COMPUTER APPLICATIONS IN PHARMAKOKINETICS

MADE BY:VIKAS JHAWAT M.PHARM 2ND SEM MMCP, MMU, MULLANA, AMBALA

INTRODUCTION
A program of instructions known as a computer package or software is written in a computer language. This software is needed to run the computer. Use of computer and computer programs in pharmaceutics makes the tedious calculations easy, more precise and reduces the chances of error. Various computer softwares are used to solve mathematical problems and to control the various complex scientific processes. Computer makes the processes and calculations faster and gives directly the accurate result. Many experimental data are feed into the software to evaluate the desired result.

BENEFITS OF COMPUTER SOFTWARES

Computer software programs allow for the rapid solution of complicated pharmacokinetic equations and rapid modeling of pharmacokinetic processes. Computers simplify tedious calculations and allow more time for the development of new approaches to data analysis and pharmacokinetics modeling. computer software is used for the development of experimental study designs, statistical data treatment, data manipulation, graphical representation of data, pharmacokinetic model simulation, and projection or prediction of drug action.

 Furthermore, computers are used frequently for written reports, documentation, and archiving. A variety of computers are now available. Personal computers (PCs) may be used independently or linked together into local networks (LANs) that share many application software packages. Each type of computer has an operating system (OS), which is a collection of programs that allocates resources and enables algorithms (well-defined rules or processes for solving a problem in a finite number of steps) to be processed. UNIX, Windows, and more recently, LINUX, are examples of commonly used operating systems.

SOFTWARES IN PHARMAKOKINETIC
Pharmacokinetic software consists of computer programs designed for computation and easy solution of pharmacokinetic problems. 1. Fitting drug concentration-versus-time data to a series of pharmacokinetic models, and choosing the one that best describes the data statistically. The mathematical method employed should be reviewed before use. 2. Fitting data into a pharmacokinetic or pharmacodynamic model defined by the user This method is by far the most useful, because any list of prepared models is often limited. The utility program provides a simple, quantitative way of relating the variables, but offers little insight into the underlying pharmacokinetic processes. 3. Simulation software programs generate data based on a model with parameter input by the user. When the parameters are varied, new data are generated based on the model chosen. The user is able to observe how the simulated model data matches the experimental observed data. Because pharmacokinetic processes are conveniently described by systems of differential equations, the simulation process involves a numerical solution of the equation with predefined precision.

 4. Experimental design To estimate the parameters of any model, the experimental design of the study must have points appropriately spaced to allow curve description and modeling For the first pharmacokinetic study, an empirical or a statistical experiment design is necessarily based on assumptions that may later prove to be wrong. 5. Clinical pharmacokinetic applications Some software programs are available for the clinical monitoring of narrow-therapeutic-index drugs (ie, critical-dose drugs) such as the aminoglycosides, other antibiotics, theophylline, or antiarrythmics. These programs may include calculations for creatinine, dosage estimation, pharmacokinetic parameter estimation for the individual patient, and pharmacokinetic simulations. 6. Computer programs for teaching Software applications for teaching have been reviewed by Pharmacalc and PharmaSim may be used for pharmacokinetic computations. SAAM II or Stella and ModelMaker may be used for "system dynamics Other software reviewed includes ADAPT for use in parameter estimation, simulation, and experimental (sample schedule) design.

Validation of Software Packages

Software used for data analysis such as statistical and pharmacokinetic calculations should be validated with respect to the accuracy, quality, integrity, and security of the data. One approach for determining the accuracy of the data analysis is to compare the results obtained from two different software packages using the same set of data (). Because software packages may have different functionalities, different results (eg, pharmacokinetic parameter estimates) may be obtained.

VARIOUS SOFTWARES FOR PHARMAKOKINETIC STUDY PCNonlin

PCNonlin is a powerful least-squares program for parameter estimation. It is the advanced version of LIN. The program accepts both differential and

regular (analytical) equations. Users may select the Hartley-modified or Levenberg-type Gauss Newton algorithm or simplex algorithm for minimizing the sum of squared residuals. Until its commercial release, Nonlin was installed mostly on mainframe computers.

WinNonlin
WinNonlin is Windows-based software for pharmacokinetic, pharmacodynamic, and noncompartmental analysis. It is designed for easy interfacing and secure data management with PkS Suite. WinNonlin can calculate individual bioequivalences for all of the common replicated crossover designs. WinNonlin has an improved user interface that makes it easier to use and to interface with other Windows applications. WinNonlin is relatively easy to use for modeling or noncompartmental analysis of data files and handles large numbers of subjects or profiles. The Noncompartmental Analysis module computes derived pharmacokinetic parameters (AUC, C max, cumulative excretion, etc).

SAS
An all-purpose data analysis system with a flexible application-development language, SAS Graph allows for multidimension plots, for bar, pie, and contour charts, and for all sorts of other graphs. Over 5000 SAS products are reported to be available. Various "procs" (subroutines) are available for statistics as well as general linear and nonlinear regression models. There are over 80 procedures for descriptive statistics; t-test, chi-square, correlation, autoregression, multidimensional scaling, nonparametric test, factor analysis, and stepwise analysis.

RSTRIP
RSTRIP is menu-driven and very suitable for student use; it fits data to models, mono-, bi-, and tri-exponentials based on model selection criteria. A good statistics menu is available for AUC, C max, T max, and mean residence time. The program gives initial parameter estimates and final parameters

after iteration. However, the program does not handle differential equations or user-defined models. Plot outputs are available, as are pharmacokinetic curve stripping, and least-squares parameter optimization.

NONMEM
NONMEM (Nonlinear Mixed Effects Model), developed by S. L. Beal and L. B. Sheiner, is a statistical program used for fitting parameters in population pharmacokinetics. It is useful in evaluating relationships between pharmacokinetic parameters and demographic data such as age, weight, and disease state. Average population parameters and intersubject variance are estimated. The program fits the data of all the subjects simultaneously and estimates the parameters and their variances. The parameters are useful in estimating doses for individuals based on population pharmacokinetics with calculated risks

The software consists of three parts:

The NONMEM program itself is a very general (non-interactive) regression program that can be used to fit models to many different types of data. With version 7, Monte Carlo expectation-maximization and Markov Chain Monte Carlo Bayesian methods have been added to the classical likelihood methods available in previous versions. NONMEM can be used to simulate data as well as fit data. PREDPP is a powerful package of subroutines that can be used by NONMEM to compute predictions for population pharmacokinetic and pharmacodynamic data. Use of PREDPP obviates the need for the user to code kinetic-type equations and it also allows complicated patient-type data to be easily used. However, the user can also directly and very generally code prediction-type, likelihood or -2 log-likelihood equations, and thus a great variety of different types of models can be used. NM-TRAN is (non-interactive) pre-processor, allowing control and other needed inputs to NONMEM/PREDPP to be specified in a user friendly manner, with quick and comprehensive detection of a variety of errors that the user may have made in so doing.

NONMEM 7 is programmed in Fortran 90/95 code and can be used with hardware and Window, Linux or Solaris operating system incorporating a Fotran 90/95-compliant compiler. Since some NONMEM runs can take considerable time, perhaps many hours or even days, depending on the speed of the computer and the size of the problem, it is advisable to use a fast machine with at least 1.0 Gb of available memory. For multiprocessor and multi-core environments 3-4 Gb of memory may be needed to accommodate several simultaneous NONMEM runs. NONMEM 7 includes the following enhancements:

Improved incidence of success in problems using the first-order conditional estimation method. Improved incidence of completion when using the Super Problem feature. Exact likelihood maximisation methods, such as importance sampling expectation maximisation (EM), and stochastic approximation EM. Full three stage hierarchical Markov Chain Monte Carlo (MCMC) methods. Additional result files, with number of significant digits selectable by the user, and which can be easily read by post-processing programs. Numbers of data items per data record increased to 50. Label names may be as large as 10 characters. Initial parameter entries in the control stream file may be of any numerical format. The NONMEM program is available on CD ROM, which together with the documentation and all updates and additions to the program and documentation, will be delivered for a license royalty fee to be paid annually. This fee is subject to change from year to year, and at each anniversary the licensee at its option may choose not to renew the license.

The current version of NONMEM (Version IV) consists of several parts. The NONMEM program itself is a general (noninteractive) regression program which can be used to fit many different types of data. PREDPP consists of

subroutines that can be used by NONMEM to compute predictions for population pharmacokinetics

MKMODEL
MKMODEL, by N. Holford, is a pharmacokinetic program from the National Institutes of Health-supported PROPHET system. The program, available for the PC, performs nonlinear least-squares regression and includes both pharmacokinetic and pharmacodynamic models (effect compartment).

ADAPT II
This program performs simulations, nonlinear regression, and optimal sampling, and includes extended least-squares and optimization. Models can be expressed as integrated or differential equations .

MATH CAD
MathCAD 11 has many general mathematical and statistical functions which can be easily adaptable for data analysis or fitting data to probability distribution models. Differential equation solvers support ordinary differential equations, systems of differential equations, and boundaryvalue problems both at the command line and in Solve blocks that use natural notation to specify the differential equations and constraints.

GASTROPLUS
GastroPlus is a computer simulation program that predicts the rate and extent of drug absorption from the gastrointestinal tract It is a physiologically based software program that simulates intravenous, oral, oral cavity, ocular, intranasal and pulmonary absorption, pharmacokinetics, and pharmacodynamics in human and animals. Using in silico/in vitro data with our whole body PBPK models, you can begin to predict first-in-human or -animal outcomes, conduct virtual population

trials, fit a wide variety of model parameters for single or multiple data sets, understand food effects, assess the impact of nonlinear metabolism or transport, track metabolites formed in any tissue, analyze various formulation strategies, generate in vitro-in vivo correlations (IVIVC), and predict drug-drug interactions (DDI).

KINETICA
Thermo Electron's pharmacokinetic analysis tool, offers fast highthroughput data analysis for clinical, preclinical, discovery, drug metabolism and drug delivery settings. This tool standardizes analyses across the organization and minimizes variability between PK analysts and analyses. Designed as a template format, Kinetica allows user to preset computation options before bringing data for analysis. With a direct link to Watson analytical LIMS, bioanalytical data are transferred electronically from Watson to Kinetica so that the overall data analysis experience improves while reducing the need to transfer data manually. From non-compartment thru to population pharmacokinetics to population model validation, Kinetica reduces the need for multiple software packages.

MEDICI-PK
It is a modular, transparent, application-specific and user-friendly software tool that supports the process of PK/PD modelling in an open way. The modular design principle implemented in MEDICI-PK allows the complete definition of a virtual patient within a few clicks. Comparative studies of different species, different individuals, different compounds and/or different models are easy and suggestive to perform. Among the features are user-defined output, additional scripting of rates and equations, bidirectional interface to Microsoft

SAAM II
It is a compartmental (differential equations) and numerical (algebraic equations) modeling program which can be used in the analysis of

pharmacokinetic, pharmacodynamic and enzyme kinetic studies. It is designed to help researchers easily create models, perform simulations and fit experimental kinetic data resulting in parameter estimates and their associated errors. SAAM II has a user-friendly graphical user interface which is fully menu-driven. Development of SAAM II, at the University of Washington

PK-MAP
It is designed for use in the early optimization phase. It is based on mechanistic, biophysical models to predict ADME-properties like fraction absorbed or volume of distribution from physicochemical data (measured or calculated) for larger sets of compounds. Its strength is a powerfull visualization and evaluation of the generated data sets including the possibility of building selection rules on the real ADME properties directly instead of basic phys.-chem.

MICRO PHARM K (MP-K)

The microcomputer program, MicroPharm-K (MP-K) was developed for pharmacokinetic modeling, including analysis of experimental data and estimation of relevant parameters, and simulation. The intention was to provide a user-friendly, interactive, event-driven program for PC computers. Methods. The data are ascribed to a predefined model from a library including various routes of administration, oral or intra-venous, bolus or infusion, and various compartmental interpretations, I to 3. Single and multiple administrations are supported. The program provides initial estimates of the parameters in most cases, and the parameters are then fitted to the model by non linear model fitting using either the Simplex, Evol, Gauss-Newton, Levenberg-Marquardt or Fletcher-Powell algorithms. The non linear model fitting is based on the maximum likelihood method, and the criterion to minimize is either the weighted least squares (Chi2 criterion) or the extended least squares. Graphical representations of nonfitted or curve-fitted data are immediately available (including log-scale representation), as well as pharmacokinetic typical parameters such as area under the curve, clearance, volumes, time-rate constants, transfer rate

constants, etc. Results. Simulated and experimental data were analysed and the results were similar to those obtained by other programs.