NON- COMPARTMENTAL MODEL

(Model independent pharmacokinetics)

DEPARTMENT OF PHARMACY ,
THE WOMEN UNIVERSITY MULTAN
 Contents
 Introduction to pharmacokinetic models
 Linear and non linear pharmacokinetics
 Model independent analysis
 Non-compartmental analysis
 Statistical moment theory
 Assumptions of NCA
 Advantages of NCA
 Limitations of NCA
 Introduction
What is pharmacokinetics? And what are
pharmacokinetic models?
In order to administer drugs optimally and setting the dosage regimen (the
manner in which the drug should be taken) knowledge of mechanisms of drug
absorption, distribution, metabolism and excretion (ADME) is not sufficient the
rate (kinetics) at which they occur is also important.
OR
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.
Pharmacokinetic model :
A pharmacokinetic model is a mathematical framework used to describe the abs
orption, distribution, metabolism, and excretion (ADME) of drugs in the body ov
er time.
 Linear Pharmacokinetics

• Linear pharmacokinetics (PK) describes a predictable drug behavior where the

amount of drug in the body (like plasma concentration or AUC) changes proportionally
with the dose, meaning doubling the dose doubles the exposure, because elimination
processes aren't saturated.
Key features include constant half-life, clearance, and bioavailability, making drug
dosing simpler and more consistent, unlike non-linear PK where saturation causes
disproportionate changes.
Key Characteristics
• Dose-Proportionality: Systemic exposure (AUC) and peak
concentrations increase linearly with dose.
• Constant PK Parameters: Clearance (CL), bioavailability (F), and
plasma protein binding remain unchanged with dose.
• Predictable Half-Life: The elimination half-life (t 1/2) is
constant, regardless of the dose or concentration.
• Predictable Drug Levels: If you double the dose, you roughly
double the drug concentration over time.
 Non-linear pharmacokinetics
• Nonlinear pharmacokinetics (PK) occurs when a drug's absorption, distribution,
metabolism, or excretion (ADME) processes become saturated at higher doses,
breaking the usual direct proportionality between dose and drug levels, leading to
disproportionate changes in concentration, clearance, or half-life, often described
by Michaelis-Menten kinetics for enzymes (e.g., phenytoin, aspirin) and requiring
careful dosing to avoid toxicity or lack of efficacy.
 Linear VS non-linear pharmacokinetics

Linear pharmacokinetics Non Linear pharmacokinetics

• dose-independent
• ADME all obey first-order kinetics. • dose-dependent)
• PK parameters (CL, V, F, Ka, and t1/2)• at least one of the ADME processes is
are constant. saturable.
• AUC is directly proportional to the • ≥1 PK parameters are dose- dependent..
dose. AUC is disproportional to the dose.
• Concentration vs. time profile is not
• Concentration vs. time profile is
superimposable for different doses
superimposable for all doses.
• Graph:
Analysis of pharmacokinetic data
 Model independent pharmacokinetic analysis

 The model-independent meth does not require the

assumption of specific compartment model. This method
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.
 Overcomes some of the drawbacks assiciated with classical
compartmental modeling.
 Basic assumption is that the drug or metabolite follows first
order kinetics.
 NON COMPARTMENTAL ANALYSIS
• Non-compartment pharmacokinetics is a new approach devised to
study the time course of drug in the body with out assuming any
compartment model. Based on the statistical moment theory .
• What does non-compartmental mean?
 Non-compartmental analysis (NCA) is a simple and quick method for
evaluating the exposure of a drug. It allows you to evaluate things like
linearity and in vivo exposure.
 Non compartmental analysis (NCA) provides the most elementary
pharmacokinetic information for a drug (i.e., peak concentration and
elimination half-life).
 NCAs are essential for characterizing new drug products and can help
guide development at each stage. It assumes that elimination follows first
order kinetics.
 Why do we need Non- compartment
model?
If the primary requirement is to determine the degree of exposure
following administration of a drug (such as AUC), and the drug's
associated pharmacokinetic parameters, such as clearance,
elimination half-life, T (max), C (max), etc., then Non-compartmental
analysis is generally the preferred methodology to use in that it
requires fewer assumptions than model-based approaches.
What is the difference between non compartmental
and compartmental analysis?
NCA often prove faster and more cost-efficient to conduct, especially
when compared to more complex compartmental analyses (e.g.,
compartmental models that are applied to population PK analyses
and that rely upon sparse/few sampling techniques)
 Assumptions of NCA
• Drug follows linear kinetics, i.e: drug exposure is proportional
to dose and PK parameters are stable.
• Drug is eliminated from the pool in which it has been
measured for PK parameters, i.e? plasma.
• All sources of drug are direct and unique to measurement
pool.
 Statistical moment theory
• Statistical moment theory is a unique way to study the time related
changes in macroscopic events.
• SMT is used to consider time related changes in variable occasions.
• Define the shape of data distribution beyond its center and
spread.
• Skewness measures asymmetry(left/negative, right/positive
tail)
• Kurtosis measures the tailedness or concentration of extreme
values( heavy or light tails) compressed to a normal
distribution.
 Pharmacokinetic parameters of NCA

[Link]: Area Under the Curve (AUC) in Non-Compartmental Analysis

(NCA) is a vital pharmacokinetic parameter representing total systemic drug
exposure, calculated as the integral of drug concentration over time using the
trapezoidal rule.
• It measures the extent of drug absorption and determines clearance.
• Key metrics include last measurable sample and extrapolated to infinity.
• FORMULA
[Link]:
AUMC (Area Under the First Moment Curve) is the integral of time multiplied
by drug concentration over time, used to calculate the mean residence time (
MRT) of a drug in the body.

It is a pharmacokinetic parameter used to characterize the drug’s exposure in t

he systemic circulation, incorporating both the concentration and time compon
ents in a moment-weighted manner.
[Link]( mean residential time):
Mean Residence Time (MRT) in non-
compartmental analysis is defined as the average time a drug molecule spend
s in the body from the moment of administration until its eventual eliminatio
n. It is calculated using the relationship between the Area Under the Concentr
ation-Time Curve (AUC) and the Area Under the First Moment Curve (AUMC).
FORMULA:

4. HALFLIFE refers to the time period required for the concentration of a

drug in the bloodstream to reduce to half of its initial value. It is a critical para
meter in pharmacokinetics as it helps in understanding the duration of action
of a drug and is essential for determining dosing intervals.
FORMULA

[Link] OF DISTRIBUTION:
• Volume of distribution is defined as the apparent volume in which a drug w
ould need to be uniformly distributed to produce the observed plasma co
ncentration.
• FORMULA

[Link](Cl)
• clearance refers to the efficiency of drug elimination from the body, quant
ifying the volume of plasma from which a drug is completely removed per
unit time.
• FORMULA
 Advantages and disadvantages of NCA
• Advantages • Disadvantages
• NCA does not assume any specific • NCA does not describe
compartment model (like one- or compartmental behavior of the
two-compartment).So, it avoids [Link], it cannot explain how
errors caused by choosing the the drug moves between tissues
wrong model. and plasma.
• Simple and easy to apply • Requires well-sampled
• More reliable for PK parameters concentration–time data,
estimation. especially in the terminal
• Has fewer assumptions. [Link] or sparse data can
lead to errors in parameters like
Area Under the Curve (AUC).
• Not suitable for complex PK
Compartmental and non compartmental models

Compartmental model Non compartmental model

• These require elaborate • Do not require assumptions to
assumptions to fit the data. compartment model.
• Curve fitting of experimental data • Simple algebraic equations. No
using computers. It is a tedious curve fitting and no computers
method. • Applicable to linear
• Applicable to linear and nonlinear pharmacokinetics.
pharmacokinetics. • C1 - time profile is regarded as
• C1 - time profile is regarded as statistical distribution.
expressions of exponents • Particularly useful for the
• These are useful for most of the applications of clinical
situations, though assumptions of pharmacokinetics, bioavailability,
modeling are involved. and bioequivalence studies.
THANK
YOU