Using previously collected data and a sequential modelling approach, we were able to describe dexmedetomidine absorption kinetics and further disposition together with its sympatholytic and haemodynamic effects. |
Accurate models for haemodynamic effects were obtained by combining norepinephrine-dependent sympatholysis with either dexmedetomidine-evoked hypertension or changes in central neural activity. |
Our final models precisely describe dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. |
1 Introduction
2 Materials and Methods
2.1 Study Protocol
2.2 Data Analysis
2.3 Model Development
2.3.1 Structural Models
2.3.2 Stochastic Model
2.3.3 Model Evaluation
2.3.4 Simulations
3 Results
Model | Degrees of freedom | OFVa | Change in OFV | Akaike information criterion |
---|---|---|---|---|
Dexmedetomidine PK | ||||
One-compartment model | 2 | − 306 | – | – |
Two-compartment model | 6 | − 631 | − 325 | – |
Three-compartment modelb | 8 | − 654 | − 348 | – |
PK + absorption | ||||
2 CMT + first-order absorption (with \({{K}}_{{a}}\)) | 7 | − 1290 | – | − 1276 |
2 CMT + first-order absorption + absorption lag time | 8 | − 1433 | − 143 | − 1417 |
2 CMT + single Weibull function | 8 | − 1310 | − 20 | − 1294 |
2 CMT + biphasic absorption | 8 | − 1430 | − 140 | − 1414 |
2 CMT + transit compartment | 8 | − 1350 | − 70 | − 1334 |
2 CMT + Michaelis–Menten absorption | 8 | − 1416 | − 126 | − 1400 |
2 CMT + fat compartment | 9 | − 1454 | − 164 | − 1436 |
2 CMT + fat compartment + bioavailability | 11 | − 1491 | − 201 | − 1469 |
Norepinephrine | ||||
One-compartment model | 6 | − 1641 | – | − 1629 |
Two-compartment model (with FSPILL) | 8 | − 2229 | − 588 | − 2213 |
Systolic blood pressure | ||||
NE-based sympatholysis | 8 | − 567 | – | − 551 |
NE + dexmedetomidine-induced hypertension | 13 | − 622 | − 55 | − 596 |
Diastolic blood pressure | ||||
NE-based sympatholysis | 7 | − 828 | – | − 814 |
NE + dexmedetomidine-induced hypertension | 11 | − 920 | − 92 | − 898 |
Heart rate | ||||
NE-based sympatholysis | 6 | − 1106 | – | − 1094 |
NE + dexmedetomidine-induced hypertensionc | 12 | 389 | – | 413 |
Parameter | Description | Parameter estimate | SIR results | ||
---|---|---|---|---|---|
Mean | %RSE | Median | 95% CI | ||
DEX | |||||
\({\text{Cl}}_{1}\) | Elimination clearance (L/h) | 31.1 | 8.74 | 31.1 | 27.5–34.6 |
\({V}_{1}\) | Volume of the central compartment (L) | 15.0 | 64.2 | 14.8 | 9.34–22.2 |
\({\text{Cl}}_{2}\) | Intercompartmental clearance (L/h) | 82.4 | 8.49 | 82.7 | 73.2–92.9 |
\({V}_{2}\) | Volume of the peripheral compartment (L) | 58.6 | 13.0 | 58.8 | 52.7–65.3 |
\({k}_{\text{a}, \text{FAST}}\) | Rate constant for fast absorption (h−1) | 0.983 | 36.5 | 0.978 | 0.673–1.363 |
\({k}_{\text{a}, \text{SLOW}}\) | Rate constant for slow absorption (h−1) | 0.151 | 41.6 | 0.149 | 0.105–0.199 |
\({k}_{\text{FAT}}\) | Rate constant for partitioning to subcutaneous fat (h−1) | 3.36 | 39.8 | 3.28 | 2.21–4.64 |
\({F}_{\text{D}\text{E}\text{P}\text{O}\text{T}}\) | Bioavailability of the fraction left in the depot after fat permeation | 0.788 | 15.2 | 0.792 | 0.671–0.941 |
\({F}_{\text{F}\text{A}\text{T}}\) | Fraction of drug that enters the fat layer | 0.552 | 29.0 | 0.581 | 0.390–0.813 |
\({\eta }_{1, \text{C}\text{L}1}\) | Inter-individual variability on CL1 | 0.124 | 76.1 | 0.137 | 0.005–0.045 |
\({\eta }_{2, \text{V}1}\) | Inter-individual variability on V1 | 0.456 | 53.9 | 0.448 | 0.068–0.431 |
\({\eta }_{3,\text{F},\text{D}\text{E}\text{P}\text{O}\text{T}}\) | Inter-individual variability on FDEPOT | 0.131 | 57.0 | 0.145 | 0.004–0.048 |
\({\eta }_{4,\text{F},\text{F}\text{A}\text{T}}\) | Inter-individual variability on FFAT | 0.337 | 78.8 | 0.371 | 0.021–0.358 |
\({\sigma }_{\text{P}\text{R}\text{O}\text{P}, \text{I}\text{V}}\) | Proportional RE for intravenous dosing | 0.129 | 17.7 | 0.131 | 0.013–0.022 |
\({\sigma }_{\text{P}\text{R}\text{O}\text{P}, \text{S}\text{C}}\) | Proportional RE for subcutaneous dosing | 0.189 | 7.2 | 0.185 | 0.027–0.042 |
NE | |||||
\({E}_{\text{M}\text{A}\text{X}}\) | Scaling factor for EMAX | 1 (fixed) | |||
\({\text{E}\text{C}}_{50, \text{N}\text{E}}\) | DEX concentration at 50% inhibition in NE release (nM) | 0.334 | 14.5 | 0.333 | 0.252–0.426 |
\({C}_{\text{E}\text{0}}\) | Baseline NE concentration in effect compartment (nM) | 0.814 | 20.5 | 0.816 | 0.634–1.018 |
\({k}_{\text{O}\text{U}\text{T}, \text{R}}\) | Rate constant for NE spill-over from release compartment (h−1) | 9.03 | 14.3 | 9.218 | 7.14–11.5 |
\({f}_{\text{S}\text{P}\text{I}\text{L}\text{L}}\) | Spill-over fraction to plasma | 0.15 (fixed) | |||
\({k}_{\text{O}\text{U}\text{T}, \text{P}}\) | Rate constant for NE elimination from plasma (h−1) | 11.4 | 7.53 | 11.5 | 10.3–12.8 |
\({\eta }_{1, \text{C}\text{E}0}\) | Interindividual variability on CE,0 | 0.446 | 20.7 | 0.230 | 0.120–0.401 |
\({\eta }_{2, \text{k}\text{O}\text{U}\text{T},\text{R}}\) | Interindividual variability on \({\text{k}}_{\text{O}\text{U}\text{T}, \text{R}}\) | 0.237 | 32.7 | 0.072 | 0.022–0.143 |
\({\sigma }_{\text{A}\text{D}\text{D}, \text{N}\text{E},\text{I}\text{V}}\) | Additive RE for NE model after intravenous dosing | 0.097 | 11.0 | 0.100 | 0.084–0.117 |
\({\sigma }_{\text{A}\text{D}\text{D},\text{N}\text{E},\text{S}\text{C}}\) | Additive RE for NE model after subcutaneous dosing | 0.125 | 6.6 | 0.126 | 0.11–0.141 |
Parameter | Description | Parameter estimate | SIR results | ||
---|---|---|---|---|---|
Mean | %RSE | Median | 95% CI | ||
SAP | |||||
\({k}_{\text{e}0, \text{H}\text{P}\text{N}}\) | Biophase rate constant for hypotensive NE effect (h−1) | 22.1 | 27.7 | 22.9 | 17.7–30.4 |
\({\text{E}\text{C}}_{50, \text{N}\text{E}}\) | Biophase NE for causing 50% maximal SAP (nM) | 4.56 | 16.7 | 4.57 | 3.49–5.80 |
\({\gamma }_{\text{H}\text{P}\text{N}}\) | Hill coefficient for hypotension | 6.01 | 15.9 | 6.29 | 4.93–7.90 |
\({E}_{\text{M}\text{I}\text{N}, \text{S}\text{A}\text{P}}\) | SAP at 100% NE inhibition (mmHg) | 49.6 | 1.6 | 49.4 | 48.2–50.8 |
\({E}_{0, \text{S}\text{A}\text{P}}\) | Baseline SAP (mmHg) | 136 | 8.7 | 134 | 123–145 |
\({E}_{\text{M}\text{A}\text{X}}\) | Maximum SAP response | 1 (fixed) | – | – | – |
\({k}_{\text{e}0, \text{H}\text{T}\text{N}}\) | Biophase rate constant for hypertensive effect (h−1) | 22.1 (fixed) | – | – | – |
\({\text{E}\text{C}}_{50, \text{D}\text{E}\text{X}}\) | Biophase DEX for 50% hypertensive effect (ng/mL) | 2.37 | 59.1 | 2.11 | 0.829–4.06 |
\({\gamma }_{\text{H}\text{T}\text{N}}\) | Hill coefficient for hypertensive effect | 1.52 | 29.9 | 1.37 | 0.896–1.95 |
\({\eta }_{1,\text{E}\text{C}50,\text{N}\text{E}}\) | Inter-individual variability on \({\text{E}\text{C}}_{50,\text{N}\text{E}}\) | 0.445 | 39.9 | 0.521 | 0.346–0.718 |
\({\eta }_{2,\text{E}0,\text{S}\text{A}\text{P}}\) | Inter-individual variability on \({\text{E}}_{0,\text{S}\text{A}\text{P}}\) | 0.104 | 70.8 | 0.137 | 0.067–0.200 |
\({\eta }_{3,\text{E}\text{C}50,\text{D}\text{E}\text{X}}\) | Inter-individual variability on \({\text{E}\text{C}}_{50, \text{D}\text{E}\text{X}}\) | 0.77 | 62.5 | 1.13 | 0.692–1.57 |
\({\sigma }_{\text{A}\text{D}\text{D}, \text{I}\text{V}}\) | Additive residual error for intravenous dosing | 9.53 | 14.4 | 9.50 | 8.22–11.0 |
\({\sigma }_{\text{A}\text{D}\text{D}, \text{S}\text{C}}\) | Additive residual error for subcutaneous dosing | 10.8 | 10.7 | 10.6 | 9.23–11.0 |
DAP | |||||
\({k}_{\text{e}0, \text{H}\text{P}\text{N}}\) | Biophase rate constant for hypotensive NE effect (h−1) | 24.3 | 61.1 | 29.4 | 17.4–50.0 |
\({\text{E}\text{C}}_{50, \text{N}\text{E}}\) | Biophase NE for causing 50% maximal DAP (nM) | 4.32 | 23.5 | 4.54 | 3.61–5.64 |
\({\gamma }_{\text{H}\text{P}\text{N}}\) | Hill coefficient for hypotensive effect | 4.99 | 25.2 | 5.07 | 3.27–7.16 |
\({E}_{\text{M}\text{I}\text{N}, \text{D}\text{A}\text{P}}\) | DAP at 100% NE inhibition (mmHg) | 30.2 | 2.1 | 30.3 | 29.5–31.2 |
\({E}_{0,\text{D}\text{A}\text{P}}\) | Baseline DAP (mmHg) | 83.5 | 5.7 | 83.4 | 79.6–87.1 |
\({E}_{\text{M}\text{A}\text{X}}\) | Maximum DAP response | 1 (fixed) | – | – | – |
\({k}_{\text{e}0, \text{H}\text{T}\text{N}}\) | Biophase rate constant for hypertensive effect (h−1) | 30 (fixed) | – | – | – |
\({\text{E}\text{C}}_{50, \text{D}\text{E}\text{X}}\) | Biophase DEX for 50% hypertensive effect (ng/mL) | 0.761 | 40.3 | 0.812 | 0.482–1.25 |
\({\gamma }_{\text{H}\text{T}\text{N}}\) | Hill coefficient for hypertensive effect | 1.99 | 20.7 | 1.99 | 1.50–2.60 |
\({\eta }_{1, \text{E}\text{C}50,\text{N}\text{E}}\) | Inter-individual variability on \({\text{E}\text{C}}_{50, \text{N}\text{E}}\) | 0.382 | 65.5 | 0.434 | 0.295–0.633 |
\({\eta }_{2, \text{E}\text{C}50,\text{D}\text{E}\text{X}}\) | Inter-individual variability on \({\text{E}\text{C}}_{50, \text{D}\text{E}\text{X}}\) | 0.541 | 66.8 | 0.635 | 0.364–0.979 |
\({\sigma }_{\text{A}\text{D}\text{D}, \text{I}\text{V}}\) | Additive residual error for intravenous dosing | 6.30 | 8.7 | 6.32 | 5.61–7.04 |
\({\sigma }_{\text{A}\text{D}\text{D}, \text{S}\text{C}}\) | Additive residual error for subcutaneous dosing | 8.73 | 2.7 | 8.82 | 8.26–9.39 |
HR | |||||
\({k}_{\text{e}0, {\text{H}\text{R}}_{\text{N}\text{E}}}\) | Biophase rate constant for NE in HR effect (h−1) | 6.15 | 25.7 | 6.28 | 3.68–8.97 |
\({E}_{0, \text{H}\text{R}}\) | Baseline HR effect (beats/min) | 62.0 | 4.17 | 62.2 | 59.2–65.2 |
\({\text{E}\text{C}}_{50,\text{N}\text{E}}\) | Biophase NE at 50% of the maximal HR (nM) | 3.12 | 25.9 | 3.20 | 2.26–4.289 |
\({\gamma }_{\text{N}\text{E}}\) | Hill coefficient for NE effect | 2.85 | 22.6 | 2.79 | 1.879–3.73 |
\({E}_{\text{M}\text{I}\text{N}, \text{H}\text{R}}\) | HR at 100% NE inhibition (beats/min) | 24.28 | 1.43 | 24.3 | 23.7–24.9 |
\({\text{E}\text{C}}_{50,\text{S}\text{A}\text{P}}\) | Biophase SAP at 50% NR inhibition (mmHg) | 0.0001 (fixed) | – | – | – |
\({k}_{\text{O}\text{U}\text{T}, \text{N}\text{R}}\) | Dissociation rate constant for NR (h−1) | 0.428 | 6.70 | 0.478 | 0.396–0.478 |
\({E}_{0,\text{N}\text{R}}\) | Baseline NR at physiological SAP levels | 0.0001 (fixed) | – | – | – |
\({k}_{\text{e}0, \text{N}\text{R}}\) | Biophase rate constant for NR in HR effect (h−1) | 0.438 | 7.39 | 0.482 | 0.396–0.482 |
\({\text{E}\text{C}}_{50,\text{N}\text{R}}\) | NR at 50% of the maximal HR | 0.0001 (fixed) | – | – | – |
\({\gamma }_{\text{N}\text{R}}\) | Hill coefficient for NR effect on HR | 12.4 | 56.7 | 11.7 | 5.92–20.7 |
\({\eta }_{1, \text{E}\text{C}50,\text{N}\text{R}}\) | Inter-individual variability on \({\text{E}\text{C}}_{50,\text{C}\text{N}\text{S}}\) | 0.497 | 40.8 | 0.666 | 0.135–0.666 |
\({\sigma }_{1}\) | Additive residual error for intravenous dosing | 5.46 | 15.0 | 6.56 | 4.88–6.56 |
\({\sigma }_{1}\) | Additive residual error for subcutaneous dosing | 5.51 | 13.6 | 6.29 | 4.89–6.29 |