Pharmacokinetic Models PDF

Pharmacokinetic models Subject Incharge Muhammad Muaaz Munir PH.D Scholar, MPhil, Pharm D, R.Ph.  Pharmacokinetic models Model is a schematic and easy way to understand representation of a complex phenomenon. Thus a pharmacokinetic model simplifie...

Pharmacokinetic models Subject Incharge Muhammad Muaaz Munir PH.D Scholar, MPhil, Pharm D, R.Ph.  Pharmacokinetic models Model is a schematic and easy way to understand representation of a complex phenomenon. Thus a pharmacokinetic model simplifies the complex pharmacokinetic processes. Pharmacokinetic models are hypothetical structures that are used to describe the fate of a drug in a biological system following its administration. It also describes the drug conc in the body and factors affecting it as a function of time. Most PK models assume that the drug conc in blood reflects drug conc globally within the body. These models are based on mathematical relationships & are used to explain and predict overall behavior of a drug in body.  Need of using pharmacokinetic models A drug after administration is in a dynamic state because multiple events are happening simultaneously including absorption, distribution, metabolism and excretion (ADME). This dynamic state of drug coupled with complex biological system necessitates simplified assumptions to describe the movement of a drug in the body as a function of time. The temporal transition (concentration change with passage of time) that a drug undergoes in the body is known as kinetics. Information can be obtained about the kinetics of drugs in the body.  Reliability of PK models A model can be made reliable by a process known as model fitting. In this method, an observed data is matched to a mathematical equation (model) by observing the best fit of the data to the model. Statistical criteria is used to evaluate a model best fitting to the data. If the proposed model does not fit accurately all the experimental observations, a more complex model may be proposed.  Applications of the pharmacokinetic models Despite of some limitations, the pharmacokinetic models are useful to: 1. Describe the underlying processes. 2. Predict the plasma, tissue and urine drug levels after drug administration. 3. Describe the time course of action. 4. Calculate the optimum dosage regimen for each patient individually. 5. Estimate the possible accumulation of drug and metabolites 6. Minimize the toxicity and adverse reactions.  Applications Continue…. 7. Correlate drug conc with the pharmacologic or toxicologic activity. 8. Evaluate differences in rate or extent of BA between formulations in BE studies. 9. Explain the effect of changes in physiology or disease on the PK of drug. 10. Explain drug interaction at the level of ADME. 11. Improve drug therapy and efficacy. 12. Develop a new drug delivery system.  Types of pharmacokinetic models Different types of models are: 1. Classical/ empirical compartment models (probabilistic) 2. Physiologically based compartment models (realistic) 3. Model-independent approach/non compartmental analysis  PHYSIOLOGIC PHARMACOKINETIC MODELS Subject Incharge Muhammad Muaaz Munir PH.D Scholar, MPhil, Pharm D, R.Ph.  Definition: Physiologic phrmacokinetic models are mathematical models describing drug movement and disposition in the body based on blood flow and the organ spaces penetrated by the drug. They are based on the known anatomy, physiology and on blood perfusion of the species under study. Grouping of tissues are based on the perfusion. Usually the critically important tissues are described individually. The rest of the tissues are collectively described as rapidly equilibrating tissues or slowly equilibrating tissues. Physiologic pharmacokinetic models are used to predict the drug levels in different organs and to simulate the drug disposition in various disease conditions. Features of Physiologic Pharmacokinetic Model These models are based on real anatomy and physiology. Drug concentrations are measureable by organ size and blood flow without data fitting. Number of tissues in a model depends upon the drugs. Besides the critical organs, the other organs are grouped as RET and SET. Physiologic models require differential equations to measure drug concentrations in each compartment. Interspecies scale up of data is possible. The compartment size or mass is measured physiologically.  Devising Physiologic Models Devising of physiological model requires the inclusion of all relevant organs into a model. This inclusion is based on the physicochemical characteristics of a drug. Simplest model is selected first which can be refined if more data is available to a more detailed or complex model. Series of differential equations are used to describe the models usually by employing computer. The physiological model identifies the compartments with actual body spaces. These model are more complex than the compartmental models, include blood perfusion models and diffusion limited models.  Deciding the Number of Compartments Usually the tissues with no drug penetration are excluded from the model. The number of compartments in a model also depends on the way the body handles the drug.  Data Analysis in Physiologic Models Data analysis is based on simulation that requires incorporation of the physiological constants, organs parameters , physicochemical parameters of drug in mathematical equations for a proposed model With simulation, concentration of drug in tissues, its clearance ,half life and other parameters can be estimated.  Types of Physiologic Pharmacokinetic Models The physiologic pharmacokinetic models can be distinguished into the following. 1. Flow limited physiologic models (also known as blood perfusion models) 2. Physiological model with binding 3. Diffusion-limited physiological model  Blood perfusion model In this model the drug movement is considered to be blood flow dependent, without resistance in membrane permeation and thus, is rapid. After tissues uptake , the drug is considered to leave via venous blood flow. Tissue and blood protein binding with drugs can be incorporated in blood perfusion model.  Kinetic Analysis of Perfusion Models The kinetic analysis of physiologic pharmacokinetic models is possible by mathematical equations. The rate of blood flow to various tissues is the basis for calculation of the rate of change of drug concentration. Rate of change in drug conc.= Qt(Cin – Cout) = Qt (Cart – Cven) (i) Cin and Cout are the drug blood concentration entering and leaving tissues, respectively. The rate of change of drug concentration in tissue Rate of blood flow x (Cin – Cout)  The ratio of drug concentrations in tissues and venous blood is tissue blood partition coefficient. Pt = Ct/Cb Where, Pt=partition coefficient Ct= conc. In tissue Cb = drug conc. In blood Cven may be estimated from the tissue/blood partition coefficient Cven =Ct/Pt Eq.i can be written as Qt (Cart – Ct/Pt)  In perfusion model the drug distribution to the eliminating as well as non eliminating organs is required to be calculated. To estimate the drug concentration in the eliminating organs, the respective elimination constants are to be added to account for the drug elimination. Clearance is also added to estimate the rate of change of drug concentrations in the eliminating organs. Rate of drug elimination = Ctissue x CL tissue For example clearance from kidney can be written as Rate of change of drug conc.= Qkid(Ckida-Ckid/Pkid)-Ckid xCLkid/Pkid  References Biopharmaceutics by Leone Shargel