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Introduction

Pharmacokinetics is the subject it deals with the rates of movement of drug and /or its metabolite (s) in the body and forces acting on the process ADME of drugs are the processes in which a drug moves in the body at various rates Pharmacokinetics will explain the rates of movement of drugs in the body with the help of suitable ‘Mathematical Model’ In pharmacokinetics, the concentration of a drug in plasma or any physiological fluid such as urine, saliva, milk, etc., is determined with respect to time following its administration This concentration of drug versus time data is used to study the dynamics of the drug in the body with the help of mathematical equations Mathematical equations are derived based on certain models and set of assumptions

Mathematical Model

Mathematical models are a collection of mathematical quantities, operations and relations together with their definitions Qualities of a mathematical model – Validity – Generality – Prediction ability – Computability – Consistency of results Why the data should be fit in a mathematical model? – To summarize the data observed – Flexibility – To calculate the unknown parameters – To predict valuable information

Mathematical Model…

– To compare different formulation of a drug – To compare the drugs with similar pharmacological action – To define therapeutic window – To get answer to various questions pertinent to drug

**Drug levels in blood
**

After extra vascular administration, the drugs reaches the blood circulation by a process known as absorption A plot of blood concentration of the drug versus time is utilized in understanding various important parameters of therapeutics

**Blood Level Profile of a Drug following Oral Administration
**

Concentration of drug (µg/ml)

Maximum safe level

Therapeutic Index

Onset of action

Duration of action T mx a

C mx a

Minimum therapeutic level

Time (Hrs)

Termination of action

**Fraction of Dose absorbed (F)
**

It is the ratio of the amount of drug ultimately reaching the blood stream to the total dose administered The value of F will be unity if the total administered dose reaches the blood circulation Many dosage forms often show F values less than unity because of the following reasons – Slow release of the drug from the dosage form and loss of the unabsorbed drug through feces – Degradation of the drug in the GIT due to chemical or enzymatic processes – The drug undergoes the first pass effect

**Desired Characteristics of an Ideal Drug
**

In order to achieve the best therapeutic effect, the drug should have the below features – Absorb quickly from the absorption site – Arrive at the site of action rapidly and in sufficient quantity – Remain for the sufficient duration of time – Be removed from the site of action eventually – Not get distributed to any other tissue – Have a large therapeutic index It is generally difficult to obtain all these characters in a drug It is very difficult / not practical to know the concentration of the drug at the tissues in site of action The basic assumption made to overcome this problem is that, “there exists a linear relationship between the drug concentration in blood and the tissues in site of action and the change in concentration in tissue reflects in blood”

Various mathematical models can be devised to simulate the rate processes of drug (i.e., ADME) These mathematical models are useful in the development of equations to describe drug concentrations in the body as a function of time As drug concentrations are dependent on time, the two variables drug concentration and time are called dependent and independent variables respectively In practice, PK parameters are not measured directly but are determined experimentally from a set of dependent and independent variables collectively known as data Generally, the data are analyzed with the simplest pharmacokinetic model and statistical methods are used to find out how best the model fits the data It is very important to realize that PK data should not replace clinical observations and sound judgment by the clinicians

Pharmacokinetic models

Pharmacokinetic models

Pharmacokinetic models are divided into 1. Compartment models 2. Physiological pharmacokinetic models (flow models) 3. Non – Compartmental Pharmacokinetics 4. Non – linear Pharmacokinetics

Compartment models

The human body is assumed to consist of a number of interconnected compartments A compartment is defined as a group of tissues which behaves uniformly with respect to the drug movement Each tissue may have a different concentration of drug but they all are in an equilibrium in a way that a change in drug concentration in these tissues is linear or similar

Compartment models

Each compartment behaves differently regarding the concentration time course data The classification of compartments is based on the degree of vascularity. i.e., the blood flow to and from the compartment, like, 1. Highly perfused tissue group: : Consisting of Plasma / Serum / blood, blood cells, heart, lungs, hepatoportal system, kidneys, glands and also the brain and spinal cord 2. Poorly perfused tissue group: Consisting of muscle and skin 3. Fat group: Consisting of adipose tissue including bone marrow 4. Negligible perfused tissue group: Consisting of bones, teeth, ligaments, tendons, cartilages and hair

Compartment models

Mammillary model:

Most common compartment model used in pharmacokinetics This model consists of one or more peripheral compartments connected to a central compartment The central compartment consist of plasma and highly perfused tissues in which the drug distributes rapidly The drug introduced into the human body reaches central compartment and from there it distributes to all other compartments which are connected to central compartment Elimination of the drug is assumed to occur from the central compartment, since the major organs involved in drug elimination, primarily kidney and liver, are present in the central compartment

Compartment models

The drawing of models – gives a visual representation of the rate processes involved – how many rate constants are necessary to describe the process – Enables to develop differential equations to describe drug concentration changes in each compartment Model 1: One – Compartment open model i.v. injection

1

K

**Model 2: One – Compartment open model with first order absorption
**

Ka

1

K

Compartment models

Model 3: Two – Compartment open model i.v. injection

K12

1 K13

2

K21

**Model 4: Two – compartment open model with first order
**

K12 Ka

absorption

1 K13

K21

2

If the amount of drug absorbed and eliminated per unit time is obtained

by sampling compartment 1, then the amount of the drug contained in the tissue compartments can be estimated mathematically

Compartment models

Caternary model:

Compartments joined to one another in a row like the compartments of a train

K12

1 2

K23

3

K21

K32

In contrast the mammillary model consists of one or more compartments around a central compartment like satellites Since most of the functional organs of the body are directly connected to the plasma, caternary model is not used as often used as mammillary model

**One compartment open model Simplest model to describe the movement of the drug in the body
**

Depicts the body as a single homogeneous unit The body is open with respect to the drug movement Useful for drugs which rapidly distribute between plasma and other body fluids and tissues upon entry into the systemic circulation Pharmacokinetic models are developed based on some assumptions (because we are trying to correlate mathematics to physiological events) The assumptions made should be realistic and practical

**One compartment open model
**

The following assumptions were made in deriving mathematical equations for One Compartment Open Model 1. The process of drug absorption from absorption site follows first order kinetics (mostly drugs absorbed through passive diffusion. For active transport and facilitated diffusion this is not valid) 2. Drug reaching the systemic circulation is distributed to other body fluids and tissues and a dynamic equilibrium is achieved instantaneously 3. Any change that occur in plasma levels of a drug reflect proportional changes in the tissue levels also (because of dynamic equilibrium) 4. Elimination of drug from the body through apparent first order kinetics and its rate constant K is known as apparent first order rate constant

i.e., in elimination of the drug gives an overall apparent first order rate constant K K = Ke + Kb + Kf1 + Kf2 + …. Where, Ke – first order rate constant of renal excretion Kb – first order rate constant of bile excretion Kf1 & Kf2 – first order rate constants of metabolism In order to develop mathematical equations that describe drug concentration in the body fluid Vs time profile, the following information should be available – The dose of drug administered (X0) – – – Route of administration (i.v (bolus/infusion) / extra vascular) Biological fluid collected for PK (blood/plasma/serum/urine) Whether PK study is for single dose / multiple dose

One compartmentofopen model the sum of the rate constants all the processes involved

**One compartment open model
**

Scheme of study of pharmacokinetic equations in one compartmental open model

Route of administration i.v. Bolus Biological fluid Blood / Plasma / Serum Urine Blood / Plasma / Serum Urine i.v. Infusion Blood / Plasma / Serum Urine Blood / Plasma / Serum Urine Extra vascular administration Blood / Plasma / Serum Urine Drug form Unchanged drug Unchanged drug Metabolite(s) Metabolite(s) Unchanged drug Unchanged drug Metabolite(s) Metabolite(s) Unchanged drug Unchanged drug

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