Loo-Riegelman Method & Different Software used in BiopharmaceuticsLoo-Riegelman Method & Different Software used in Biopharmaceutics

Presented By: Tushar R. Bambharoliya 09MPH110Institute Of PharmacyNIRMA UNIVERSITY

Guided By: Shital Bariya Dr. Tejal Mehta

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) .

Central compartmentDp Vp Cp

Tissue Compartment

Dt Vt Ct

KaK12

K21

K

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)

(5)

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∞

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

Divide the equation by Vp

(6)

(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.

Time (Cp)t n ∆CP ∆TK12∆CP∆T/2 (Cp)t n-1

K12 /K21*(1-e-K21∆T)

K12/K21*(1-e-K21∆T)(Cp)tn-1

(Ct)tn-1*e-K21∆t (Ct)t n

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

Ex. : K12=0.29, K21=0.31, K=0.16, Find Ka

Time (Cp)t n [AUC]tntn–1 [AUC]tn

t 0 k[AUC]tn t 0 (Ct)t n Ab/Vp %Ab/Vp

100% – Ab/Vp%

Log unabsorbed

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

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

Different software used in Biopharmaceutics

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.

AbstractA 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 Publication Date: 1986 Oct

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 Pharmacol Publication Date: 1986 Oct

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, 1979, Pages 67-80

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 1985, Pages 129-136

PKC, a new pharmacokinetic software using SAS@

Data model

Integration of the application

European Journal of Pharmaceutics and Biopharmaceutics 43 (1997) 197-199

Other softwareBoomer nonlinear regression programModern biopharmaceuticsNCSS