NONCOMPARTMENTAL

PHARMACOKINETICS

Presented by: Mr. Nair Rahul R

 Contents
✓What is PK?
✓Compartmental v/s Noncompartmental PK Analysis
✓Deciding when to Use NCA
✓How is an NCA Performed?
✓Advantages and Disadvantages of NCA
✓Statistical Moments Theory
✓MRT
✓Physiological PK models
 What is Pharmacokinetics?
• Pharmacokinetics (PK) is the branch of pharmacology exploring the
effects of the body on a drug.
• Inparticular, PK helps us to understand in a quantitative way how a
drug moves into, passes through, and is eventually cleared from the
body. Put another way, PK is used to describe the absorption,
distribution, metabolism, and excretion (ADME) of a drug.
• Importantly,
insights into a drug’s PK are used not only to inform the
drug development program but are also critical for guiding input and
decision making by regulatory authorities like the FDA.
Compartmental v/s Noncompartmental PK Analysis

• Thereare two common approaches to understanding a drug’s PK. One is

compartmental PK analysis and the other is noncompartmental PK
analysis (NCA).
• Compartmental methods consider the body to consist of a finite number of
interconnected, well-mixed, and kinetically homogeneous compartments
(e.g., blood and other tissues/organs). Based upon this view, the
pharmacokineticist makes certain assumptions and develops models based
upon change in concentration over time to describe the PK of the drug. As
a result of this approach, there is the potential for variability in the output
of the analysis from one analyst to another, since the assumptions used to
build the PK model may be somewhat different.
Compartmental v/s Noncompartmental PK Analysis
• Incontrast, noncompartmental analysis (NCA) methods are model-
independent, meaning they do not rely upon assumptions about body
compartments, and they tend to provide more analyst-to-analyst
consistency.
• 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.
Compartmental v/s Noncompartmental PK Analysis

• NCAs often prove to be a faster and more cost-efficient type of

analyses to perform, especially when compared to more complex
compartmental analyses
• In
addition, an NCA relies almost exclusively upon algebraic
equations to estimate PK parameters, making the analysis less
complex than compartmental methods.
 Deciding when to use NCA
• Deciding whether to use a noncompartmental analysis versus a
compartmental approach is not a function of how sophisticated the
method is but really depends in large part upon the purpose of the
analysis.
• Compartmental methods boast key advantages for characterizing PK
across multiple studies, for exploring PK variability due to intrinsic
factors (e.g., age, sex, race, renal impairment, hepatic impairment) and
extrinsic factors, and for informing dosage adjustments based upon
these factors.
 Deciding When to Use NCA
• Onthe other hand, NCAs are typically favored for characterizing PK
within a single study, including both final analyses and any interim
analyses used to make dose escalation decisions.
• Inaddition, NCA is the most commonly used approach for
establishing the initial exposure characteristics of a drug prior to
entry into the clinic (i.e., during nonclinical PK and toxicology
studies).
 How is an NCA Performed?
• Inan ideal world, the way a drug moves through the body could be
tracked directly in every body fluid and tissue.
• In
the real world, this approach is not practical and we must instead
make estimates based upon what can be realistically measured.
• PK analysis relies on observed drug concentration measurements
over time in a relevant, accessible matrix (typically blood or plasma).
These measurements are provided to the pharmacokineticist by a
bioanalytical lab, where blood or plasma samples from study subjects
are analyzed using sensitive detection techniques.
 Applications of NCA
1. It is widely used to estimate the important pharmacokinetic
parameters like bioavailability, clearance and apparent volume of
distribution.
2. The method is also useful in determining half-life, rate of
absorption and first-order absorption rate constant of the drug.
Main PK parameters estimated using NCA
 Advantages of NCA
• Easeof derivation of PK parameters using simple
algebraic equations
• Detailed description of drug disposition is not required
 Disadvantages of NCA
• Provideslimited information regarding the plasma drug
concentration-time profile.
• The method is not suitable for non-linear cases
 How is an NCA Performed?
• Once the pharmacokineticist receives the drug concentration data,
he or she uses a PK software package to construct concentration
versus time plots to graphically display the pharmacokinetics of
the drug in the given matrix and to estimate relevant PK
parameters.
 Statistical moment theory
• Statistical
moments are parameters that describe the
characteristics of the time courses of plasma concentration
(area, mean residence time-MRT, and variance of residence
time-VRT) and of the urinary excretion rate that follow
administration of a single dose of a drug.
 Statistical moment theory
• NCAs are based on statistical moment theory, which provides a
unique way to study time-related changes in macroscopic events.
• A macroscopic event is considered the overall event brought about by
the constitutive elements involved. For example, in chemical
processing, a dose of tracer molecules may be injected into a reactor
tank to track the transit time (residence time) of materials that stay in
the tank. The constitutive elements in this example are the tracer
molecules, and the macroscopic events are the residence times shared
by groups of tracer molecules.
 MRT
• MRT provides a fundamentally different approach than classical
pharmacokinetic models, which involve the concept of dose, half-life,
clearance, volume, and concentration. The classical approach does
not account for the observation that molecules in a cluster move
individually through space and are more appropriately tracked as
statistical distribution based on residence-time considerations.
• MRT is an alternative concept to describe how drug molecules move
in and out of a system.
 MRT
• After an intravenous bolus drug dose, the drug molecules
distribute throughout the body. These molecules stay (reside) in
the body for various time periods. Some drug molecules leave the
body almost immediately after entering, whereas other drug
molecules leave the body at a much later time period.
• The term MRT describes the average time that drug molecules
stay in the body or in a kinetic space.
 MRT
• Theequation to calculate the MRT following intravenous bolus or
constant infusion administrations is described in Equation 1

…(1)
Where,
AUMC0t is the area under the (first) moment-versus-time curve from t = 0 to infinity,
AUC0∞ (or zero moment curve) is the area under the concentration-versus-time curve
from t = 0 to infinity, and
Duration is the duration of the drug infusion.
MRT
 Physiological PK models
• They are drawn on the basis of known anatomic and physiological
data and thus present a more realistic picture of drug disposition in
various organs and tissues. The number of compartments to be
included in the model depends upon the disposition
• characteristicsof the drug. Organs or tissues such as bones that have
no drug penetration are excluded. Since describing each organ/tissue
with mathematic equations makes the model complex, tissues with
similar perfusion properties are grouped into a single compartment.
For example, lungs, liver, brain and kidney are grouped as rapidly
equilibrating tissues (RET) while muscles and adipose as slowly
equilibrating tissues (SET).
• Schematic representation of a physiological pharmacokinetic model. The term Q indicates blood flow
rate to a body region. HPT stands for other highly perfused tissues and PPT for poorly perfused tissues.
Km is rate constant for hepatic elimination and Ke is first-order rate constant for urinary excretion.
Since the rate of drug carried to a tissue organ and tissue drug
uptake are dependent upon two major factors –
• Rate of blood flow to the organ, and
• Tissue/blood partition coefficient or diffusion coefficient of drug
that governs its tissue permeability,
• The physiological models are further categorized into two types –
1. 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.
• 2.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.
Advantages over the conventional compartment modelling
1. Mathematical treatment is straightforward.
2. Since it is a realistic approach, the model is suitable where tissue drug concentration and binding
are known.
3. Data fitting is not required since drug concentration in various body regions can be predicted on
the basis of organ or tissue size, perfusion rate and experimentally determined tissue-to-plasma
partition coefficient.
4. The model gives exact description of drug concentration-time profile in any organ or tissue and
thus better picture of drug distribution characteristics in the body.
5. The influence of altered physiology or pathology on drug disposition can be easily predicted
from changes in the various pharmacokinetic parameters since the parameters correspond to actual
physiological and anatomic measures.
6. The method is frequently used in animals because invasive methods can be used to collect tissue
samples.
7. Correlation of data in several animal species is possible and with some drugs, can be
extrapolated to humans since tissue concentration of drugs is known.
8. Mechanism of ADME of drug can be easily explained by this model.
Disadvantages of physiological modelling

1. Obtaining the experimental data is a very exhaustive process.

2. Most physiological models assume an average blood flow for individual
subjects and hence prediction of individualized dosing is difficult.
3. The number of data points is less than the pharmacokinetic parameters to be
assessed.
4. Monitoring of drug concentration in body is difficult since exhaustive data
is required
Comparison of features of compartment and physiological models

Compartment Modelling Physiological Modelling

Hypothetical/empirical approach – no relation with Realistic approach since it is based on physiological

real physiology or anatomy and anatomic information
Experimentally simple and flexible approach as far as Difficult experimentally since exhaustive data
data collection is concerned collection is required.
Owing to its simplicity, it is widely used and is often Less commonly used owing to complexity.
the ―first model.
Complex multiexponential mathematical treatment is Mathematical treatment is straightforward.
necessary for curve fitting.
Data fitting is required for predicting drug Data fitting is not necessary since drug concentration
concentration in a particular compartment. in various tissues is practically determined.
Used when there is little information about the tissues. Used where tissue drug concentration and binding are
known
Comparison of features of compartment and physiological models
Compartment Modelling
Easy to monitor time course of drug in body with
limited data.
Extrapolation from data to humans and vice versa
is not possible
Mechanism of drug’s ADME cannot be explained
Effect of pathological condition on drug ADME
cannot be determined.
Frequently used for data comparison of various
drugs.
Physiological Modelling
Exhaustive data is required to monitor time course
of drug in body.
Extrapolation of animal data to humans is easy on
the basis of tissue concentration of drugs.
Easy to explain drug’s ADME mechanisms.
Effect of pathology on drug ADME can be easily
determined.
Less commonly used for data comparisons
 Distributed Parameter Model
This model is analogous to physiological model but has been designed
to take into account –
• Variations in blood flow to an organ, and
• Variations in drug diffusion in an organ.

Such a model is thus specifically useful for assessing regional

differences in drug concentrations in tumours or necrotic tissues.
The distributed parameter model differs from physiological models in
that the mathematical equations are more complex and collection of
drug concentration data is more difficult