Noncompartment Model - Pharmacokinetics

Dr C. V. S. Subrahmanyam
Principal
Gokaraju Rangaraju College of Pharmacy
Hyderabad

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Noncompartment Model - Pharmacokinetics
Objectives of this session
The participant shall be able to:
- Explain the concepts of noncompartment
model
- Explain the differences between
compartment and noncompartment models
- Describe different pharmacokinetic
parameters in noncompartment model

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Noncompartment Model - Pharmacokinetics
Noncompartmen model pharmacokinetics is a
new approach devised to study the time
course of drug in the body based on the
statistical moment theory
Model independent method
Overcomes some of the drawbacks
associated with classical compartment
modeling
Peak plasma drug concentration, Cmax
Time of peak concentration, tmax
Area under the curve, AUC
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Noncompartment Model - Pharmacokinetics

Cmax

Graphic
method

Equation: Cmax is a function of several factors

F KaD
Cmax = (e-k10tmax e-katmax)
V1(ka k10) Grcp
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Noncompartment Model - Pharmacokinetics
Cmax First point Cmax
It raises a question about the measurement
of true Cmax, because of insufficient early
sampling times
It requires a carefully chosen pilot study
Early time points between 3 to 15 minutes
Followed by additional sample collection (two
to five) in the first hour

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Noncompartment Model - Pharmacokinetics
tmax

Graphic
method

Eq: tmax is a function of several factors

2.303 log (ka /k10)
tmax = Grcp
(ka k10)
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AUC

Area of one trapezoid =

(1/2)(Cn-1 + Cn)(tn tn-1)
Area under the curve, AUC = Grcp
(areas of the trapezoids) CVS
Noncompartment Model - Pharmacokinetics
AUC

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 Noncompartment Model AUC
C t*
[AUC]0 = [AUC]0t +
Z
Where Ct* = last measurable Ct, g/ml
Z = termination elimination rate constant, h-1
Elimination rate constant is calculated
separately

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Noncompartment Model - Pharmacokinetics
Applications
Useful for estimating certain pharmacokinetic
parameters without specifically
referring to any models
Estimating PK parameters
Bioavailability Clearance
Apparent volume of distribution
Fraction of dose of drug absorbed
Mean absorption time
Mean resident time,
Average plasma steady state conc. of drug
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or its metabolite
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Noncompartment Model - Pharmacokinetics
Advantages
Derivation of PK parameters is easy, because
of simple algebraic equations
Mathematical treatment remains same, for
drug or metabolite, provided elimination
follows first order kinetics
Drug disposition kinetics need not be
described in detail

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Noncompartment Model - Pharmacokinetics
Disadvantages
a) Information regarding plasma drug
concentration-time profile is expressed as
an average
b) Generally not useful for describing the
time course of drug in the blood
c) It is applicable only for linear
pharmacokinetics

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Noncompartment and Compartment models
Comparison
Compartment models Noncompartment models
These require elaborate Do not require assumptions to
assumptions to fit the data. compartment model.
Curve fitting of experimental Simple algebraic equations. No
data using computers. It is a curve fitting and no computers.
tedious method.
Time course changes in C1 can Time course changes in C1
be predicted precisely. cannot be predicted precisely.
Applicable to linear and Applicable to linear
nonlinear pharmacokinetics pharmacokinetics.
C1 - time profile is regarded as C1 time profile is regarded as
expressions of exponents. statistical distribution.
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Noncompartment and Compartment models
Comparison
Compartment models Noncompartment models
These are useful for most of Particularly useful for the
the situations, though applications of clinical
assumptions of modeling are pharmacokinetics,
involved. bioavailability, and
bioequivalence studies.

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Noncompartment Model
Statistical Moment Theory
Approach is based on the statistical moment
theory
Categorisation of moments
Zero Moment
Zero moment of a drug concentration in
plasma versus time curve is referred to
as the total area under concentration
from zero to infinity, or simply AUC
[AUC]0 = C dt
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Noncompartment Model
Statistical Moment Theory
Area of trapezoid =
(1/2)(Cn-1 + Cn)(tn tn-1)
Area under the curve, AUC =
(areas of the trapezoids)
C t*
[AUC]0 = [AUC]0t +
Z
Where Ct* = last measurable Ct, g/ml
Z = termination elimination rate constant, h-1
Elimination rate constant is calculated
separately
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Noncompartment Model
Statistical Moment Theory
Applications
Used for calculating bioavailability and
drug clearance
First Moment
First moment of a plasma drug concentration
- time profile is referred to as mean
residence time (MRT)
[AUMC]0 t x C. dt
MRT = =
[AUC]0 C.dt
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Noncompartment Model
Statistical Moment Theory
Area of one trapezoid
Area under the curve, AUC
t*Ct* C*
[AUC]0 = [AUC]0t + +
Z Z2
Where Ct* = last measurable Ct, g/ml
Z = termination elimination rate constant, h-1
Elimination rate constant is calculated
separately

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 Noncompartment Models Analysis

I.v. bolus injection Calculation of AUC Grcp

and AUMC CVS
Noncompartment Models Analysis

I.v. bolus injection - AUC Grcp

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Noncompartment Models Analysis

I.v. bolus injection - AUMC Grcp

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Noncompartment Models Analysis

Oral product - Calculation of AUC and Grcp

AUMC CVS
Noncompartment Models PK Parameters

Oral product - AUC Grcp

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Noncompartment Models PK Parameters

Oral product - AUMC Grcp

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Noncompartment Model
Statistical Moment Theory
Second Moment
Second moment is referred to as variance of
the mean residence time (VRT) of the
drug in the body
t2.C dt (1MRT)2 C dt
VRT = =
C dt AUC
Higher moments are prone to unacceptable
level of errors

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Noncompartment Models PK Parameters
Mean Residence Time Half Life
Mean residence time (MRT) defined as the
average amount of time spent by the
drug in the body before being eliminated
AUMC t x C. dt
MRT = =
AUC C.dt
MRT represents the time for 63.2% of drug
eliminated when given i.v. bolus injection
It is analogous to plasma elimination half life,
t1/2, i.e., 50% elimination
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Noncompartment Models PK Parameters
Mean Residence Time Half Life
Like half life, MRT is a function of both
distribution and elimination
1
MRT =
k10
0.693
Plasma elimination half life, t1/2 =
k10
Plasma elimination half life, t1/2 = 0.693MRT
In two compartment model, concept of MRT
would be still useful, because of non
compartment model
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Noncompartment Models PK Parameters
Mean Residence Time Half Life
MRTiv is used for comparison. For eg: following
constant rate of infusion
T
MRTiv = MRTinst -
2
Where T = duration of infusion, h

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Noncompartment Models PK Parameters
Apparent Volume of Distribution at Steady State
Apparent volume of distribution (V1ss) is
independent of drug elimination
AUMC
V1ss = doseiv
(AUC)2
This equation is applicable to i.v. bolus
administration
It solely reflects the anatomic space occupied
by the drug and the relative degree of drug
binding in blood and extravascular space

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Noncompartment Models PK Parameters
Apparent Volume of Distribution at Steady State
If drug is given by short term constant rate i.v.
infusion
Infused dose (AUMC)
V1ss =
(AUC)2
Infused dose x
V1ss =
2(AUC)
Since infused dose is equal to R0
R0 x (AUMC) R0 2
V1ss = =
2(AUC)2 2(AUC)
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Noncompartment Models PK Parameters
Drug Clearance (Cl)
Clearance is defined as the ratio of the dose
after a single i.v. injection to the total area
under the drug concentration time curve
After a single i.v. bolus injection
Doseiv
Cl =
AUC
Since infused dose is equal to R0
R0
Cl =
C1ss

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Noncompartment Models PK Parameters
Mean Absorption Time (MAT) - Drug Absorption
MAT is defined as the differences in mean
residence time (MRT) after different modes
of administration
MAT = MRTni MRTiv
MRTni = mean residence time of drug by non-
instantaneous route, h
MRTiv = mean residence time of drug by i.v.
bolus injection, h
Same equation is used for i.m. injection
Absorption follows first order kinetics Grcp
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Noncompartment Models PK Parameters
Mean Absorption Time (MAT)
1
MAT =
ka
0.693
Absorption half life, t1/2 =
ka
Absorption half life, t1/2 = 0.693MAT
When absorption follows zero order
T
MAT =
2
T = time over which absorption takes place, h

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Noncompartment Models PK Parameters
MAT - Applications
Used for the comparison of dosage forms
Eg: comparison of furosemide dosage forms

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Noncompartment Models PK Parameters

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Noncompartment Models PK Parameters
Steady State Plasma Drug Concentration
The C1ss is a function of the effective rate
of dosing and total body clearance of the
drug in a patient
In continuous infusion
Ro
C1ss =
Cl
In multiple dosage regimen
AUCss
Cavss =

When absorption follows zero order
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Noncompartment Models PK Parameters
Steady State Plasma Drug Concentration
Average plasma drug concentration at steady
state, Cavss
F x dosing rate
Cavss =
Cl
If a drug is given in a dose of 400 mg every
8 hours, dosing rate is 400/8, i.e., 50
mg/hour

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Noncompartment Models PK Parameters
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 ss takes longer than predicted by
biological half life
In multicompartment disposition, time
required to attain to ss is shorter than
that predicted by terminal half life
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Noncompartment Models PK Parameters
Predicting the Time to Steady State
In noncompartment models, when the drug is
administered repetitive dosing, fss
AUC0
fss =
AUC
AUC = area under the curve in single dose
Bioavailability
Bioavailability refers to the fractional dose of
a dosage form reaches systemic circulation
For i.v. bolus injection, bioavailability is
referred as unity (=1)
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Noncompartment Models PK Parameters
Bioavailability
Bioavailability (F) of a dosage form
AUCoral Div
Absolute bioavailability, F =
AUCiv Doral
Equation assumes equal clearances in oral
and i.v. doses
Relative bioavailability, Fr, may be
expressed by comparing the zero
moments of a product with a standard
product
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Noncompartment Models PK Parameters
Fraction of Drug Metabolised, fm
Fraction of a drug metabolized, fm, is equal
to ratio of zero moments of the metabolite,
administered the drug to the metabolite
directly
AUCx1
Fraction metabolized, fm =
AUC1
AUCx1 = AUC of metabolite, when drug is
administered by i.v. bolus injection,
zero to infinity time, g.h/ml
AUC1 = AUC of metabolite, when metabolite
is administered by i.v. bolus injection, Grcp
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Noncompartment Models PK Parameters
Fraction of Drug Metabolised, fm
Metabolite is administered in equimolar i.v.
dose

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