Pharmacokinetics, systems models

Importantly, the currently available transporter models only cover a small fraction of all transporters involved in drug disposition. Other than incorporating current stand-alone transporter models into systemic models to directly predict drug pharmacokinetic properties, continued efforts are still needed to investigate other transporters such as MRP, BCRP, NTCP, and OAT, to get a more complete understanding of the drug pharmacokinetic profile. 

Elizabetli, C.M., Della, P., Oscar Ploeger, B.A. and Voskuyl, R.A. (2007) Mechanism-based pharmacokinetic-pharmacodynamic modeling hiophase distribution, receptor theory, and dynamical systems analysis. Annual Review of Pharmacology and Toxicology, 47, 357-400. 

The first two sections of Chapter 5 give a practical introduction to dynamic models and their numerical solution. In addition to some classical methods, an efficient procedure is presented for solving systems of stiff differential equations frequently encountered in chemistry and biology. Sensitivity analysis of dynamic models and their reduction based on quasy-steady-state approximation are discussed. The second central problem of this chapter is estimating parameters in ordinary differential equations. An efficient short-cut method designed specifically for PC s is presented and applied to parameter estimation, numerical deconvolution and input determination. Application examples concern enzyme kinetics and pharmacokinetic compartmental modelling. 

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

Danhof, M., de Jongh, J., De Lange, E. C., Della Pasqua, O., Ploeger, B. A., Voskuyl, R. A. Mechanism-based pharmacokinetic-pharmacodynamic modeling biophase distribution, receptor theory, and dynamical systems analysis. Anna Rev Pharmacol Toxicol 2007,47 357-400. 

Conceiving models based on block diagrams may be quite complex, involving feedback loops and time delays. A paper [361] shows in detail how such a model can be constructed for a pharmacokinetic system. On the other hand, retentiontime reversible models can be very powerful and flexible for simulation and data fitting. 

Tsokos, J. and Tsokos, C., Statistical modeling of pharmacokinetic systems, Journal of Dynamic Systems, Measurement, and Control, Vol. 98, 1976, pp. 37-43. 

Durisova, M., Dedik, L., and Balan, M., Building a structured model of a complex pharmacokinetic system with time delays, Bulletin of Mathematical Biology, Vol. 57, No. 6, 1995, pp. 787-808. 

Pharmacokinetic Anaiysis Models of Data vs Models of System... 

Unlike the estimates of dosage rates and average steady-state plasma concentrations, which may be determined independently of any pharmacokinetic model in that systemic clearance is the only pharmacokinetic parameter used, the prediction of peak and trough steady-state concentrations requires pharmacokinetic compartmental model assumptions. It is assumed that, (i) drug disposition can be adequately described by a one-compartment pharmacokinetic model, (ii) disposition is independent of dose (i.e. linear pharmacokinetics apply), and (iii) the absorption rate is much faster than the rate of elimination of the drug, which is always valid when the drug is administered intravenously. For clinical applications, these assumptions are reasonable. 

Figure 24.3 Compartmental pharmacokinetic model linking skin absorption determined in an in vitro model to a systemic model to predict plasma concentration time profiles in vivo.

J. Mandema, D. Verotta, and L. B. Sheiner, Building population pharmacokinetic-pharmacodynamic models, in Advanced Pharmacokinetic and Pharmacodynamic Systems Analysis, D. Z. D Argenio (Ed.). Plenum Press, New York, 1995, pp. 69-86. 

Danhof, M. et al., Mechanism-based pharmacokinetic-pharmacodynamic modeling Biophase distribution, receptor theory, and dynamical systems analysis. Annu. Rev. 

A pharmacokinetic profile of sulfisoxazole was determined from data obtained from I.V. administration of the drug in humans. The data suggested the use of a two compartment open system model (16). The excellent agreement between the simulated and experimental data reflects the reliability of the assumption of psuedo first order kinetics for all processes (15). 

The relative advantages and disadvantages of linear system analysis (LSA) and noncompartmentally based pharmacokinetic (PK) modeling to other modeling... 

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