* Introduction Pharmacokinetic models Compartment Models Physiological Models Noncompartmental Analysis One-compartment open model Intravenous Bolus Administration Intravenous Infusion Extravascular Administration Pharmacokinetic parametersQ INTRODUCTION © The duration of drug therapy ranges from a single dose of a drug taken for relieving an acute condition such as headache to drugs taken life- long for chronic conditions such as hypertension, diabetes, asthma or epilepsy. The frequency of administration of a drug in a particular dose is called as dosage regimen. Depending upon the therapeutic objective to be attained, the duration of drug therapy and the dosage regimen are decided. Rational and optimal therapy with a drug depends upon - a. Choice ofa suitable drug, and b. A balance between the therapeutic and the toxic effects. Pharmacokinetics is defined as the kinetics of drug absorption, distribution, metabolism and excretion (KADME) and _ their relationship with the pharmacological, therapeutic or toxicological response in man and animals. There are two aspects of pharmacokinetic studies - 1. Theoretical aspect - which involves development of pharmacokinetic models to predict drug disposition after its administration. Statistical methods are commonly applied to interpret data and assess various parameters. 2. Experimental aspect - which involves development of biological sampling techniques, analytical methods for measurement of drug (and metabolites) concentration in biological samples and data collection and evaluation.Several relevant terms can now be defined - * Clinical Pharmacokinetics is defined as the application pharmacokinetic principles in the safe and effective management individual patient. * Population Pharmacokinetics is defined as the study pharmacokinetic differences of drugs in various population groups. of of of = Toxicokinetics is defined as the application of pharmacokinetic principles to the design, conduct and interpretation of drug safety evaluation studies. The three important pharmacokinetic parameters that describe the plasma level-time curve and useful in assessing the bioavailability of a drug from its formulation are - 1. Peak Plasma Concentration (Cmax) The point of maximum concentration of drug in plasma is called as the peak and the concentration of drug at peak is known as peak plasma concentration. It is also called as peak height concentration and maximum drug concentration. Cmax is expressed in mcg/ml. © The peak plasma level depends upon - ¥ The administered dose v_ Rate of absorption, and ¥ Rate of elimination. © The peak represents the point of time when absorption rate equals elimination rate of drug. © The portion of curve to the left of peak represents absorption phase ie. when the rate of absorption is greater than the rate of elimination.a © The section of curve to the right of peak generally represents | elimination phase i.e. when the rate of elimination exceeds rate of absorption. © Peak concentration is often related to the intensity of pharmacological response and should ideally be above minimum effective concentration (MEC) but less than the maximum safe concentration (MSC). 2. Time of Peak Concentration (tmax) The time for drug to reach peak concentration in plasma is called as the time of peak concentration. It is expressed in hours and is useful in estimating the rate of absorption. 3. Area Under the Curve (AUC) Itrepresents the total integrated area under the plasma level-time profile and expresses the total amount of drug that comes into the systemic circulation after its administration. AUC is expressed in mcg/ml X hours. It is the most important parameter in evaluating the bioavailability of a drug from its dosage form as it represents the extent of absorption. «» Pharmacodynamic Parameters The various pharmacodynamic parameters are — 1. Minimum Effective Concentration (MEC) It is defined as the minimum concentration of drug in plasma required to produce the therapeutic effect. It reflects the minimum concentration of drug at the receptor site to elicit the desired pharmacological response. 2. Maximum Safe Concentration (MSC) Also called as minimum toxic concentration (MTC), it is the concentration of drug in plasma above which adverse or unwanted effects are precipitated.3. > o 7. 8. om % ———— Onset of Action The beginning of pharmacological response is called as onset of action. It occurs when the plasma drug concentration just exceeds the required MEC. Onset Time It is the time required for the drug to start producing pharmacological response. It corresponds to the time for the plasma concentration to reach MEC after administration of drug. Duration of Action The time period for which the plasma concentration of drug remains above the MEC level is called as duration of drug action. It is also defined as the difference between onset time and time for the drug to decline back to MEC. Intensity of Action It is the maximum pharmacological response produced by the peak plasma concentration of drug. It is also called as peak response. Therapeutic Range The drug concentration between MEC and MSC represents the therapeutic range. It is also known as therapeutic window. Therapeutic Index The ratio of MSC to MEC is called as therapeutic index. It is also defined as the ratio of dose required to produce toxic or lethal effects to dose required to produce therapeutic effect. Rate, Rate Constants and Orders of Reactions Pharmacokinetics is the mathematical analysis of processes of ADME. The movement of drug molecules from the site of application to the systemic circulation, through various barriers, Their conversion into another chemical form and finally their exit out of the body can be expressed mathematically by the rate at which they proceed, the order of such processes and the rate constants.The rate of forward reaction is expressed as = . NNN The velocity with which a reaction or a process occurs is called as its rate. The manner in which the concentration of drug (or reactants) influences the rate of reaction or process is called as the order of | reaction or order of process. Consider the following chemical reaction: Drug A—— Drug B “dt Negative sign indicates that the concentration of drug A decreases with time t. As the reaction proceeds, the concentration of drug B increases and the rate of reaction can also be expressed as: 4B dt Experimentally, the rate of reaction is determined by measuring the decrease in concentration of drug A with time t. IfC is the concentration of drug A, the rate of decrease in C of drug A as it is changed to B can be described by a general expression as a function of timet. dc 4 where, K = rate constant — = -KC' A dt n= order of reaction If n = 0, its a zero-order process, if n = 1, it is a first-order process and so on. The three commonly encountered rate processes in a physiological system are — Y Zero-order process Y First-order process ¥ Mixed-order process. The pharmacokinetics of most drugs can be adequately described by zero- and first order processes.> Zero-Order Kinetics (Constant Rate Processes) Ifn=0, # _ _K0C% Ky where Ky = zero-order rate constant (inmg/min) The zero-order process can be defined as the one whose rate is independent of the concentration of drug undergoing reaction i.e. The rate of reaction cannot be increased further by increasing the concentration of reactants. Rearrangement of equation yields: dC =-Ky dt Integration of equation gives: C - Cp = -Kgt where ,Co = concentration of drug at t = 0, and C = concentration of drug yet to undergo reaction at time t. * A plot of C versus t yields such a straight line having slope - Ko and y- intercept Cy ac steady drug loss dt slope =~ Ky —- — 0 —_—+ ES ¢ Examples of a processes are - 1. Metabolism/protein-drug binding/enzyme or carrier-mediated transport under saturated conditions. The rate of metabolism, binding or transport ofdrug remains constant as long as its concentration is in excess of saturating concentration. 2. Administration ofa drug as a constant rate i.v. infusion. 3. Controlled drug delivery such as that from i.m. implants or osmotic pumps. » First-Order Kinetics (Linear Kinetics) Ifn=1, - = —-KC Where, K = first-order rate constant (in time-1 or per hour) ° A first-order process is the one whose rate is directly proportional to the concentration of drug undergoing reaction i.e. Greater the concentration, faster the reaction. It is because of such proportionality between rate of reaction and the concentration of drug that a first-order process is said to follow linear kinetics. slope = - —— C © Most pharmacokinetic processes viz. absorption, distribution and elimination follow first-order kinetics First-Order Half-Life Substituting the value of C = Co/2 at t% in equation and solvingit yields:The half-life of a first-order process is a constant and independent of initial drug concentration i.e. irrespective of what the initial drug concentration is, the time required for the concentration to decrease by | one-half remains the same. The t% of a first-order process is an important pharmacokinetic parameter. Mixed-Order Kinetics (Nonlinear Kinetics) In some instances, the kinetics of a pharmacokinetic process changes from predominantly first-order to predominantly zero-order with increasing dose or chronic medication. A mixture of both first-order and zero-order kinetics is observed in such cases and therefore the process is said to follow mixed-order kinetics. The rate process of such a drug is called as nonlinear kinetics. Mixed order kinetics is also termed as dose-dependent kinetics as it is observed at increased or multiple doses of some drugs. Nonlinearities in pharmacokinetics have been observed in - v Drug absorption (e.g. vitamin C) Y Drug distribution (e.g. naproxen), and ¥ Drug elimination (e.g. riboflavin). PHARMACOKINETIC MODELS Drug movement within the body is a complex process. The major objective is therefore to develop a generalized and simple approach to describe, analyse and interpret the data obtained during in vivo drug disposition studies. The two major approaches in the quantitative study of various kinetic processes of drug disposition in the body are -Y Model approach, and ¥ Model-independent approach (non-compartmental analysis). Pharmacokinetic Model Approach In this approach, models are used to describe changes in drug concentration in the body with time. Amodel isa hypothesis that employs mathematical terms to concisely describe quantitative relationships. Pharmacokinetic models provide concise means of expressing mathematically or quantitatively, the time course of drug throughout the body and compute meaningful pharmacokinetic parameters. Types of Pharmacokinetic Models Pharmacokinetic models are of three different types - 1. Compartment models - are also called as empirical models, and 2. Physiological models - are realistic models. 3. Distributed parameter models ~ are also realistic models.Compartmental analysis is the traditional and most commonly used approach to pharmacokinetic characterization of a drug. These models | simply interpolate the experimental data and allow an empirical | formula to estimate the drug concentration with time. \| A compartment is not a real physiological or anatomic region but an | imaginary or hypothetical one consisting of tissue/ group of tissues with similar blood flow & affinity. Our body is considered as composed of several compartments connected | reversibly with each other. Advantages Gives visual representation of various rate processes involved in drug | disposition. | Possible to derive equations describing drug concentration changes in each compartment. One can estimate the amount of drug in any compartment of the system after drug is introduced into a given compartment. Disadvantages Drug given by IV route may behave according to single compartment model but the same drug given by oral route may show 2 compartment | behaviour. The type of compartment behaviour i.e. Type of compartment model may | change with the route of administration. | Depending upon whether the compartments are arranged parallel or in — a series, compartment models are divided into two categories — v Mammillary model v Catenary model |> Mammillary Model * This model is the most common compartment model used in pharmacokinetics. It consists of one or more peripheral compartments connected to the | central compartment (ie. they are joined parallel to the central | compartment). The central compartment (or compartment 1) comprises of plasma | and highly perfused tissues such as lungs, liver, kidneys, etc. which rapidly | equilibrate with the drug. | The drug is directly absorbed into this compartment (i.e. blood). Elimination too occurs from this compartment since the chief organs involved in drug elimination are liver and kidneys. The peripheral compartments or tissue compartments (denoted by numbers 2, 3, etc.) are those with low vascularity and poor perfusion. Distribution of drugs to these compartments is through blood. Movement of drug between compartments is defined by characteristic first-order rate constants denoted by letter K. The subscript indicates the direction of drug movement; thus, K,, (K-one- two) refers to drug movement from compartment 1 to compartment 2 and reverse for K2. basically Ka, the first-order absorption rate constant and Ko is KE, the first- order elimination rate constant. Various mammillary compartment models. The rate constant Ko, is One compartment open model, intravenous administrationModel 2 Ko: Kio One compartment open model , extravascular (oral, rectal etc.) administration Model 3 Ky, | Sa Ka Two compartment open model, intravenous administration Model 4 Kor Model 5 Three compartment open model, intravenous administration Model 6 Three compartment open model, extravascular administration> Catenary Model © In this model, the compartments are joined to one another ina series like compartments of a train. This is however not observable physiologically /anatomically as the various organs are directly linked to the blood compartment. Hence this model is rarely used. | . pharmacokinetic models (PB-PK models). * They are drawn on the basis of known anatomic and physiological data and thus present a more realistic picture of drug disposition in various organs and tissues. ° The number of compartments to be included in the model depends upon the disposition characteristics of the drug. Since describing each organ/tissue with mathematic equations makes the model complex, tissues with similar perfusion properties are grouped into a single compartment. For example, lungs, liver, brain and kidney are grouped as rapidly equilibrating tissues (RET) while muscles and adipose as slowly equilibrating tissues (SET). A physiological model where the compartments are arranged in a series in | * These models are also known as_ physiologically-based a flow diagrami p= — wr Schematic representation of a physiological pharmacokinetic VENOUS BLOOD model. The term Q indicates blood flow rate to a body region. HPT stands for other highly perfused tissues and PPT for poorly perfused tissues. Km is rate constant for hepatic elimination and Keis first-order rate constant for urinary excretion. © Since the rate of drug carried to a tissue organ and tissue drug uptake are dependent upon two major factors — ¥ Rate of blood flow to the organ, and ¥ Tissue/blood partition coefficient or diffusion coefficient of drug that governs its tissue permeability The physiological models are further categorized into two types - 1. Blood flow rate-limited models -based on the assumption that the drug movement within a body region is much more rapid than its rate of delivery to that region by the perfusing blood. These models are therefore also called as perfusion rate-limited models.. Membrane permeation rate-limited models - These models are more | complex and applicable to highly polar, ionised and charged drugs, in which case the cell membrane acts as a barrier for the drug that | gradually permeates by diffusion. These models are therefore also | called as diffusion-limited models. This model is analogous to physiological model but has been designed to | take into account - | v Variations in blood flow to an organ, and v Variations in drug diffusion in an organ. Such a model is thus specifically useful for assessing regional differences in drug concentrations in tumours or necrotic tissues. The distributed parameter model differs from physiological models in that the mathematical equations are more complex and collection of drug concentration data is more difficult. Model independent approach Noncompartmental Analysis The noncompartmental analysis, also called as the model-independent method, does not require the assumption of specific compartment model. This method is, however, based on the assumption that the drugs or metabolites follow linear kinetics, and on this basis, this technique can be applied to any compartment model. The noncompartmental approach, based on the statistical moments theory, involves collection of experimental data following a single dose of drug.i Where, MRT = mean residence time If one considers the time course of drug concentration in plasma as a statistical distribution curve, then: AUMC MRT= “AUC AUMC = area under the first-moment curve AUC = area under the zero-moment curve Practically, the AUMC and AUC can be calculated from the respective graphs by the trapezoidal rule (the method involves dividing the curve by a series of vertical lines into a number of trapezoids, calculating separately the area of each trapezoid and adding them together). LY Lo ’ L7 5S ——> Concentration X Time ——> Concentration My OX oF 535 Zz oy K OOK Soe Soe Or Pe pees oS Bo S35 bess IS MRT is defined as the average amount of time spent by the drug in the body before being eliminated. In this sense, it is the statistical moment analogy of half-life, t¥%. In effect, MRT represents the time for 63.2% of the intravenous bolus dose to be eliminated. The values will always be greater when the drug is administered in a fashion other than iv. bolus.|G ONE-COMPARTMENT OPEN MODEL (Instantaneous Distribution Model) The one-compartment open model is the simplest model. Owing to its — simplicity, it is based on following assumptions - 1. The body is considered as a single, kinetically homogeneous unit that has no barriers to the movement of drug. 2. Final distribution equilibrium between the drug in plasma and | other body fluids (ie. mixing) is attained instantaneously and maintained at all times. This model thus applies only to those drugs that distribute rapidly throughout the body. 3. Drugs move dynamically, in (absorption) and out (elimination) of this compartment. 4. Elimination is a first-order (monoexponential) process with first- order rate constant. 5. Rate of input (absorption) > rate of output (elimination). 6. The anatomical reference compartment is plasma and concentration of drug in plasma is representative of drug concentration in all body tissues i.e. any change in plasma drug concentration reflects a proportional change in drug concentration throughout the body. However, the model does not assume that the drug concentration in plasma is equal to that in other body tissues. The term open indicates that the input (availability) and output (elimination) are unidirectional and that the drug can be eliminated from the body. One-compartment open model is generally used to describe plasma levels following administration of a single dose of a drug.Output Input (Elimination) (absorption) Depending upon the rate of input, several one-compartment open models can be defined: . 1. One-compartment open model, iv. bolus administration. . 2. 3. One-compartment open model, e.v. administration, zero-order absorption. 4. One-compartment open model, e.v. administration, first-order absorption > Intravenous Bolus Administration © When a drug that distributes rapidly in the body is given in the form of a rapid intravenous\ injection (i.e. iv. bolus or slug), it takes about one to three minutes for complete circulation and therefore the rate of absorption is neglected in calculations. The model can be depicted as follows: | One-compartment open model, continuous iv. infusion. | | The general expression for rate of drug presentation to the body is: x. Rate in (availability)-Rate out (elimination) Since rate in or absorption is absent, the equation becomes: m -Rate out (elimination) If the rate out or elimination follows first-order kinetics, then:ae RK where, KE = first-order elimination rate constant, and X= amount of drug in the body at any time t remaining to be eliminated. Negative sign indicates that the drug is being lost from the body. Estimation of Pharmacokinetic Parameters For a drug that follows one-compartment kinetics and administered as rapid iv. injection, the decline in plasma drug concentration is only due to elimination of drug from the body (and not due to distribution), the phase being called as elimination phase. Elimination phase can be characterized by 3 parameters— 1. Elimination rate constant 2. Elimination half-life 3. Clearance. Elimination rate constant & fy (a) Regular (Cartesian) Plot (b) Semilogarithmic Plot Concentration — log Concentrationo Elimination Half-Life: * Also called as biological half-life. It is defined as the time taken for the amount of drug in the body as well as plasma concentration to decline by one-half or 50% its initial value. It is expressed in hours or minutes. Half-life is related to elimination rate constant by the following equation: 0.693 te vy Apparent Volume of Distribution: The two separate and independent pharmacokinetic characteristics of a drug are - 1. Apparent volume of distribution, and 2. Clearance. Since these parameters are closely related with the physiologic mechanisms in the body, they are called as primary parameters. o Clearance: Difficulties arise when one applies elimination rate constant and half- life as pharmacokinetic parameters in an anatomical/physiological context and as a measure of drug elimination mechanisms. A much more valuable alternative approach for such applications is use of clearance parameters to characterize drug disposition. Clearance is the most important parameter in clinical drug applications and is useful in evaluating the mechanism by which a drug is eliminated by the whole organism or by a particular organ.* Clearance is defined as the theoretical volume of body fluid containing drug (ie. that fraction of apparent volume of distribution) from which the drug is completely removed in a given period of time. It is expressed in ml/min or liters/hour. Y Total Body Clearance: Elimination of a drug from the body involves processes occurring in kidney, liver, lungs and other eliminating organs. Clearance at an individual organ level is called as organ clearance. It can be estimated by dividing the rate of elimination by each organ with the concentration of drug presented to it. Thus, Renal Clearance Che Rate of. Seine by kidney Hepatic Clearance Cly= Rate of timiggton by Liver Other Organ Clearance Cl oyers= Rate of slimminetion by other organs The total body clearance, Cl, also called as total systemic clearance, is an additive property of individual organ clearances. Hence, > Intravenous Infusion ° Rapid iv. injection is unsuitable when the drug has potential to precipitate toxicity or when maintenance of a stable concentration or amount of drug in the body is desired. ° In such a situation, the drug is administered at a constant rate (zero- order) byi.v. infusion. In contrast to the short duration of infusion of an i.v. bolus (few seconds), the duration of constant rate infusion is usually much longer than the half-life of the drug.Advantages of zero-order infusion of drugs include— 1. Ease of control of rate of infusion to fit individual patient needs. | 2. Prevents fluctuating maxima and minima (peak and valley) plasma level, desired especially when the drug has a narrow therapeutic index. | 3. Other drugs, electrolytes and nutrients can be conveniently | administered simultaneously by the same infusion line in critically ill patients, The model can be represented as follows: Zero order infusion rate +— Infusion rate = 2R, — Infusion stopped Infusion rate = Ry! when plotted on a — semilog graph, yields a straight line with slope = - K,/2.303 —+ Plasma Drug Concentration v Infusion Plus Loading Dose: © It takes a very long time for the drugs having longer half lives before the plateau concentration is reached (eg. phenobarbital, 5 days). Thus, initially, such drugs have subtherapeutic concentrations.This can be overcome by administering an i.v. loading dose large enough to yield the desired steady-state immediately upon injection prior to | starting the infusion. It should then be followed immediately by i.v. infusion at a rate enough to maintain this concentration. resultant constant z 7'0ading dose plasma level z -*— asymptotic rise 3 of infused drug 3S 3. € 7 exponential fall + g— of loading dose te ~ > Extravascular Administration When a drug is administered by extravascular route (e.g. oral, i.m., rectal, etc.), absorption is a prerequisite for its therapeutic activity. ° The rate of absorption may be described mathematically as a zero-order or first-order process. A large number of plasma concentration-time profiles can be described by a one-compartment model with first-order absorption and elimination. However, under certain conditions, the absorption of some drugs may be better described by assuming zero-order (constant rate) kinetics. * Distinction between zero-order and first-order absorption processes. Figure a is regular plot, and Figure b a semilog plot of amount of drug remaining to be absorbed (ARA) versus timet.—— Plasma Drug Concentration Zero-order absorption is characterized by a constant rate of absorption. It is independent of amount remaining to be absorbed (ARA), and its regular ARA versus t plot is linear with slope equal to rate of absorption while the semilog plot is described by an ever-increasing gradient with time. In contrast, the first-order absorption process is distinguished by a decline in the rate with ARA ie. absorption rate is dependent upon ARA; Its regular plot is curvilinear and semilog plot a straight line with absorption rate constantas its slope. Crsx__ Absorption rate = Elimination ratei. Zero-Order Absorption Model This model is similar to that for constant rate infusion. 5 “E+ mination Zero order absorption © The rate of drug absorption, as in the case of several controlled drug delivery systems, is constant and continues until the amount of drug at the absorption site (e.g. GIT) is depleted. © All equations that explain the plasma concentration-time profile for constant rate i.v. infusion are also applicable to this model. ii. First-Order Absorption Model For a drug that enters the body by a first-order absorption process, gets distributed in the body according to one-compartment kinetics and is eliminated by a first-order process, the model can be depicted as follows: Zero order absorption Q PHARMACOKINETIC PARAMETERS + Elimination rate constant * The elimination rate constant describes the fraction of drug eliminated per unit of time or the rate at which plasma concentrations will decline during the elimination phase. Elimination rate constant Consider a single IV bolus injection of drug X. As time proceeds, the amount of drug in the body is eliminated. Thus the rate of elimination can be described (assuming first-order elimination) as:KX where dt X = amount of drug X, Xo = dose and Hence X = X) exp(-kt) _k = first-order elimination rate constant * Half-life © The time required to reduce the plasma concentration to one half its | initial value is defined as the half-life (t,,2). 0.693 t= K, ° This parameter is very useful for estimating how long it will take for levels to be reduced by half the original concentration. ° Itcan be used to estimate for how long a drug should be stopped if a patient has toxic drug levels, assuming the drug shows linear one-compartment pharmacokinetics. © The volume of distribution (V,) has no direct physiological meaning; it is not a ‘real’ volume and is usually referred to as the apparent volume of distribution. * Itis defined as that volume of plasma in which the total amount of drug in the body would be required to be dissolved in order to reflect the drug concentration attained in plasma. * The body is not a homogeneous unit, even though a one-compartment model can be used to describe the plasma concentration-time profile of a number of drugs. * Itis important to realise that the concentration of the drug (Cp) in plasma is not necessarily the same in the liver, kidneys or other tissues. * Thus C, in plasma does not equal C, or amount of drug (X) in the kidney or C, or amount of drug (X) in the liver or C, or amount of drug (X) in tissues. However, changes in the drug concentration in plasma (Cp) are proportional to changes in the amount of dru; in the tissues. Sinceee C, (plasma) a C, (tissues) i.e.C, (plasma)a X (tissues) | ° where V, is the constant of proportionality and is referred to as the volume of distribution, which thus relates the total amount of drug in the body at any time to the corresponding plasma concentration. Thus * Clearance Drug clearance (CL) is defined as the volume of plasma in the vascular compartment cleared of drug per unit time by the processes of metabolism and excretion. Clearance for a drug is constant if the drug is eliminated by first-order kinetics. Drug can be cleared by renal excretion or by metabolism or both. With respect to the kidney and liver, etc., clearances are additive, that is: Mathematically, clearance is the product of the first-order elimination rate constant (k) and the apparent volume of distribution (Vd). Thus | ° Hence the clearance is the elimination rate constant - i.e. the fractional rate of drug loss - from the volume of distribution. * Clearance is related to half-life byo % % Absorption rate constant (K,) Fractional rate of drug absorption from the site of administration into the systemic circulation. The absorption rate constant K, is a value used in pharmacokinetics to describe the rate at which a drug enters into the system. It is expressed in units of time“. The K, is related to the absorption half-life (t;/2,) per the following equation: K, = In(2) / ty2x Clinical importance - determines time required for administration drug to reach an effective plasma concentration. Influences both Cmax & tmax Significance of Absorption-Rate Constant For many immediate-release dosage forms, the absorption process is first-order due to the physical nature of drug diffusion. The calculation of K, is useful in designing a multiple- dosage regimen. Knowledge of K, and k allows for the prediction of peak and trough plasma drug concentrations following multiple dosing. In bio-equivalent studies, time of peak concentrations can be very useful in comparing respective rates of absorption of a drug from chemically equivalent drug products. Area under curve Area under curve It reflects the total amount of active drug which reaches the systemic circulation. It is independent of route of administration and elimination process as long as itdoes not changes. AUC a dose Area Under Plasma Concentration-Time Curve:AUC segment Importance of AUC Toxicology: Measure of drug exposure Biopharmaceutics: Comparison of drug products. SN NO Vv Pharmacokinetics: Measure of Pharmacokinetic parameters Clearance, BA. > Calculation of AUC 1. Planimeter 2. Cut & Weigh method 3. Mathematical :- Trapezoidal rule 4. Counting Squares method A. Cut And Weigh Method Y Plot the plasma profile vs time on graph paper Cut the curve drawn carefully Require an analytical balance The weight of this cut portion is W1 so we presume AUC1 @W1 Weight of whole graph paper is W2 Area of whole paper = AUC2 NNN NN KK Area length x breath eg.. Counting Squared Method The plasma concentration Vs time graph is plotted on graph paper Total number of squares are counted Area of each square is measured in cm or the units on x and y axis of graph | Total full squares counted and total number of small squares in shaded area | counted to get total number of full squares. . Planimeter AKA platometer, r measuring instrument - to determine the | area of an arbitrary two-dimensional shape D. Trapezoidal Rule Steps | ¥ Dividing whole AUC into trapezoidal segments ¥ Summation of all the area Y Calculate Total area | ¥ Counting the area of each segments separately |