PHARMACOKINETICS MODEL AND IT’S SIGNIFICANCES

CONTENT
• Basic considerations in pharmacokinetics
• Compartment models
• One compartment model
• Assumptions
• Intravenous bolus administration
• Intravenous infusion
• Extravascular administration (zero order and first
order absorption model)
• Multi-compartment model

• BASIC CONSIDERATIONS IN PHARMACOKINETICS

 Pharmacokinetic parameters
 Pharmacodynamics parameters
 Zero, first order & mixed order kinetic
 Rates and orders of kinetics
 Plasma drug conc. Time profiles
 Compartmental models – physiological model
 Applications of pharmacokinetics
 Non compartment model
 Common units in Pharmacokinetics

S.N Parmacokin Abbrevia Fundament Units

o etic tion al Units Exampl
parameter e
1. Area Under AUC Concentra µg x
the curve ction x time hr/mL

02. Total body ClT Volume x Litres/ti

clearance time me

03. Renal ClR Volume x Litres/ti

clearance time me

04. Hepatic ClH Volume x Litres/ti

clearance time me

05. Apparent VD Volume Litres

volume of
distribution

 Mixed Order Kinetics

 Ø Kinetics of a pharmacokinetic process changes from First order
to Zero order
 with increasing dose or chronic medication.
 Ø Deviations from original Linear kinetic profile – Non Linear
kinetics.
Pharmacokinetics:
Pharmacokinetics is defined as the kinetics of drug absorption,
distribution, metabolism and excretion (KAMD) and their relationship
with the pharmacological, therapeutic or toxicology response in man
and animals. There are two aspects of pharmacokinetic studies-
1.Theoetical aspect.
2.Experimental aspect.

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 date 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
1.Model approach, and
2.Model-independent approach.

Pharmacokinetic Model approach

A model is hypothesis that employs mathematical terms to
concisely describe quantitative relationships. Pharmacokinetic
model provide concise means of expressing mathematically or
quantitatively, the time course of drug(s) throughout the body
and compute meaningful pharmacokinetic parameters.

Applications of Pharmacokinetic Model-

1.Characterizing the behaviour of drugs in patients.
2.predicting the behaviour of drug in various body fluids with
any dosage regimen.
3.predicating the multiple-dose concentration curves from
single dose experiments.
4.Calculating the optimum dosage regimen for individual
patients.
5.Evaluating the risk of toxicity with certain dosage regimens.
6.Correlating plasma drug concentration with pharmacological
response.
7.Estimating the bioequivalence/bioinequivalence between
different formulation of the same drug.
8.Estimating the possibility of drug and/or metabolite(s)
accumulation in the body.
9.Determing the influence the altered physiology/diseases state
on the drug ADME.
10.Explaining drug interactions.
Types of Pharmacokinetic Models
Pharmacokinetic models are of three different types-
Compartment models- are also called as empirical models, and
Physiological models- are realistic models.
Distributed parameter models- are also realistic models.

Compartment Models
Compartmental analysis is the traditional and most commonly
used approach to pharmacokinetic characterization of drug.
These models simply interpolate the experimental date and
allow an empirical formula to estimate the drug concentration
with time.
Depending upon weather the compartments are arranged
parallel or in a series, compartment models are divided into
two categories-
1.Mammillary model
2.Catenary model.

Since compartments are hypothetical in nature compartment

models are based on certain assumptions-
1.The body is represented as a series of compartments
arranged either in series or parallel each other, that
communicate reversibly with each other.
2.Each compartment is not real physiological or automatic
region but a fictitious or virtual one and considered as tissue or
group of tissues that have similar drug distribution
characteristics .This assumption is necessary because if every
organ, tissue or body fluid that can get equilibrated with the
drug is considered as a separate compartment, the body will
comprise of infinite number of compartments and
mathematical description of such a model will be too complex.
3.within each compartment, the drug considered to be rapidly
and uniformly distributed i.e. the
compartment is well-stirred.
4.The rate of drug movement between compartment is
described by first order kinetics.
5.Rate constants are used to represent rate of entry into and
exit from the compartment.
Mammillary Model
This model is the most common compartment model used in
pharmacokinetics.
The number of rate constants which will appear in a particular
compartment model is given by R.
For intravenous administration, R=2n-1
For extravascular administration, R=2n
Where n= number of compartments.
Physiological Models
These model are also known as physiologically-based
pharmacokinetic models (PB-PK models). They are down on the
basis of known anatomic and physiological date and thus
present a more realistic picture of drug disposition in various
organs and tissues. The number of compartment to be included
in the model depends upon the disposition characteristics of
the drug. Organs or tissues such as bones that have no drug
penetration are excluded.

The physiological models are further categorized into two

types-
1.Blood flow are limited models.
2.Membrane permeation rate limited models.

The physiological models are further categorized into two types

–
Blood flow rate-limited models – These models are more
popular and commonly used than the second type, and are
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. This assumption is however
applicable only to the highly membrane permeable drugs i.e. low
molecular weight, poorly ionised and highly lipophilic drugs, for
example, thiopental, lidocaine, etc.
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. Owing to the time lag in equilibration between the
blood and the tissue, equations for these models are very
complicated.

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. If one considers the time course
of drug concentration in plasma as a statistical distribution curve,
then:
MRT = AUMC/AUC
where MRT = mean residence time
AUMC = area under the first-moment curve
AUC = area under the zero-moment curve
MRT is defined as the average amount of time spent by the
drug in the body before being eliminated.

ONE-COMPARTMENT OPEN MODEL

(INSTANTANEOUS DISTRIBUTION MODEL)
The one-compartment open model is the simplest model.
1. Elimination is a first-order (monoexponential) process with
first-order rate constant.
2. Rate of input (absorption) > rate of output (elimination).
3. 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.

Estimation of Pharmacokinetic Parameters

Elimination phase can be characterized by 3 parameters—

1. Elimination rate constant
2. Elimination half-life
3. Clearance.

A review on pharmacokinetic modeling and significance

Background: The current guidelines regarding drug dosage,

routes of administration and
contraindication employed by the Canadian Forces (CF) were
developed by Health Canada for
the civilian population in a controlled clinical laboratory setting
that does not reflect military
operational environments. Considering some of the extreme
and hostile environmental conditions
that the CF might encounter during operations, the
pharmacokinetics and pharmacodynamics of
the drugs are expected to be different from controlled clinical
laboratory conditions. Therefore,
we conducted a literature search into the effects of
environmental stressors on the
pharmacokinetics of commonly prescribed medications
employed by the CF. This report is a
comprehensive review of the subject matter in preparation for
further experimental validation of
an advanced pharmacological model to advise the CF on the
modification of dosage and other
related issues in operational pharmacokinetics.
Results: Our literature review of numerous experimental
studies have demonstrated the effects of
a number of physiological, psychological and environmental
stressors on the pharmacokinetics of
a broad spectrum of drugs, in particular the influence of
isolated physical activity. To a lesser
extent, psychological stressors were also shown to alter the
pharmacokinetics as a result of
psycho-somatic changes. In addition, our review suggested that
various pharmacokinetic models,
specifically a physiologically-based model, may be able to
provide theoretical predictions for the
interactions of military stressors with pharmacokinetics.
Significance: The review enables us to conduct further research
toward the development of a
system that will provide a guideline on dosage, route of
administration, contraindications etc. to
the CF especially, Director General of Health Services, Director
of Medical Policy / Pharmacy
Policy & Standards.
Future plans: Based on the literature review, pharmacokinetic
models will be developed and
laboratory studies simulating the operational environments will
be conducted in order to provide
recommendations on better use of the common
pharmaceuticals employed by the CF.