Loo-Riegelman Method &

Different Software used in

Biopharmaceutics

Guided By: Shital Bariya

Dr. Tejal Mehta

Presented By: Tushar R.

Bambharoliya
09MPH110
Institute Of Pharmacy
NIRMA UNIVERSITY
 Introduction

• Absoption rate constant in

– One compartment open model-Extravascular
administration(First order)
• Feathering method (Peeling, stripping, method of residual)
• Wagner-Nelson Method
• Determination of Ke from urinary excretion data(First
order)
• Rate of Excretion method
• Sigma-minus method
• Two-compartment open model-Extravascular
administration(First order)
• Loo-Riegelman method
 Determination of ka from Two-Compartment Oral
Absorption Data (Loo–Riegelman Method)
• Plotting the percent of drug unabsorbed versus time to
determine the k a may be calculated for a drug exhibiting a
two-compartment kinetic model. As in the method used
previously to obtain an estimate of the k a, no limitation is
placed on the order of the absorption process. However, this
method does require that the drug be given intravenously as
well as orally to obtain all the necessary kinetic constants.
• After oral administration of a dose of a drug that exhibits
two-compartment model kinetics, the amount of drug
absorbed is calculated as the sum of the amounts of drug in
the central compartment (D p) and in the tissue compartment
(D t) and the amount of drug eliminated by all routes (D u) .
 K12
Central Tissue
Ka
compartment Compartment
Dp Vp Cp K21 Dt Vt Ct

Two-compartment pharmacokinetic mode. Drug

absorption and elimination occur from the central
compartment
Each of these terms may be expressed in terms of kinetics constants and
plasma drug concentration, as follows:

(1)

(2)

(3)

(4)

Now, The fraction of drug absorbed at any time t is equal to the amount of drug
absorbed at this time Abt, divided by the total amount of drug absorbed, Ab∞

(5)
From equation (1),(2) and (5)

(6)

Divide the equation by Vp

(7)

(8)

Eq. (7) devided by (8)

A plot of the fraction of drug unabsorbed, 1 – Ab/Ab∞, versus time gives –k
a/2.3 as the slope from which the value for the absorption rate constant is
obtained.

Cp and k [AUC]t 0 are calculated from a plot of C p versus time. Values for (D
t/V p) can be approximated by the Loo–Riegelman method, as follows:

where C t is D t/V p, or apparent tissue concentration; t = time of sampling for

sample n; t n –1 = time of sampling for the sampling point preceding sample n;
and (C p)t n–1 = concentration of drug at central compartment for sample n – 1.
Ex. : K12 =0.29, K21 =0.31, K=0.16, Find Ka
Time (Cp)tn ∆CP ∆T K12 ∆CP∆T/2 (Cp)tn-1 K12 /K21 *(1- K12 /K21 *(1-e- (Ct)tn- (Ct)tn
e-K21 ∆T) K21 ∆T)(Cp)tn-1 1*e-K21 ∆t

0 0 0 0 0 0 0 0
0.5 3 3 0.5 0.2175 0 0.134321 0 0 0.218
1 5.2 2.2 0.5 0.1595 3 0.134321 0.402963857 1.87 0.749
1.5 6.5 1.3 0.5 0.09425 5.2 0.134321 0.698470685 0.642 1.433
2 7.3 0.8 0.5 0.058 6.5 0.134321 0.873088356 1.228 2.157
2.5 7.6 0.3 0.5 0.02175 7.3 0.134321 0.980545385 1.849 2.849
3 7.75 0.15 0.5 0.010875 7.6 0.134321 1.02084177 2.442 3.471
3.5 7.7 -0.05 0.5 -0.00362 7.75 0.134321 1.040989963 2.976 4.019
4 7.6 -0.1 0.5 -0.00725 7.7 0.134321 1.034273899 3.444 4.469
5 7.1 -0.5 1 -0.0725 7.6 0.249356 1.895106156 3.276 5.103
6 6.6 -0.5 1 -0.0725 7.1 0.249356 1.77042812 3.74 5.442
7 6 -0.6 1 -0.087 6.6 0.249356 1.645750083 3.989 5.552
9 5.1 -0.9 2 -0.261 6 0.432246 2.593473157 2.987 5.318
11 4.4 -0.7 2 -0.203 5.1 0.432246 2.204452183 2.861 4.861
15 3.3 -1.1 4 -0.638 4.4 0.66477 2.924986251 1.361 3.891
Time (Cp)tn [AUC]tn tn –1 [AUC]tn t 0 k[AUC]tn t0 (Ct)tn Ab/Vp %Ab/Vp 100% – Log unabsorbed
Ab/Vp%

0 0 0 0 0
0.5 3 0.75 0.75 0.12 0.218 3.338 16.57481 83.42519 1.921297
1 5.2 2.05 2.8 0.448 0.749 6.397 31.76424 68.23576 1.834012
1.5 6.5 2.925 5.725 0.916 1.433 8.849 43.93962 56.06038 1.748656
2 7.3 3.45 9.175 1.468 2.157 10.925 54.24798 45.75202 1.66041
2.5 7.6 3.725 12.9 2.064 2.849 12.513 62.13317 37.86683 1.578259
3 7.75 3.8375 16.7375 2.678 3.471 13.899 69.01534 30.98466 1.491147
3.5 7.7 3.8625 20.6 3.296 4.019 15.015 74.55683 25.44317 1.405571
4 7.6 3.825 24.425 3.908 4.469 15.977 79.33363 20.66637 1.315264
5 7.1 7.35 31.775 5.084 5.103 17.287 85.83842 14.16158 1.151112
6 6.6 6.85 38.625 6.18 5.442 18.222 90.48116 9.518844 0.978584
7 6 6.3 44.925 7.188 5.552 18.74 93.05328 6.94672 0.84178
9 5.1 11.1 56.025 8.964 5.318 19.382 96.24112 3.758876 0.575058
11 4.4 9.5 65.525 10.484 4.861 19.745 98.0436 1.956403 0.291458
15 3.3 15.4 80.925 12.948 3.891 20.139 100 0
From Graph slope : 0.156
Ka : 0.359
 Different software used in Biopharmaceutics

1. NONLIN84/PCNONLIN
2. AUC-RPP
3. KINPAK
4. Boomer
5. SAAM II
6. WinNonlin Professional
7. ADAPT II
8. KINETICA
9. NONMEM
10. ACT
11. DATALIN
12. PKC
 Four widely available computer programs were used to perform pharmacokinetic
analysis of data: JANA, PKCALC, F8SD and PCNONLIN.
Programs were run on an 80386 standard personal computer. F8SD and PKCALC
allow compartmental and noncompartmental modelling to be performed, and JANA
and PCNONLIN are restricted to compartmental analysis.
JANA(Statistical Consultants, Inc., Lexington, KY, USA) is a program for
preliminary statistical analysis of polyexponential models (including
pharmacokinetic models). It uses an iterative curve-stripping technique to produce
parameter estimates for the models.
PCNONLIN (Statistical Consultants, Inc., Lexington, KY, USA) is a software
package for the statistical analysis of general nonlinear models, including
pharmacokinetic models, that ®nd estimates of the parameters of the non-linear
functions in the sense of least squares (default type of ®tting algorithm: Levenberg-
Hartley modi®cation of Gauss-Newton).
The F8SD (non-pro®t-making, available on request from the authors) is an iterative
method of non-linear regression in the sense of least squares.
PKCALC (Merrell Dow Pharmaceuticals Inc., Indianapolis, IN, USA) is a BASIC
interactive computer program for pharmacokinetic analysis of multisubject data sets.

Comparative study of four different pharmacokinetic computer programs:

case study of a factor VIII preparation, Eur J Clin Pharmacol (1997) 52: 59±64
 NONLIN84/PCNONLIN: software for the statistical analysis of
nonlinear models.

Abstract
A new software package, NONLIN84, has been developed for the
analysis of general nonlinear models including pharmacokinetic
models.
NONLIN84 is easier to use than the older NONLIN77, and can
handle a wider class of estimation problems, such as maximum
likelihood estimation involving iterative reweighting.
Two large libraries of pharmacokinetic models are distributed with
NONLIN84 and can be accessed by simply specifying a model
number. A companion program, PCNONLIN, runs on DOS based
microcomputers and retains most of the features of NONLIN84.

Methods and findings in experimental and clinical pharmacology     Volume: 

8     ISSN:  0379-0355     ISO Abbreviation:  Methods Find Exp Clin Pharmacol
 AUC-RPP: BASIC computer program for
compartment model independent pharmacokinetic
analysis.

A computer program in BASIC for compartment

model independent analysis (AUC-RPP) is presented.
The program is based on regression analysis of the
terminal phase, the area under the curve and the area
under the first moment curve.
It is designed for i.v. constant rate infusion, i.v. push
and extravascular administration. For the latter route
a simple estimate on the absorption rate constant is
performed.
Methods and findings in experimental and clinical pharmacology     Volume: 
8     ISSN:  0379-0355     ISO Abbreviation:  Methods Find Exp Clin
 KINPAK--a program for standardized
pharmacokinetic analysis.

Concept and routines of a new program package (KINPAK) for

standardized evaluation of kinetic parameters are described.
The package is mainly designed for the investigation of bioavailability
or bioequivalence of pharmaceutical products. The data analysis is not
based on compartmental or other specific model assumptions.
Instead, the experimental data are fitted by new descriptive smoothing
functions which are well adapted to the general form of concentration-
time curves, but sufficiently flexible to give a good fit for nearly all
experimental data sequences.
The results are checked and, when necessary, corrected by a set of
biologically based plausibility tests, which were heuristically derived
from about 33,000 experimental concentrations.
During the program development 2264 data sequences based on 40 different drugs
were used as references; 95% could be evaluated successfully. The relevant biological
parameters are calculated from the geometric properties of the fitted curves.
Therefore, they will yield valid results even for curves which cannot be evaluated by
compartmental models (e.g., multiple peak curves).
The results are listed by KINPAK in various tables ready for presentation to
regulatory agencies. Thus, errors of transcription are eliminated.
The program, developed primarily for the investigation of bioavailability and
bioequivalence in industrial drug research, should be of great interest for research
laboratories, universities, and hospitals who are in need of a standardized evaluation
system for comparative studies.
 Nonlinear Regression
Software
• Boomer (available for Macintosh and
Windows),
• SAAM II (loaded on Macintosh and
Windows computers in the Bird library),
• WinNonlin Professional (loaded on
Windows computers in the Bird Library),
• ADAPT II ,
• KINETICA, and
• NONMEM
 Compartmental analysis—II: ACT, a program for
compartmental models of the generalized
Michaelis-Menten type
An adequate approach of biological systems requires most
of the time the use of non-linear models.
A general theoretical model for compartmental analysis,
essentially based on the Michaelis-Menten laws, is
presented here, as well as the algorithmical developments
solving the classical problems of simulation and of fitting,
and the problems of predetermination and of latency time.
Besides the theoretical aspect, a new FORTRAN program,
ACT, allowing to handle all the mentioned problems, is
made available.

Computers in Biology and Medicine Volume 9, Issue 1,

 DATALIN—An interactive data entry program for
use with NONLIN
A package of FORTRAN programs for data entry into
NONLIN (version II) is described which may be used in
the analysis of plasma-concentration time curves after
single or multiple doses for fourteen pharmacokinetic
models described in terms of the model's microconstants
(volume of compartments, rate constants).
In all cases, infusion rates must be zero-order and
absorption rates first-order. The program contains an edit
subroutine allowing for changes in initial parameter
estimates and their lower and upper limits, weighting
factors, number of iterations in the NONLIN analysis, and
plot option. Individual X and Y values may be changed and
listed and X-Y data pairs may be inserted or deleted.

Journal of Pharmacological Methods Volume 14, Issue 2, September

PKC, a new pharmacokinetic
software using SAS@

Data model
 Integration of the application

European Journal of Pharmaceutics and Biopharmaceutics 43

Other software
Boomer nonlinear regression program
Modern biopharmaceutics
NCSS