Upholding or Breaking the Law of Superposition in Pharmacokinetics
Abstract
:1. Introduction
Law of Superposition
2. Modeling a Hypothetical Drug “Canadamycin”
2.1. Pharmacokinetics after a Single Intravenous Dose
2.2. Pharmacokinetics after Multiple Intravenous Dosing
2.3. Pharmacokinetics after Multiple Oral Dosing
3. Breaking the Law of Superposition
- The dosing is in a range where the pharmacokinetics are linear and dose proportional;
- The rate and extent of absorption and average clearance are the same for each dosing interval;
- Each dose acts independently from one another, and the sum of all these dosing events provides the total concentration of the drug in circulation.
3.1. Less than Proportional Increase in AUC (AUCSS < AUCSingle Dose)
3.2. More than Proportional Increase in AUC (AUCSS > AUCSingle Dose)
3.3. Other Factors Affecting Adherence to the Law of Superposition
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Dose | Canadamycin (mg/L) | Start Multiple | Trough End (r) | Time (h) | Concentration Lost during Dosage Interval |
---|---|---|---|---|---|
1 | 20.00 | 20.00 | 5.0 | 8 | 15.00 |
2 | 5.00 | 25.00 | 6.25 | 16 | 18.75 |
3 | 1.25 | 26.25 | 6.56 | 24 | 19.69 |
4 | 0.3125 | 26.56 | 6.64 | 32 | 19.92 |
5 | 0.078125 | 26.64 | 6.66 | 40 | 19.98 |
6 | 0.01953125 | 26.66 | 6.67 | 48 | 19.99 |
7 | 0.004882812 | 26.67 | 6.67 | 54 | 20.00 |
1 | 20.00 | 20.00 | 5.0 | 8 | 15.00 |
ADME Process | Main Related Causes of Non-Linearity | Examples | ||
---|---|---|---|---|
Absorption | Carrier-mediated transport | Gabapentin [46], Metformin [47] | ||
Saturable pre-systemic loss | Gut metabolism | Verapamil [48] | ||
First-pass metabolism | Propranolol [49] | |||
Distribution | Saturable plasma protein binding | Paclitaxel [50] | ||
Saturable tissue binding | Imipramine [51] | |||
Elimination | Metabolism | Saturable metabolism | Theophylline [52] | |
Enzyme induction | Carbamazepine [53] | |||
Excretion | Saturable renal excretion | Saturable active secretion | Zidovudine [54] | |
Saturable reabsorption | Methotrexate [55] | |||
Saturable biliary excretion | Tetracycline [56] |
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Yousef, M.; Yáñez, J.A.; Löbenberg, R.; Davies, N.M. Upholding or Breaking the Law of Superposition in Pharmacokinetics. Biomedicines 2024, 12, 1843. https://doi.org/10.3390/biomedicines12081843
Yousef M, Yáñez JA, Löbenberg R, Davies NM. Upholding or Breaking the Law of Superposition in Pharmacokinetics. Biomedicines. 2024; 12(8):1843. https://doi.org/10.3390/biomedicines12081843
Chicago/Turabian StyleYousef, Malaz, Jaime A. Yáñez, Raimar Löbenberg, and Neal M. Davies. 2024. "Upholding or Breaking the Law of Superposition in Pharmacokinetics" Biomedicines 12, no. 8: 1843. https://doi.org/10.3390/biomedicines12081843