Pharmacokinetic Model-Based Control across the Blood–Brain Barrier for Circadian Entrainment
Abstract
:1. Introduction
- To develop two passive and three active transport models that describe drug concentration profiles of a circadian pharmaceutical at the brain level under oral administration;
- To design an MPC-based control framework based on each PK profile for phase resetting.
2. Material and Methods
2.1. Pharmacokinetic Models
- Simple passive diffusion: linear distribution from the plasma compartment to the brain compartment (Figure 1A);
- Carrier-mediated transport: saturable transport from the plasma compartment to the brain compartment (Figure 1B);
- Polymeric nanoparticle transcytosis: reversible kinetics between the plasma and the brain compartments (Figure 1C).
2.1.1. Passive Diffusion
2.1.2. Carrier-Mediated Transport
2.1.3. Polymeric Nanoparticle Transcytosis
2.2. Model Parameters Identification
Extended Kalman Filter
2.3. Circadian Oscillator Model
2.4. MPC Formulation
3. Results
3.1. Pharmacokinetic Models
3.2. Controller Performance
4. Discussion
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Transport System | F [%] | [min] | [min] | [min] | [min] | [mL] | [mL] | [mg/min] | [mg/mL] |
---|---|---|---|---|---|---|---|---|---|
Passive diffusion [26,27,28] | 0.14 | 0.11 | 0.11 | 4.53 | 2.82 | 1.80 | 3.30 | - | - |
Carrier-mediated transport (Amine) [29,30] | 0.80 | 2.90 | 0.10 | - | 3.38 | 3.00 | 0.90 | 10.00 | 0.44 |
Carrier-mediated transport (Neutral Amino Acid) [29,30] | 0.30 | 1.40 | 1.30 | - | 2.82 | 1.00 | 0.30 | 30.00 | 0.12 |
Carrier-mediated transport (T3) [29,30] | 0.75 | 4.00 | 0.02 | - | 1.30 | 1.50 | 3.00 | 0.10 | 1.00 |
Polymeric nanoparticle transcytosis [35] | 0.14 | 0.11 | 0.11 | 6.10 | 8.30 | 1.80 | 3.30 | - | - |
Reference | Sample Size | Trasport System (Substrate) | Dose [mg] | [mg/mL/min] | [mg/mL/min] | [mg/mL] | [mg/mL] |
---|---|---|---|---|---|---|---|
De Muro et al. [31] | 12 | Passive diffusion | 2.00 | 2.37 | 2.31 | 3.40 | 4.67 |
Jonklass et al. [32] | 12 | T3 (Triiodothyronine) | 0.05 | 1.12 | 1.94 | 3.46 | 3.81 |
Bockmann et al. [33] | 6 | Amine (Choline) | 550.00 | 0.40 | 0.30 | 1.04 | 2.30 |
Nyholm et al. [34] | 19 | Neutral amino acid (L-Dopa) | 100.00 | 8.48 | 0.12 | 9.46 | 1.13 |
Transport System | % Administered Dose | [min] |
---|---|---|
Passive diffusion | 30.70 | 117 |
Carrier-mediated transport (Amine) | 0.23 | 50 |
Carrier-mediated transport (Neutral Amino Acid) | 2.12 | 61 |
Carrier-mediated transport (T3) | 0.18 | 193 |
Polymeric nanoparticle transcytosis | 5.48 | 380 |
Transport System | [mg] | Time Required for 5-h Phase Advance [h] | Time Required for 11-h Phase Delay [h] | |
---|---|---|---|---|
Passive diffusion | 2.00 | 1.00 | 60 | 66 |
Carrier-mediated transport (Amine) | 16.50 | 1.00 | 50 | 54 |
Carrier-mediated transport (Neutral Amino Acid) | 3.00 | 0.10 | 30 | 48 |
Carrier-mediated transport (T3) | 4.30 | 0.10 | N/A | 72 |
Polymeric nanoparticle transcytosis | 0.06 | 1.00 | N/A | 84 |
Baseline [24] | 0.06 | 1.00 | 30 | 36 |
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Murdoch, S.Ó.; Aiello, E.M.; Doyle, F.J., III. Pharmacokinetic Model-Based Control across the Blood–Brain Barrier for Circadian Entrainment. Int. J. Mol. Sci. 2023, 24, 14830. https://doi.org/10.3390/ijms241914830
Murdoch SÓ, Aiello EM, Doyle FJ III. Pharmacokinetic Model-Based Control across the Blood–Brain Barrier for Circadian Entrainment. International Journal of Molecular Sciences. 2023; 24(19):14830. https://doi.org/10.3390/ijms241914830
Chicago/Turabian StyleMurdoch, Síofra Ó., Eleonora M. Aiello, and Francis J. Doyle, III. 2023. "Pharmacokinetic Model-Based Control across the Blood–Brain Barrier for Circadian Entrainment" International Journal of Molecular Sciences 24, no. 19: 14830. https://doi.org/10.3390/ijms241914830