# A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults

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## Abstract

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## 1. Introduction

^{/}kg) decreasing with increasing age [11,13].

## 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/m
^{2}. 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/m
^{2}) and 20 non-obese individuals (BMI 18.5–30 kg/m^{2}, 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/m
^{2}) 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

_{0}is the observed concentration and C

_{p}is the concentration predicted by the adult model. Precision was evaluated using the root mean squared prediction error (rmse) (Equation (2)).

#### 2.3. Pooled Data Analysis

#### 2.3.1. Pharmacokinetic Analyses

_{STD}) to predict the value in a given individual.

^{2}(Equation (6)).

_{TV}is the typical value for that parameter, and η is the random effects variable.

_{RUV,i}) of the RUV was also estimated for both PK and PD data. The population mean parameters, between subject variance and residual variance, were estimated using the first-order conditional interaction estimate method using ADVAN13 TOL=9 of NONMEM. Convergence criterion was 3 significant digits.

_{ij}is the dexmedetomidine plasma concentration in the ith individual at the jth time. Individual predictions of dexmedetomidine concentration were calculated using Equation (8) with the random effects ($\epsilon $) fixed to 1.

#### 2.3.2. Covariate Analysis for Age and Size

_{STD}. The standardised value for NFM can be defined using a FFM of 56.1 kg, expected for a male with a TBM of 70 kg and height of 1.76 m. Theory-based allometric scaling can be used to compare CL values for a child in terms of a standardised NFM value, most widely expressed for a 70 kg individual, with the allometric exponent of ¾. This is shown in Equation (15).

_{50}is the maturation half-time, and the Hill exponent relates to the steepness of the maturation profile [31].

#### 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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**Figure 1.**Prediction-corrected visual predictive check (PC-VPC) for dexmedetomidine pharmacokinetics using the model by Hannivoort [7] with observed dexmedetomidine plasma concentrations sought from Potts [19]. Plots show median (solid) and 90% intervals (dashed lines). The left-hand plot shows all prediction-corrected observed dexmedetomidine concentrations. Right-hand plot shows prediction-corrected percentiles (10%, 50%, and 90%) for observations (grey dashed lines) and predictions (red dashed lines) with 95% confidence intervals for prediction percentiles (median, pink shading; 5th and 95th blue shading).

**Figure 2.**Violin plot showing the distribution of age (years), fat-free mass (kg), weight (kg), and height (cm) in the pooled dexmedetomidine data used to develop the universal PK model. A box and whisker plot overlays the violins in blue.

**Figure 3.**Prediction-corrected visual predictive check (PC-VPC) for the universal dexmedetomidine PK model. Model developed using pooled paediatric [19] and adult [16,26] dexmedetomidine plasma concentrations. Plots show median (solid) and 90% intervals (dashed lines). The left-hand plot shows all prediction-corrected observed dexmedetomidine concentrations. Right-hand plot shows prediction-corrected percentiles (10%, 50%, and 90%) for observations (grey dashed lines) and predictions (red dashed lines) with 95% confidence intervals for prediction percentiles (median, pink shading; 5th and 95th blue shading).

**Figure 4.**Maturation of dexmedetomidine clearance when scaled using fat-free mass, determined from pooled published data.

**Figure 5.**Simulated per kilo (TBW) dexmedetomidine maintenance infusion rates to maintain plasma concentration of 1 mcg/L. Infusion rates are affected by the effects of maturation and size in metabolic clearance. Clearance in term neonates is 42% of adult values, reaching 80% by 3 years of age. Allometric relationships between size and clearance explain the decrease in infusion rates (mcg/kg/min) in patients older than 3 years.

**Table 1.**Dexmedetomidine population pharmacokinetic parameter estimates for the final universal model. Parameter estimates and population variability displayed as medians determined from 1000 bootstrap estimates.

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 | - | - | - |

TM_{50} | 52.4 | - | 43.5, 68.8 | - |

Hill | 1 FIX | - | - | - |

Additive Residual Error (µg/mL) | 0.004 | η_{RUV} 0.32 | - | |

Proportional Residual Error (%) | 0.19 | - | 0.18, 0.20 |

_{50}: maturation halftime; Hill: exponent describing the steepness of the maturation profile. FFATV: factor on fat for volume; FFATCL: factor on fat for clearance. Residual unidentified variability: RUV; population parameter variability: PPV%. Sh% = shrinkage. Size is accounted for using theory-based allometric scaling to a 70 kg individual with the allometric exponents of ¾ for CL and 1 for V. PPV% = $\surd variance$.

**Table 2.**Effect of covariate analysis on variance (ω

^{2}). Impact of each covariate on CL when added sequentially to the model.

Sequential Nested Model | PPVt^{2} | BSVR^{2} | BSVP^{2} | BSVP^{2}/PPVt^{2} |
---|---|---|---|---|

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 |

**Table 3.**Dexmedetomidine maintenance infusion rates, determined using simulation, that maintain plasma concentration of 1 mcg/L. The loading dose was given over 30 min and the maintenance infusion scheme was designed to maintain dexmedetomidine a plasma concentration of 1 mcg/L.

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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**MDPI and ACS Style**

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

**AMA Style**

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 Style**

Morse, 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