COMPARTMENT MODELS OF DRUG DISTRIBUTION

Pharmacokinetic Modeling approaches

There are three approaches that have been suggested for pharmacokinetic modeling, Compartmental model Physiological model Model independent approach

Compartmental model
The first is an empirical approach, which is based on a simple compartmental model. These compartments have no strict physiological or anatomic basis. The compartment can represent a body volume, or just as easily it could represent a chemical state, for example a metabolite of the drug. Usually this approach uses one or two compartments. Despite its simplistic nature, many useful quantities can be derived using this approach and by comparing predicted values with actual data.

Physiological model
The physiological model identifies the compartments with actual body spaces. The model is a great deal more complex than the compartmental models. Actual transfer and flow rates are employed together with experimentally measured blood/tissue concentration ratios. This model can be used for predictions, and is more adaptable to clinical therapy and to changing situations such as alterations of flow rates due to conditions such as swelling, or fever.

Model independent approach

The is the most recent, and is purely mathematical. It avoids recourse to kinetic parameters which may not be valid, and is a lot less complex. It is good for absorption and elimination rates, and clearances, but gives no specific information about how the drug is distributed.

Compartmental model
The compartment concept is utilized in pharmacokinetics when it is necessary to describe the plasma concentration versus time data adequately and accurately To obtain accurate estimates of selected fundamental pharmacokinetics parameters such as the apparent volume of drug distribution, the elimination half life and the elimination rate constant of a drug. Constitute the basis for the calculation of the dosage regimen (dose and dosing interval) that will provide the desired plasma concentration and duration of action for an administered drug

Compartmental model
Compartmental analysis is the traditional and most commonly used approach to pharmacokinetic characterization of a drug. In this, body is considered to be composed of several compartments that communicate reversibly with each other. As infinite number of compartments can exist in body (each organ, tissue or body fluid can a form a compartment), tissues having approximately similar drug distribution are pooled to form a kinetically homogeneous hypothetical compartment.

 The selection of a compartment model solely depends upon the distribution characteristics of a drug following its administration The equation required to characterize the plasma concentration versus time data, however, depends upon the compartment model chosen and the route of drug administration. The selected model should be such that it will permit accurate predictions in clinical situations. Generally, the slower the drug distribution in the body, regardless of the route of administration, the greater the number of compartments required to characterize the plasma concentration versus time data, the more complex is the nature of the equatio Slow distribution suggests that the distribution equilibrium is attained slowly and at a finite time (from several minutes to a few hours, depending upon the nature of the administered drug). Furthermore, it suggests that the vasculature,tissues and organs are not behaving in a similar fashion toward this drug and, therefore, it may be considered that the body to comprise two compartments or, if necessary, more than two compartments.

 Highly perfused systems: liver, the kidney and the blood, may be pooled together in one compartment (i.e. the central compartment: compartment 1) Systems that are not highly perfused; bones, cartilage, fatty tissue and many others, can also be pooled together and placed in another compartment (i.e. the tissue or peripheral compartment: compartment 2). In this type of model, the rates of drug transfer from compartment 1 to compartment 2 and back to compartment 1 will become equal at a time greater than zero (from several minutes to a few hours).

 Such compartments are, thus, only mathematical entities and have no physiological or anatomical meaning. Generally, model consisting of one, two or at the most three compartments arranged parallel to each other are used to describe kinetics of most drugs.

These compartments are called open models because there is no restriction to the movement of drugs between compartments as drugs freely move from one compartment to the other.

 It is also assumed that the rate of drug transfer between compartments and the rate of drug elimination from compartments follow first-order or linear kinetics.
Compartment characteristics of a drug are best understood by giving it as intravenous bolus and observing the manner in which the plasma concentration declines with time The number of exponents required to describe such a plasma level-time profile determines the number of compartments in which a drug will distribute.

Rate of Transfer of drug between compartments

Rates of reaction
The transfer of drug between the compartments is represented by rate constants The rate of a reaction or process is defined as the velocity at which it proceeds and can be described as either zeroorder or first-order. Zero-order reaction Consider the rate of elimination of drug A from the body. If the amount of the drug, A, is decreasing at a constant rate, then the rate of elimination of A can be described as:

where k* the zero-order rate constant.

 The reaction proceeds at a constant rate and is independent of the concentration of A present in the body. An example is the elimination of alcohol. Drugs that show this type of elimination will show accumulation of plasma levels of the drug and hence nonlinear pharmacokinetics.

First-order reaction
If the amount of drug A is decreasing at a rate that is proportional to A, the amount of drug A remaining in the body, then the rate of elimination of drug A can be described as:

where k the first-order rate constant

 The reaction proceeds at a rate that is dependent on the concentration of A present in the body. It is assumed that the processes of ADME follow first-order reactions and most drugs are eliminated in this manner.
Most drugs used in clinical practice at therapeutic dosages will show first-order rate processes. However, there are notable exceptions, for example phenytoin and high-dose salicylates.

 For drugs that show a first-order elimination process, as the amount of drug administered increases, the body is able to eliminate the drug accordingly and accumulation will not occur.
If you double the dose you will double the plasma concentration. However, if you continue to increase the amount of drug administered then all drugs will change from showing a first-order process to a zero-order process, for example in an overdose situation.

 It is important to note that this does not imply that the drug concentration in plasma (Cp) is equal to the drug concentration in the tissues.
However, changes in the plasma concentration quantitatively reflect changes in the tissues. When plotted on a log Cp vs time graph they show a linear relation; this represents a one-compartment model.

Conc. vs. time plots

Types of Kinetics Commonly Seen

First Order Kinetics Zero Order Kinetics Rate = k C C = Co e-kt Rate = k Rate of elimination C = Co - kt proportional to plasma Constant rate of concentration. elimination regardless Constant fraction of of [D]plasma drug eliminated per C vs. t graph is LINEAR unit time. C vs. t graph is NOT linear, decaying exponential. Log C vs. t graph is linear.

First-Order Kinetics

Comparison
Zero Order Elimination
[drug] decreases linearly with time Rate of elimination is constant Rate of elimination is independent of [drug] No true t 1/2

First Order Elimination

[drug] decreases exponentially w/ time Rate of elimination is proportional to [drug] Plot of log [drug] or ln[drug] vs. time are linear t 1/2 is constant regardless of [drug]

One-Compartment Open Model

One-compartment open model is the simplest model, which considers the whole body as a single, kinetically homogeneous unit. In this model, the final distribution equilibrium between the drug in plasma and other body fluids is attained rapidly and maintained at all times. Any change in the plasma levels of drug reflects proportional changes in tissue drug concentrations.

 The one-compartment open model applies to only those drugs, which distribute rapidly throughout the body. The model is generally used to describe plasma levels following administration of a single dose of a drug, and can be observed following either intravenous bolus or extravascular administration of drugs.

Intravenous bolus administration: When a drug that distributes instantaneously in body is given as rapid IV bolus, the entire dose of drug enters the body and is distributed immediately via circulation to all tissues. In such a situation, the drug concentration-time curve will be obtained as a straight line on semi-logarithmic paper showing monophasic exponential decline. In this model, the decline in plasma drug concentration occurs only due to elimination of drug from the body, therefore, the phase is called the elimination phase. The distribution phase is normally neglected in calculations because distribution is so rapid that it cannot be shown on graph.

 The extrapolated zero-time intercept of linear elimination phase gives the coefficient B, and the elimination rate constant is given by . The value of B is an estimate of zero-time concentration of drug in plasma (C0or Cp).
Extravascular administration: When a drug is administered by extravascular route (e.g., oral, IM, SC, etc.), absorption is a pre-requisite for its action. If it is distributed according to one compartment open model, the rate of change in drug concentration in the central compartment is described by 2 exponents - an absorption exponent and an elimination exponent.

Intravenous bolus administration, one-compartment model

Intravenous bolus administration, one-compartment model The plotted curve is a straight line, which clearly indicates the presence of a single pharmacokinetic phase (namely, the elimination phase.) Since the drug is administered intravenously, there is no absorption phase. The straight line also suggests that distribution is instantaneous; thus the drug is rapidly distributed in the body. These data can be accurately and adequately described by employing the following monoexponential equation

 This approach models the entire body as a single compartment into which drug is added by a rapid single dose, or bolus. It is assumed that the drug concentration is uniform in the body compartment at all times and is eliminated by a first order process that is described by a first order rate constant kel.

 The one compartment model fails to describe the actual drug disposition for example, a particular organ has a small, but strong affinity for a drug, which does not affect the overall plasma concentration, but which leads to toxicity on repeated doses. If this area is the site of drug action, the effect could continue after blood levels had subsided.

Extravascular administration: one-compartment model

Two phases in the profile: absorption and elimination. The profile clearly indicates the presence of only one phase in the post-absorption period. Since distribution is the sole property that determines the chosen compartment model and, since the profile contains only one phase in the post-absorption period, These data can be described accurately and adequately by employing a onecompartment model. However, a biexponential equation would be needed to characterize the concentration versus time data accurately.

Two-Compartment Open Model

Two-compartment open model assumes that body is composed of two compartments

Central compartment Peripheral compartment.

The central compartment (compartment 1) consists of blood and highly perfused organs like liver, kidneys, lungs, heart, brain, etc;

The less perfused tissues like skin, muscles, bone, cartilage, etc. make the peripheral compartment (compartment 2).

 The drug is directly administered (IV route) or absorbed (extravascular route) into the central compartment and various organs in it rapidly equilibrate with it.
Elimination of drug occurs from central compartment since main organs involved in drug elimination (e.g. liver and kidneys) are located in it. The distribution of drugs to peripheral compartment is through blood (central compartment) and occurs slowly.

 It is assumed that drug transfer from central compartment to peripheral compartment, and back from peripheral compartment to central compartment occurs by first-order process and is defined by rate constants denoted by letter k.
The subscript indicates the direction of drug movement e.g., k12 refers to drug movement from compartment 1 (central compartment) to compartment 2 (peripheral compartment), and reverse for k21 (Figure 5.2).

The two compartment open model adequately describes the disposition kinetics of most therapeutic agents in humans and animals.

Intravenous bolus administration:

After the intravenous bolus administration of a drug that follows two-compartment kinetics, the decline in plasma concentration is biexponential.
When plasma drug concentration-time curve is plotted on a semi-logarithmic paper, the plasma concentration declines rapidly in first phase followed by a slow terminal decline. The initial steep decline in drug concentration is attributed mainly to distribution of drug from the central compartment to the peripheral compartment, and terminal shallow decline is mainly due to elimination of drug from the central compartment.

 The linear terminal portion of curve is called the elimination phase.

The extrapolated zero-time intercept of linear distribution phase (residual line) is denoted by letter A, and the elimination phase by letter B

 The sum of A and B coefficients gives the initial concentration of drug in the plasma (C0 or Cp). For two compartment model, a is the rate constant for distribution, and is the rate constant for elimination; they are expressed in units of reciprocal time (min1). is used for rate constant for elimination from the entire body, whereas Kel is used for rate constant for elimination of drug from the central compartment. In drug disposition studies, the coefficients (A and B) and rate constants ( and ) are calculated from the experimental data by least square regression analysis.

Two-Compartment Open Model, Intravenous administration

Two-Compartment Open Model, Intravenous administration

The first phase (curvilinear portion) represents drug distribution in the body; and only after a finite time (indicated by a discontinuous perpendicular line) do we see a straight line. The time at which the concentration versus time plot begins to become a straight line represents the occurrence of distribution equilibrium. This suggests that drug is being distributed slowly and requires a twocompartment model for accurate characterization. The equation employed to characterize these plasma concentration versus time data will be biexponential (contain two exponential terms):

A and alpha are parameters associated with drug distribution and B and beta are parameters associated with drug post-distribution phase.

Two compartment model: Extravascular administration: For a drug that enters the body by an extravascular route (e.g., oral, IM, SC, etc.) and is distributed according to two compartment model, the rate of change in drug concentration in plasma is described by 3 exponents 1. Ka an absorption exponent, 2. a distribution exponent and 3. an elimination exponent.

Extravascular route of drug administration, two-compartment mod

The presence of three phases in the plasma concentration versus time data for a drug administered by an extravascular route. Three phases include absorption, distribution and post-distribution The plasma concentration versus time profile, in the post-absorption period looks identical to that for an intravenous bolus two-compartment model These data, therefore, can be described accurately by employing a two-compartment model and the equation will contain three exponential terms (one for each phase: absorption, distribution, and postdistribution.)

Three-Compartment Open Model

The pharmacokinetic behaviour of some drugs, which have a high affinity for a particular tissue or undergo redistribution, is best interpreted according to a three compartment open model.

In this compartmental model, body is conceived as consisting of three compartments one central and two peripheral compartments.

 The central compartment (Compartment 1) comprises of plasma and highly perfused organs, Compartments 2 comprise of moderately perfused tissues e.g., skin and muscles Compartments 3 comprise poorly perfused tissues - e.g., bone, teeth, ligaments, hair, and fat If a drug is administered in body by intravenous bolus injection, it is first distributed immediately into the highly perfused tissues (compartment 1), then slowly into the moderately perfused tissues (compartment 2) and thereafter very slowly to the poorly perfused tissues (compartment 3). If plasma level-time profile is plotted on semi-logarithmic graph, it gives a triexponential appearance.

(a) Plasma concentration versus time profile of a drug showing multicompartment model. (b) Time profile of a multicompartment model showing log Cp versus time.

II.NON-COMPARTMENT MODELS/NONCOMPARTMENT ANALYSIS

Non-compartment analysis is another approach to study the time course of drugs in body. It does not require the assumption of specific compartment model. It considers the time course of drug concentration in plasma as a statistical distribution curve and derives pharmacokinetic parameters by simple algebraic equations. The disadvantage of this method is that it often deals with averages and provides limited information regarding plasma drug concentration-time profile.

II.NON-COMPARTMENT MODELS/NON- COMPARTMENT ANALYSIS

The noncompartmental approach for data analysis does not require any specific compartmental model for the system (body) and can be applied to virtually any pharmacokinetic data. Various noncompartmental approaches: statistical moment analysis, system analysis, or the noncompartmental recirculatory model. The main purpose of the noncompartmental approach is to estimate various pharmacokinetic parameters, such as systemic clearance, volume of distribution at steady state, mean residence time, and bioavailability without assuming or understanding any structural or mechanistic properties of the pharmacokinetic behavior of a drug in the body. In addition, many noncompartmental methods allow the estimation of those pharmacokinetic parameters from drug concentration profiles without the complicated, and often subjective, nonlinear regression processes required for the compartmental models. Owing to this versatility and ruggedness, the noncompartmental approach is a primary pharmacokinetic data analysis method for the pharmaceutical industry Moment analysis, the most commonly used noncompartmental method,

III.

PHYSIOLOGICAL MODELS

Physiological models (perfusion rate-limited models) technique is a newer approach devised to study the time course of drugs in body. The basis of this method is that each major organ system, plus any specialised target site, represents a physiological compartment. Each separate compartment has its own blood flow, tissue volume, uptake process, affinity for the compound (i.e., partition coefficient) and elimination process.

 Thus, the kinetics of the drug is described by a series of flowrelated equations, which can be solved following the incorporation of known physiological values (e.g., organ or tissue volume, and perfusion rate) and experimental estimates (e.g. tissue to plasma partition coefficients)

The physiological models have some advantages as they are drawn on the basis of known anatomical and physiological data and they present a more realistic picture of drug disposition in various organs and tissues.
The physiological models also allow an assessment of the impact of altered physiology (e.g. ageing) or pathology on the drug disposition.

 More importantly, species differences can be predicted based on known perfusion rates. The only disadvantage of physiological models is obtaining experimental data, which is very exhaustive.

A physiological model.

 Possibly the simplest application of multi-compartment model is in the single-cell concentration monitoring (see the figure above). If the volume of a cell is V, the mass of solute is q, the input is u(t) and the secretion of the solution is proportional to the density of it within the cell, then the concentration of the solution C within the cell over time is given by

 As the number of compartments increases, the model can be very complex and the solutions usually beyond ordinary calculation. Below shows a three-cell model with interlinks among each other. The formula for n-cell multi-compartment models become:

Model topologies
As the number of compartments increase, it is challenging both to find the algebraic and numerical solutions of the model. However, there are special cases of models, which rarely exist in nature, when the topologies exhibit certain regularities that the solutions become easier to find. The model can be classified according to the interconnection of cells and input/output characteristics:

 Closed model: No sinks or source, lit. Open model: There are sinks or/and sources among cells. Catenary model: All compartments are arranged in a chain, with each pool connecting only to its neighbors. This model has two or more cells. Cyclic model: It's a special case of the catenary model, with three or more cells, in which the first and last cell are connected Mammillary model: Consists of a central compartment with peripheral compartments connecting to it. There are no interconnections among other compartments. Reducible model: It's a set of unconnected models.

Pharmacokinetic parameters
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:

Hence X= X0 exp(kt) where X amount of drug X, X0 dose and k first-order elimination rate constant.

 Volume of distribution
The volume of distribution (Vd) has no direct physiological meaning; it is not a real volume and is usually referred to as the apparent volume of distribution. It is 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.

It is important to realise that the concentration of the drug (Cp) in plasma is not necessarily the same in the liver, kidneys or other tissues.

 Then Cp (plasma) =Vd X (tissues) where Vd 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

Half-life
The time required to reduce the plasma concentration to one half its initial value is defined as the half-life (t1/2). Consider ln Cpt = ln Cp0 kt Let Cp0 decay to Cp0/2 and solve for t=t1/2

 This parameter is very useful for estimating how long it will take for levels to be reduced by half the original concentration.
It can 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.

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: CLtotal =CLrenal + CLnonrenal

 Mathematically, clearance is the product of the firstorder elimination rate constant (k) and the apparent volume of distribution (Vd).

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

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