenal Suppression
5.2 Pain on Injection
5.3 Post-operative Nausea and Vomiting
6 Pharmacokinetics
6.1 Pharmacokinetics of Etomidate in Adults
Study (year) | Population | N (male/female) | Blood PK samples | Patient characteristics | Drug administration | Models | |
---|---|---|---|---|---|---|---|
No. of samples | Last sample | Age/weight/height | |||||
Van Hamme (1978) [48] | Eye or ear surgery patients | 8 (5/3) | 14; venous | 10 h postoperatively | 29 years (18–42) 75.3 kg (52.2–102.0) | Induction dose of 0.3 mg/kg | 3-compartment model |
De Ruiter (1981) [51] | General surgery patients | 8 (6/2) | 16; venous | 10 h postoperatively | 31 years (19–65) 70 kg (54–84) | Bolus dose of 0.22 mg/kg | 3-compartment model |
Fragen (1983) [49] | Minor surgical patients | 11(6/5) | 21; arterial | 4 h postoperatively | 34.5 years (19–54) 71.4 kg (50–98) 172.4 cm (152–193) | 0.1 mg/kg/min for 3 min, 0.02 mg/kg/min for 27 min, 0.01 for rest of surgery (maximum 109 min) | 3-compartment model |
Hebron (1983) [50] | Patients with maxillofacial surgery | 6 (3/3) | Not well described; “Blood samples were drawn from the intra-arterial cannula at frequent intervals for the first 2 h and at 4-hourly intervals thereafter” | 22 years (15–38) 62.3 kg (51–98) 167 cm (160–189) | 0.3 mg/kg followed by 1–25 µg/kg/min for approximately 48 h | 3-compartment model | |
Schüttler (1985) [52] | Healthy volunteers | 6 (5/1) | 40–60; venous | Approximately 5 h post-infusion | 25.5 years (± 1.9) 73.5 kg (± 15.8) | Microprocessor controlled infusion to achieve 3 consecutive increasing plasma concentrations of 0.05 µg/mL/min | 2-compartment model |
Arden (1986) [53] | Elective surgical patients | 21 (20/1) | 7 arterial, 7 venous | Arterial: 120 min, venous: 12 h after beginning of the infusion | 56.7 years (22–82) 81.9 kg (11.5) | 5–10 mg/min until “stage 3” of anesthesia | 3-compartment model |
Kaneda (2011) [45] | Healthy volunteers | 18 (10/8) | Irregular; arterial | Awakening | 38.9 years (± 8.5) 63.6 kg (± 8.2) 166.8 cm (± 5.8) | 5 mg/min until loss of eyelash reflexes | 2-compartment model with no significant influence of tested covariates |
Reference (year) | Model parameters | Remark |
---|---|---|
Van Hamme et al. (1978) [48] | Vc (L/kg): 0.310 ± 0.152 k10 (h−1): 2.774 ± 1.386 k12 (h−1): 10.079 ± 4.723 k21 (h−1): 5.464 ± 2.119 k13 (h−1): 3.459 ± 2.843 k31 (h−1): 0.453 ± 0.210 | |
Fragen et al. (1983) [49] | Vc (L/kg): 0.15 ± 0.03 V2 (L/kg): 0.43 ± 0.12 V3 (L/kg): 1.94 ± 0.88 Cl1 (mL/min/kg): 17.9 ± 5.6 Cl2 (mL/min/kg): 25.1 ± 16.2 Cl3 (mL/min/kg): 5.7 ± 2.1 | |
Hebron et al. (1983) [50] | Vc (L/kg): 0.155 k10 (h−1): 0.687 ± 0.089 k12 (h−1): 15.71 ± 1.63 k21 (h−1): 4.31 ± 1.02 k13 (h−1): 7.22 ± 0.97 k31 (h−1): 0.687 ± 0.089 | Vc is not reported in the paper and was calculated as the sum of A, B, and C from the poly-exponential equation |
De Ruiter et al. (1981) [51] | Vc (L/kg): not estimated in this study Vdarea (L/kg): 3.68 ± 0.66 Vdsteady state (L/kg): 2.16 ± 0.32 Cl1 (L/min): 0.879 t1/2α (min): 2.83 ± 2.35 t1/2β (min): 22.3 ± 10.4 t1/2γ (min): 208.8 ± 64.9 | Model parameters based on both non-compartment and compartmental modeling |
Schüttler et al. (1985) [52] | Vc (L): 49.7 ± 10.9 k10 (min−1): 0.036 ± 0.010 k12 (min−1): 0.053 ± 0.011 k21 (min−1): 0.020 ± 0.003 | |
Arden et al. (1986) [53] | Vc (L/kg): 0.090 ± 0.027 Vdsteady state (L/kg): 4.7 ± 1.8 Cl1 (mL/min/kg): 18.3 ± 6.1 Cl2 (mL/min/kg): 25.5 ± 8.2 Cl3 (mL/min/kg): 18.8 ± 4.8 t1/2α (min): 0.93 ± 0.23 t1/2β (min): 12.1 ± 5.1 t1/2γ (min): 324 ± 162 | |
Kaneda et al. (2011) [45] | Vc (L): 4.45 (7.4)a V2 (L): 74.9 (41.7)a Cl1 (L/min): 0.63 (88.9)a Cl2 (L/min): 3.16 (21.4)a | |
Lin et al. (2012) [56] | Vc = θVc.(age/4)−0.451.(WT/70) V2 = θV2. (WT/70) V3 = θV3. (age/4)−0.23. (WT/70) Cl1 = θCl1 (1 − (age − 4) 0.0288)∙(WT/70)0.75 Cl2 = θCl2∙(WT/70)0.75 Cl3 = θCl3∙(WT/70)0.75 Estimates are: Vc (L): 9.51 (10.4)a V2 (L): 11.0 (16.0)a V3 (L): 79.2 (11.0)a Cl1 (L/min): 1.50 (4.0)a Cl2 (L/min): 1.95 (10.6)a Cl3 (L/min): 1.23 (6.7)a | This is the full covariate model including allometric scaling |
Su et al. [57] | Vc (L/70 kg): 8.07 (11.6)a V2 (L/70 kg): 22.8 (23.6)a Cl1 (L/min/70 kg): 0.466 (15.5)a Cl2 (L/min/70 kg): 0.289 (17.5)a | |
Shen et al. [58] | Vc = θVc∙(WT/70) V2 = θV2∙(WT/70) V3 = θV3∙(WT/70) Cl1 = θCl1∙0.733TOF. (WT/70)0.75 Cl2 = θCl2∙(WT/70)0.75 Cl3 = θCl3∙(WT/70)0.75 Estimates are: Vc (L): 8.07 (14)a V2 (L): 13.7 (11.4)a V3 (L): 41.9 (22.9)a Cl1 (L/min/): 1.31 (10.4)a Cl2 (L/min): 1.91 (12.5)a Cl3 (L/min): 0.322 (17.7)a TOF effect on Cl1 = 0.733 (12.9)a | This is the full covariate model including allometric scaling TOF = 0 and 1 for children with and without TOF |
6.1.1 Absorption
6.1.2 Distribution
6.1.3 Metabolism/Elimination
6.2 Pharmacokinetics of Etomidate in Children
Study (year) | Population | N (male/female) | Blood PK samples | Patient characteristics | Drug administration | Tested covariates | Covariate models | |
---|---|---|---|---|---|---|---|---|
No. of samples | Last sample | Age/weight/height Mean (range) or (SD) | ||||||
Lin (2012) [56] | Children aged older than 6 months; elective surgery | 48 (29/19) | 11; arterial | 120 min after the start of the infusion | 4.0 years (0.53–13.21) 15.7 kg (7.5–52) 103 cm (65–170) | 0.3 mg/kg bolus within 15 s | Age and weight | 3-compartmental model with weight on CL and V |
Su (2015) [57] | Neonates and infants with congenital heart disease | 20 (12/8) | >10; venous | Upon cardiopulmonary bypass | 3.35 months (8 days to 11.74 months) 4.98 kg (2.5–8.35) | 0.3 mg/kg bolus upon induction prior to surgery | Age, weight, effect of shunt | 2-compartmental model with no significant influence of tested covariates |
Shen (2016) [58] | Neonates/infants with unrepaired tetralogy of Fallot and normal cardiac anatomy | 29 (17/12) | 9–10; arterial | 120 min after the start of the infusion | 236 days (± 72) 7.7 kg (± 1.2) | 60 µg/kg/min until BIS < 50 | Age, sex, height, hemoglobin, hematocrit, creatinine, alanine aminotransferase, aspartate aminotransferase, total bilirubin, total protein, prothrombin time | 3-compartmental model with TOF on CL |