Transcript Noncompartmental Models

Noncompartmental Models
Introduction
• The noncompartmental approach for data analysis does
not require any specific compartmental model for the
system (body) and can be applied to virtually any
pharmacokinetic data.
• There are various noncompartmental approaches,
including statistical moment analysis, system analysis, or
the noncompartmental recirculatory model
• The main purpose of the noncompartmental approach is
to estimate various pharmacokinetic parameters, such
as systemic clearance, volume of distribution at steady
state, mean residence time, and bioavailability without
assuming or understanding any structural or mechanistic
properties of the pharmacokinetic behavior of a drug in
the body
Introduction
• In addition, many noncompartmental methods
allow the estimation of those pharmacokinetic
parameters from drug concentration profiles
without the complicated, and often subjective,
nonlinear regression processes required for the
compartmental models
• Owing to this versatility and ruggedness, the
noncompartmental approach is a primary
pharmacokinetic data analysis method for the
pharmaceutical industry
Statistical moment theory
• Suppose one could observe a single molecule,
from the time it is administered into the body ( t
= 0) until it is eventually eliminated ( t = tel )
• Clearly, tel is not predictable
• This individual molecule could be eliminated
during the first minute or could reside in the
body for weeks. If, however, one looks at a large
number of molecules collectively, their behavior
appears much more regular
• The collective, or mean time of residence, of all
the molecules in the dose, is called the mean
residence time (MRT).
Mean Residence Time (MRT)
• A mean time interval during which a drug
molecule resides in the body before being
excreted

AUMC
MRT 

AUC
 t  C (t ).dt
 C (t ).dt
0

0
AUC vs. AUMC
Estimating AUC and AUMC
Linear trapezoidal method
0
t1
t2
t3
tlast
Estimating AUC and AUMC
Linear trapezoidal method
• For samples until the last observed
concentration (t2<= tlast)
C2  C1
AUCt1t 2  (t 2  t1 ) 
2
t 2  C2  t1  C1
AUMCt1t 2  (t 2  t1 ) 
2
Estimating AUC and AUMC
Linear trapezoidal method
• For the last observed sample and infinity (t2= ∞)
AUCtlast  
Clast

AUMCtlast  
tlast  Clast


Clast

2
• Clast is the last observed conc. at time tlast ,λ is
the slope of the terminal phase of the plasma
drug concentration-time profile on a semilog
scale (i.e. log(Conc) vs. time)
Estimating Pharmacokinetic
Parameters with Moment Analysis
A. Clearance: The systemic clearance (Cl)
of a drug can be estimated as the
intravenous dose (Div) divided by the
AUC after intravenous bolus
administration (AUCiv):
Div
Cl 
AUCiv
Estimating Pharmacokinetic
Parameters with Moment Analysis
B. Volume of Distribution at Steady
State: The volume of drug distribution at
steady state (Vdss) can be estimated as
the product of MRT after intravenous
bolus injection (MRTiv) and CI:
AUMCiv Div
VDSS  MRTiv  Cl 

AUCiv AUCiv
Estimating Pharmacokinetic
Parameters with Moment Analysis
C. Bioavailability. Bioavailability (F) of a
drug generally refers to the fraction of a
dose administered via a route other than
intravenous injection that reaches the
systemic circulation:
Div AUCoral
F

Doral AUCiv
Estimating Pharmacokinetic
Parameters with Moment Analysis
D.Mean Residence Time. The mean residence
time (MRT) is the average time spent by a single
drug molecule in the body before being excreted
via elimination processes, regardless of the
route of administration.
• The MRT values after administration by routes
other than intravenous bolus injection are
always greater than MRTiv
Estimating Pharmacokinetic
Parameters with Moment Analysis
• Differences in MRT values following
administration via these other routes and MRTiv
can be viewed as the average time required for
drug molecules to reach the systemic circulation
from the site of administration
mean absorption time (MAT)
• The difference between MRT after oral
administration (MRToral) and MRTiv is the mean
absorption time (MAT), representing the average
time required for the drug to reach the systemic
circulation from the gastrointestinal tract after
oral administration:
MAT  MRToral  MRTiv
AUMCiv
AUMCoral
MRTiv 
, MRToral 
AUCiv
AUCoral
intravenous infusion
• If the dose of drug is administered by
intravenous infusion, the MRTiv may be
calculated as:
(Infusion time)
MRTiv  MRTinfusion 
2