Differences between compartment and non-compartment models

Concepts of non-compartmental model

Statistical moment’s theory-Mean residence time

Different pharmacokinetic parameters in non-compartment model

Mathematical Model

A model is a mathematical description of biologic system and used to express quantitative relationships.

Mathematical models are a collection of mathematical quantities, operations and relations together with
their definitions and they must be realistic and practical.

A model is a hypothesis that employs mathematical terms to concisely describe quantitative relationships

QUALITIES OF A MATHEMATICAL MODEL

Validity: It should have practical applicability and should be valuable in describing events chosen
accurately with high precision.

Prediction ability: These models predict the qualitative and quantitative changes in these parameters that
are rate constants and half-lives of drugs.

Consistency of results: Reproducibility is an important quality of a mathematical model.

Pharmacokinetic Models:

"A pharmacokinetic compartment is a mathematical concept which describes a space in the body which a
drug appears to occupy. It does not need to correspond to any specific anatomical space or physiological
volume".

It is a hypothesis that utilized mathematical terms to describe quantitative relationships

Modeling requires

 Thorough knowledge of anatomy and physiology

 Understanding the concepts and limitations of mathematical models.
 Assumptions are made for simplicity

The development of equations to describe drug concentrations in the body as a function of time

HOW?

By fitting the model to the experimental data known as variables.

A PK function relates an independent variable to a dependent variable.

Pharmacokinetic models are hypothetical structures that are used to describe the fate of a drug in a
biological system following its administration.

A Model is a Mathematic description of a biologic system and its use to express Quantitative relationship.

A Compartment is a group of tissues with SIMILAR BLOOD FLOW and drug AFFINITY.

Complexity of PK model will vary with:

1- Route of administration

2- Extent and duration of distribution into various body fluids and tissues.

3- The processes of elimination.

4- Intended application of the PK model.

One Compartment Two Compartments

Rapid or prompt equilibrium is attained.
There is a single disposition phase
Linear: drug elimination follows first order kinetics
Distribution equilibrium is slow (takes finite time).
Distribution and post-distribution are two distinct
phases.
Linear: distribution and
elimination both follow first order
Based on the statistical moment theory Model independent method
Non-compartment pharmacokinetics is a new approach devised to study the time course of drug in the
body without assuming any compartment model.

Based on the statistical moment theory.

Model independent method

Overcomes some of the drawbacks associated with

Classical compartment modeling.

Basic assumption is that drug or metabolite follows

First-order kinetics.

Non-compartment models

Non-compartment and Compartment models – Comparison

Compartment models Non-compartment models

These require elaborate assumptions to fit the data. Do not require assumptions to compartment model.

Curve fitting of experimental data using computers. It Simple algebraic equations. No curve fitting and no
is a tedious method computers.

Applicable to linear and nonlinear pharmacokinetics. Applicable to linear pharmacokinetics

C1 - time profile is regarded as expressions of C1 – time profile is regarded as statistical distribution.

exponents.

These are useful for most of the situations, though Particularly useful for the applications of clinical
assumptions of modeling are involved. pharmacokinetics, bioavailability, and bioequivalence
studies.
Summary of Published Non-Compartment Model Midazolam Pharmacokinetics Parameters

Non-Compartment PK Parameters Reported Missed

Cmax 9 1
AUC 10 0

Tmax 7 3
T1/2,fast 2 8
T1/2,slow 8 2
Vd 5 5
CLiv 4 6

Advantages
1. Derivation of PK parameters is easy, because of simple algebraic equations.
2. Mathematical treatment remains same, for drug or metabolite, provided elimination follows first
order kinetics.
3. Drug disposition kinetics need not be described in detail.

Disadvantages:
1. Information regarding plasma drug concentration-time profile is expressed as an average
2. Generally not useful for describing the time course of drug in the blood
3. It is applicable only for linear pharmacokinetics

Application of Pharmacokinetics
 Characterizing the behavior of drugs in patients.
 Calculating the optimum dosage regimens for individual patients.
 Evaluating the bioequivalence between different formulations of same drug.
 Determining the influence of altered physiology or disease state on drug ADME.
 Explaining the drug interactions.

Steady State Plasma Drug Concentration:

The Concentration is a function of the effective rate of dosing and total body clearance of the drug in a
patient
In continuous confusion Concentration= k0

Cl

In Multiple dosage regimen Concentration = AUCSS

F is fraction bioavailable
AUC is AUC from t=0 to t= during a dosing interval at steady state

F is fraction bioavailable

Method of superposition is used for predicting steady state

Concentration on repetitive dosing from data obtained after a single dose.

Predicting the Time to Steady State:

Time required for the drug to reach steady state, i.e., 99%, takes 6.65 half-lives.

In extravascular route (or prolonged release drug products), the time required to attain steady states takes
longer than predicted by biological half life

In multicompetent disposition, time required to attain to steady state is shorter than that predicted by
terminal half life

Conclusion
 The non-compartmental pharmacokinetic methods permit a comprehensive pharmacokinetic
analysis without resort to curve fitting, sophisticated computers or tedious mathematical
equations.
 Although these methods cannot be applied to all pharmacokinetic problems, they are useful for
most problems and are particularly useful for the clinical application of pharmacokinetics.