A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults
Abstract
:1. Introduction
2. Methods
2.1. Data Sources
- Hannivoort Model: Hannivoort and colleagues [7] recruited 18 (9 male and 9 female) individuals 18–72 years old with BMI scores between 18 and 30 kg/m2. Dexmedetomidine was delivered using the Dyck model [22] targeting concentrations of 1, 2, 3, 4, 6, and 8 ng/mL after an initial infusion of 6 µg/kg/h for 10 s. Each step was maintained for 30 min. Blood samples for dexmedetomidine assay were obtained at 2 minutes after the initial drug infusion, before each increase in target concentration and at 2, 5, 10, 20, 60, and 120 min after the drug infusion stopped. A large local database [23] was used to sample 18 individuals representative of the demographics in the Hannivoort population. Simulated predicted concentrations in these 18 individuals given 2 mcg/kg loading dose over 10 min followed by infusion 1 mcg/kg for 2 h were used to develop the universal model.
- Potts Model: Potts and colleagues [12] recruited 45 children (22 males and 23 females) after cardiac surgery. Dexmedetomidine was administered (1–4 µg/kg) over 10 min. Three to four blood samples were obtained in the first 30 min after infusion. Samples were obtained at 1–2, 3–4, and 6–10 h thereafter. These data were pooled with two other PK studies (n = 34) of dexmedetomidine [24,25]. These studies are summarised in Supplementary Materials Table S1.
- Cortinez Model: Cortinez and colleagues [16] recruited 20 obese (BMI >35 kg/m2) and 20 non-obese individuals (BMI 18.5–30 kg/m2, 18–60 years old), undergoing elective laparoscopic surgery. Dexmedetomidine 0.5 µg/kg was given to all participants for 10 min. Subsequently, participants were randomised to two infusion regimens: 0.25 or 0.5 µg/kg/h. Doses were based on total body weight (TBW). Blood samples were obtained at 2, 5, 10, 15, 20, 30, 45, 60, 90, and 120 min during dexmedetomidine infusion and at 0, 2, 5, 10, 20, 30, 60, 90, 120, 240, and 360 min after the infusion was stopped.
- Rolle Model: This study enrolled 40 adults (age 18 to 60 years, weights 47 to 126 kg, BMI 18–49 kg/m2) scheduled for abdominal laparoscopic surgery [17]. Dexmedetomidine bolus of 0.5 mcg/kg over 10 min was followed by an infusion of 0.5 mcg/kg/h. Venous blood samples were drawn at 0, 5, 10, 20, 30, 45, 60 min after the start of dexmedetomidine administration and thereafter every 30 min during anaesthesia maintenance. Once dexmedetomidine infusion was stopped at the end of surgery, samples were drawn at the end of dexmedetomidine infusion, and then 5, 10, 20, 30, 60, 90, 120, 240, 360 min, with a last sample between 720 and 1200 min.
- Talke Model: Talke and colleagues recruited 10 healthy individuals (21–36 years old and 52–89 kg) [26]. Dexmedetomidine 4 µg/mL was administered for 15 min to target a plasma concentration of 0.3 ng/ml. Blood samples were obtained at 1, 2, 3, 4, 5, 7.5, 10, and 15 min during drug infusion and 15, 30, and 60 min after the end of the infusion.
2.2. Hannivoort Model Performance in Children Older Than 1 Year
2.3. Pooled Data Analysis
2.3.1. Pharmacokinetic Analyses
2.3.2. Covariate Analysis for Age and Size
2.3.3. Model Selection
2.4. Model Simulation
3. Results
4. Discussion
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Parameter | Estimate | PPV (%) | 95% CI | Sh% |
---|---|---|---|---|
V1 (L/70 kg) | 25.2 | 103.9 | 20.9, 31.3 | 16.4 |
V2 (L/70kg) | 34.4 | 41.8 | 24.3, 44.2 | 15.5 |
V3 (L/70 kg) | 65.4 | 61.6 | 53.4, 74.5 | 8.4 |
CL (L/min/70 kg) | 0.897 | 35.8 | 0.81, 1.02 | 4.1 |
Q2 (L/min/70kg) | 1.68 | 63.2 | 1.22, 1.97 | 12.5 |
Q3 (L/min/70 kg) | 0.62 | 89.7 | 0.45, 0.83 | 21.4 |
FFATV | 0.293 | - | 0.13, 0.55 | - |
FFATCL | 0 FIX | - | - | - |
TM50 | 52.4 | - | 43.5, 68.8 | - |
Hill | 1 FIX | - | - | - |
Additive Residual Error (µg/mL) | 0.004 | ηRUV 0.32 | - | |
Proportional Residual Error (%) | 0.19 | - | 0.18, 0.20 |
Sequential Nested Model | PPVt2 | BSVR2 | BSVP2 | BSVP2/PPVt2 |
---|---|---|---|---|
Clearance | ||||
no covariates | 0.861 * | 0.861 * | 0 | 0 |
TBW with allometric scaling (EXP = 3/4) | 0.861 * | 0.140 | 0.721 | 0.838 |
TBW with PMA on CL | 0.861 * | 0.136 | 0.725 | 0.842 |
FFM with PMA on CL | 0.861 * | 0.114 | 0.747 | 0.867 |
Central compartment (V1) | ||||
no covariates | 1.5 * | 1.5* | 0 | 0 |
TBW allometric scaling (EXP = 1) | 1.5 * | 1.02 | 0.48 | 0.320 |
Peripheral compartment (V2) | ||||
no covariates | 1.46 * | 1.46* | 0 | 0 |
TBW allometric scaling (EXP = 1) | 1.46 * | 0.25 | 1.209 | 0.823 |
Age | Weight (kg) | Height (cm) | Clearance (L/min) | Loading Dose (mcg/kg) | Maintenance (mcg/kg/h) |
---|---|---|---|---|---|
Term neonate | 3.6 | 50 | 0.05 | 0.40 | 0.77 |
3 months | 6 | 62 | 0.08 | 0.38 | 0.80 |
6 months | 7.8 | 67 | 0.11 | 0.37 | 0.81 |
1 year | 10 | 75 | 0.15 | 0.37 | 0.88 |
3 years | 14 | 95 | 0.25 | 0.40 | 1.04 |
6 years | 21 | 115 | 0.36 | 0.39 | 1.02 |
12 years | 40 | 149 | 0.60 | 0.35 | 0.90 |
20 years | 70 | 175 | 0.87 | 0.31 | 0.75 |
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Morse, J.D.; Cortinez, L.I.; Anderson, B.J. A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults. J. Clin. Med. 2020, 9, 3480. https://doi.org/10.3390/jcm9113480
Morse JD, Cortinez LI, Anderson BJ. A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults. Journal of Clinical Medicine. 2020; 9(11):3480. https://doi.org/10.3390/jcm9113480
Chicago/Turabian StyleMorse, James D., L. Ignacio Cortinez, and Brian J. Anderson. 2020. "A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults" Journal of Clinical Medicine 9, no. 11: 3480. https://doi.org/10.3390/jcm9113480