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Authors

Leon Shargel, PhD, RPh


Vice President, Biopharmaceutics
Eon Labs, Inc.
Wilson, North Carolina

Adjunct Associate Professor


School of Pharmacy
University of Maryland
Baltimore, Maryland

Susanna Wuâ​​Pong PhD, RPh


Associate Professor
Department of Pharmaceutics
Medical College of Virginia Campus
Virginia Commonwealth University
Richmond, Virginia

Andrew B.C. Yu PhD, RPh


Registered Pharmacist
Gaithersburg, MD
Formerly Associate Professor of Pharmaceutics
Albany College of Pharmacy
Present Affiliation: HFDâ​​520, CDER, FDA*

*The content of this book represents the personal views of the authors
and not that of the FDA.
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Preface

The fifth edition of Applied Biopharmaceutics and Pharmacokinetics


continues to maintain the scope and objectives of the previous editions.
The major objective is to provide the reader with a basic understanding of
the principles of biopharmaceutics and pharmacokinetics that can be
applied to drug product development and drug therapy. This revised and
updated edition of the popular text remains unique in teaching the
student the basic concepts that may be applied to understanding the
complex issues associated with the processes of drug delivery and the
essentials of safe and effective drug therapy.

This text integrates basic scientific principles with clinical pharmacy


practice and drug product development. Practical examples and questions
are included to encourage students to apply the principles in patient care
and drug consultation situations. Active learning and outcome-based
objectives are highlighted.

The primary audience is pharmacy students enrolled in pharmaceutical


science courses in pharmacokinetics and biopharmaceutics. This text
fulfills course work offered in separate or combined courses in these
subjects. A secondary audience for this textbook is research and
development scientists in the pharmaceutical industry, particularly those
in pharmaceutics, biopharmaceutics, and pharmacokinetics.

Some of the improvements in this edition include the re-ordering of the


chapters and content to reflect the current curriculum in pharmaceutical
sciences and the addition of two new chapters including Pharmacogenetics
and Impact of Drug Product Quality and Biopharmaceutics on Clinical
Efficacy. Each chapter has been revised to include the latest concepts in
biopharmaceutics and pharmacokinetics with new practice problems and
clinical examples that can be applied to pharmacy practice and research.

Susanna Wu-Pong, PhD, RPh, Associate Professor, Department of


Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia,
has collaborated with the original authors. Her expertise adds to the
quality of this edition.

Leon Shargel
Susanna Wu-Pong
Andrew B.C. Yu
August 2004
Applied Biopharmaceutics & Pharmacokinetics, 5th Edition
Leon Shargel, Susanna Wu-Pong, Andrew B.C. Yu

CONTENTS

Glossary
Chapter 1. Introduction to Biopharmaceutics and Pharmacokinetics
Chapter 2. Mathematical Fundamentals in Pharmacokinetics
Chapter 3. One-Compartment Open Model: Intravenous Bolus Administration
Chapter 4. Multicompartment Models: Intravenous Bolus Administration
Chapter 5. Intravenous Infusion
Chapter 6. Drug Elimination and Clearance
Chapter 7. Pharmacokinetics of Oral Absorption
Chapter 8. Multiple-Dosage Regimens
Chapter 9. Nonlinear Pharmacokinetics
Chapter 10. Physiologic Drug Distribution and Protein Binding
Chapter 11. Hepatic Elimination of Drugs
Chapter 12. Pharmacogenetics
Chapter 13. Physiologic Factors Related to Drug Absorption
Chapter 14. Biopharmaceutic Considerations in Drug Product Design
Chapter 15. Bioavailability and Bioequivalence
Chapter 16. Impact of Drug Product Quality and Biopharmaceutics on Clinical Efficacy
Chapter 17. Modified-Release Drug Products
Chapter 18. Targeted Drug Delivery Systems and Biotechnological Products
Chapter 19. Relationship between Pharmacokinetics and Pharmacodynamics
Chapter 20. Application of Pharmacokinetics to Clinical Situations
Chapter 21. Dose Adjustment in Renal and Hepatic Disease
Physiologic Pharmacokinetic Models, Mean Residence Time, and Statistical Moment
Chapter 22.
Theory
Appendix A. Statistics
Appendix B. Applications of Computers in Pharmacokinetics
Appendix C. Solutions to Frequently Asked Questions (FAQ) and Learning Questions
Appendix D. Guiding Principles for Human and Animal Research
Appendix E. Pharmacokinetic and Pharmacodynamic Parameters for Selected Drugs
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Applied Biopharmaceutics & Pharmacokinetics > Glossary >

GLOSSARY
A, B, C: Preexponential constants for three-compartment model equation
a, b, c: Exponents for three-compartment model equation
, , : Exponents for three-compartment model equation (equivalent to a, b, c above)
1, 2, 3:
Exponents for three-compartment-type exponential equation (equivalent to a, b, c above; more
terms may be added and indexed numerically with subscripts for multiexpontial models)
Ab: Amount of drug in the body of time t; see alsoD B

Ab∞: Total amount of drug in the body


ANDA: Abbreviated New Drug Application; see also NDA
ANOVA: Analysis of variance
AUC: Area under the plasma level–time curve
[AUC]∞ 0: Area under the plasma level–time curve extrapolated to infinite time

[AUC]t 0: Area under the plasma level–time curve from t = 0 to last measurable plasma drug concentration
at time t
AUMC: Area under the (first) moment–time curve
BA: Bioavailability
BCS: Biopharmaceutics classification system
BE: Bioequivalence
BMI: Body mass index
C: Concentration (mass/volume)
C a Drug concentration in arterial plasma

C ∞
av : Average steady-state plasma drug concentration
C c or C p: Concentration of drug in the central compartment or in plasma
C C r: Serum creatinine concentration, usually expressed as mg%
C eff: Minimum effective drug concentration
C GI : Concentration of drug in gastrointestinal tract
CI Confidence interval
C m: Metabolite plasma concentration
C max : Maximum concentration of drug

C ∞
max : Maximum steady-state drug concentration
C min: Minimum concentration of drug

C ∞
min: Minimum steady-state drug concentration
C p: Concentration of drug in plasma

C 0
p: Concentration of drug in plasma at zero time (t = 0)

C ∞
p: Steady-state plasma drug concentration (equivalent to C SS )

C p n
: Last measured plasma drug concentration

C SS : Concentration of drug at steady state


C t: Concentration of drug in tissue
Cl C r: Creatinine clearance
Cl D: Dialysis clearance
Cl h: Hepatic clearance
Cl int: Intrinsic clearance
Cl'int: Intrinsic clearance (unbound or free drug)
Cl nr: Nonrenal clearance
Cl R: Renal clearance

Cl u
R: Renal clearance of uremic patient
Cl T: Total body clearance
CRFA Cumulative relative fraction absorbed
C v : Drug concentration in venous plasma
D: Amount of drug (mass, eg, mg)
D A : Amount of drug absorbed
D B : Amount of drug in body
D E: Drug eliminated
D GI : Amount of drug in gastrointestinal tract
D L: Loading (initial) dose
D m: Maintenance dose
D : Total amount of metabolite excreted in the urine
D N Normal dose
D P: Drug in central compartment
D t: Amount of drug in tissue
D u: Amount of drug in urine
D 0: Dose of drug

D 0: Amount of drug at zero time (t = 0)


E: Pharmacologic effect
e: Intercept on y axis of graph relating pharmacologic response to log drug concentration
E max : Maximum pharmacologic effect
E 0: Pharmacologic effect at zero drug concentration
EC50: Drug concentration that produces 50% maximum pharmacologic effect
ELS: Extended least square
ER: Extraction constant (equivalent to Eh); extraction ratio
F: Fraction of dose absorbed (bioavailability factor)
f: Fraction of dose remaining in body
f e : Fraction of unchanged drug excreted unchanged in urine
f u: Unbound fraction of drug
FDA: U.S. Food and Drug Administration
f(t): Function representing drug elimination over time (time is the independent variable)
f'(t): Derivative of f(t)
GFR: Glomerular filtration rate
GI: Gastrointestinal tract
GMP: Good Manufacturing Practice
IBW: Ideal body weight
IVIVC: In-vitro–in-vivo correlation
k: Overall drug elimination rate constant (k = k e +k m); first-order rate constant, similar to k e1

K a: Association binding constant


k a: First-order absorption rate constant
K d: Dissociation binding constant
k e Excretion rate constant (first order)
k e0: Transfer rate constant out of the effect compartment
K M: Michaelis–Menten constant
k m: Metabolism rate constant (first order)
k N: Normal elimination rate constant (first order)

k N
NR : Nonrenal elimination constant of normal patient

k U
NR : Renal elimination constant of uremic patient
k u: Uremic elimination rate constant (first order)
k 0: Zero-order absorption rate constant
k le : Transfer rate constant from the central to the effect compartment
k 12: Transfer rate constant (from the central to the tissue compartment); first-order transfer rate
constant from compartment 1 to compartment 2
k 21: Transfer rate constant (from the tissue to the central compartment); first-order transfer rate
constant from compartment 2 to compartment 1
LBW Lean body weight
m: Slope (also slope of E versus log C)
M u: Amount of metabolite excreted in urine
MAT: Mean absorption time
MDT: Mean dissolution time
MEC: Minimum effective concentration
MLP: Maximum life-span potential
MRT: Mean residence time
MRTc: Mean residence time from the central compartment
MRTp: Mean residence time from the peripheral compartment
MRTt: Mean residence time from the tissue compartment (same as MRTp)
MTC: Minimum toxic concentration
0 Area under the zero moment curve (same as AUC)

1: Area under the first moment curve (same as AUMC)


NDA New Drug Application
NONMEN: Nonlinear mixed effect model
P: Amount of protein
PD: Pharmacodynamics
PK: Pharmacokinetics
Q: Blood flow
R: Infusion rate; ratio of C max after N dose to C max after one dose () (accumulation ratio); pharmacologic
response ()
r: Ratio of mole of drug bound to total moles of protein
R max : Maximum pharmacologic response
SD: Standard deviation
t: Time (hours or minutes); denotes tissue when used as a subscript
t eff: Duration of pharmacologic response to drug
t inf: Infusion period
t lag: Lag time
t max : Time of occurrence for maximum (peak) drug concentration
t 0: Initial or zero time
t 1/2: Half-life
: Time interval between doses
USP: United States Pharmacopeia
V: Volume (L or mL)
v: Velocity
V app: Apparent volume of distribution (binding)
V C: Volume of central compartment
V D: Volume of distribution
V e : Volume of the effect compartment
V max : Maximum metabolic rate
V p: Volume of plasma (central compartment)
V t: Volume of tissue compartment
(V D )exp: Extrapolated volume of distribution
(V D )SS or V DSS : Steady-state volume of distribution

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Applied Biopharmaceutics & Pharmacokinetics > Appendix B: Applications of Computers in


Pharmacokinetics >

APPENDIX B: APPLICATIONS OF COMPUTERS IN


PHARMACOKINETICS: INTRODUCTION
The availability of computers and improvements in bioanalytical chemistry have greatly accelerated the
development of pharmacokinetics. Computer software programs now 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. In addition, 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.
Windows NT is used mostly in network systems that link many PCs. Most PCs today are equipped with a
modem to allow access to remote information. Netscape and Microsoft Internet Explorer are browsers that
allow PCs to access remote information at various sites on the Internet referred to as Websites.
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. The computer operating system must support the computer
language of the software. In the past, computer users needed to be competent in computer programming
and usually had knowledge of at least one computer language such as Pascal, C, or Basic. As a result of the
availability of various commercial and noncommercial pharmacokinetic applications and spreadsheets, such
as Excel, very little computer programming is required for many applications in pharmacokinetics. Some
examples are given below.

PHARMACOKINETIC SOFTWARE
Pharmacokinetic software consists of computer programs designed for computation and easy solution of
pharmacokinetic problems. Not all computer programs satisfy the user's full requirements, but many
provide the following.
1. Fitting drug concentration-versus-time data to a series of pharmacokinetic models, and choosing the
one that best describes the data statistically
Typically, a least-squares program is employed, in which the sum of squared differences between
observed data points and theoretic prediction is minimized. Usually, a mathematical procedure is used
iteratively (repetitively) to achieve a minimum in the sum of squares (convergence). Some data may allow
easier convergence with one procedure rather than another. 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 flexibility
of user-defined models allows continuous refinement of the model as new experimental information
becomes available. Some software merely provides a utility program for fitting the data to a series of
polynomials. This utility program provides a simple, quantitative way of relating the variables, but offers
little insight into the underlying pharmacokinetic processes.
3. Simulation
Some 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. Although statisticians stress the need for
proper experimental design, little information is generally available for experimental design in
pharmacokinetics when a study is performed for the first time. 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 clearance using the Cockcroft–Gault equation (see ),
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 . These authors taught a course in which
students used (download free ware). Pharmacalc and PharmaSim may be used for pharmacokinetic
computations. SAAM II or Stella and ModelMaker may be used for "system dynamics." The latter takes
into account stochastic processes in the simulation and may be more suitable when variability is
considered to be an important factor in a clinical situation. 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.

PHARMACOKINETIC SOFTWARE
Various pharmacokinetic programs (software) are available on the Internet. These programs may not have
been validated by the programmer. Thus, the user is responsible for validating the program. Other
programs are available from commercial suppliers. Dr. David Bourne of the University of Oklahoma has
compiled a listing of pharmacokinetic programs, general references in pharmacokinetics, pharmacodynamics,
and other information, available at www.boomer.org. The Website http://www.boomer.org/pkin/soft.html
lists numerous pharmacokinetic software packages with user comments. Students should consult the site
for updated information.

Popular Programs
Some popular commercially available computer software programs are listed below. The descriptions may
not represent the latest versions. New features are often added or old features improved. The user should
contact the program vendor directly for more information. See below for information about Internet
resources, including user evaluations of software packages.
PCNONLIN
PCNonlin is a powerful least-squares program for parameter estimation. Both a user-defined model and a
library of over 20 compartmental models are available. The program accepts both differential and regular
(analytical) equations. Users may select the Hartley-modified or Levenberg-type Gauss–Newton algorithm
or the (Nelder and Mead) simplex algorithm for minimizing the sum of squared residuals. Some training is
needed. Until its commercial release, Nonlin was installed mostly on mainframe computers. PCNonlin includes
additional features and was designed to run on PCs. PCGRAPH (Version 4) was bundled to improve the
quality of the plots from previous versions of Nonlin. Compartmental models, curve fitting, and simulations
are specially designed for pharmacokinetics.
WINNONLIN
Pharsight Corporation Main
800 W. El Camino Real, Suite 200
Mountain View, CA 94040
(650) 314-3800
www.pharsight.com/products/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. WinNonMix is
associated software for population pharmacokinetic analysis. 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.
WinNonlin's input and output data may be managed via Excel (Microsoft)-compatible spreadsheet files. The
Noncompartmental Analysis module computes derived pharmacokinetic parameters (AUCt 0, AUC0 ∞, C
max , cumulative excretion, etc). PCNonlin's extensive library of models for nonlinear regression and
parameter estimation are included in this software. Standard descriptive statistics and confidence intervals
are determined from datasets.
SAS
SAS Institute, Inc.
Cary, NC 27511
(919) 677-8000
www.sas.com
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 univariate descriptive
statistics; t-test, chi-square, correlation, autoregression, multidimensional scaling, nonparametric test,
factor analysis, and discriminant and stepwise analysis. SAS runs in many user environments, including
PCSAS for personal computers. A special startup interface, ASSIST, facilitates beginners who are unfamiliar
with the default batch data entry.
The U.S. Code of Federal Regulations, 21CFR Part 11, requires all datasets to be provided in special format
for review and inspection. SAS Institute published the SAS XPORT format (Version 5) for electron data
submission for regulatory purposes. Details about SAS EXPORT can be found at www.sas.com/fda-esub.
Guidance for Industry: Providing regulatory submissions in electronic format—General considerations
1999.
RSTRIP
MicroMath Research
1710 South Brentwood Blvd.
Saint Louis, MO 63144
www.micromath.com
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 (Akaike Information 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. The original software was written for PC DOS but has now been replaced by a
Windows version with additional features.
SCIENTIST FOR WINDOWS
Scientist for Windows V2.01 is a general mathematical modeling application from MicroMath,
www.micromath.com. It can perform nonlinear least-squares minimization and simulation. Models can
consist of both analytic and differential equations. The software has many functions with pharmacokinetic
applications.
PKANALYST FOR WINDOWS
MicroMath Scientific Software
PO Box 21550
Salt Lake City, UT 84121
PKAnalyst is a bundled pharmacokinetic software incorporating many features of RSTRIP but with more
statistics and mathematical functions. The program operates under Windows and is generally easy to use.
It is very user-friendly for routine data analysis in pharmacokinetics.
DIFFEQ AND DIFFEQ PHARMACOKINETICS LIBRARY
MicroMath Scientific Software
PO Box 21550
Salt Lake City, UT 84121
DIFFEQ is a nonlinear least-squares program for PCs. Model entry uses a generic language with syntax
similar to Basic; it may be used with DIFFEQ Pharmacokinetic Library, which includes many models used in
pharmacokinetics. The original version was updated under a different name.
P-STAT
P-Stat Inc.
Princeton, NJ 08540
(609) 924-9100
This program supplies statistical data handling for mainframe computers.
STELLA
High Performance Systems
Lyme, NH 03755
(603) 643-9636
STELLA is a structural thinking experimental learning laboratory with animation, available for Windows-
based PCs. The program was developed on the MAC. STELLA solves differential equations and simulates
pharmacokinetic models and other physiologic systems. The software is particularly suitable for teaching
because of its animation and learning simulation by drawing the model.
NONMEM
NONMEM Project Group, C255
University of California
San Francisco, CA 94143
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. The NONMEM program first appeared in 1979. 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. A regression program is written in ANSI (American National
Standards Institute) Fortran 77 for mainframe computers.
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. NM-TRAN is a preprocessor, allowing control and other needed inputs and error
messages to NONMEM/PREDPP.
MKMODEL
Biosoft
PO Box 10398
Ferguson, MO
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
D. Z. D'Argenio and A. Schumitzky
Biomedical Simulation Resource
University of Southern California
Los Angeles, CA
Supplied as Fortran code for various operating systems, this program performs simulations, nonlinear
regression, and optimal sampling, and includes extended least-squares and Bayesian optimization. Models
can be expressed as integrated or differential equations ().
USC*PACK PC PROGRAMS
USC Laboratory of Applied Pharmacokinetics
2250 Alcazar St, CSC 134B
Los Angeles, CA 90033
www.lapk.org/software.php
This software package consists of various pharmacokinetic programs bundled for clinical pharmacokinetic
applications and model parameter estimation. The program NPEM2 (Version 3) is an improved version of the
nonparametric expectation maximization algorithm that is well adapted for population pharmacokinetics.
The program is now available for a three-compartment model with various routes of dosing. Lahey Fortran
F77EM32 and its associated package is used in this program.
Clinical programs include related routines in which past therapy data for individual patients are entered into
files along with parameter and dose-prediction programs for various drugs (eg, aminoglycosides, other
antibiotics, and drugs of special interest). Bayesian fitting procedures are included to fit a selected drug
population model to a patient's data of doses and serum concentrations and to adaptive control of the
individual dose regimen. Some program selections include:
Amikacin (Amik)
Gentamicin (Gent)
Netilmicin (Net)
Tobramycin (Tob)
Bayesian General Modeling (MB)
Least-Squares General Modeling (MLS)
Many patient-oriented programs for adaptive dosing based on pharmacokinetics and pharmacodynamic are
featured in the package. Maximum Aposteriori Probability (MAP) Bayesian fitting is useful in individual
dosing; an example is shown in for gentamicin dose prediction. This method yields better prediction than
conventional clinical methods even in patients with unstable renal function.

Figure B-1.
An example of gentamicin dosing prediction in patients using MAP Bayesian fitting and K slope method
(one compartment): Predicted versus measured serum gentamicin. (r = correlation coefficient, ME = mean
error, MSE = mean squared error, WME = mean weighted error. WMSE = weighted mean squared error.)
()

S-PLUS
S-plus is a versatile package that can be used for analyzing data using the included software, and also
includes its own programming language, which can be used to write your own routines. S is a statistical
package developed at AT&T's Bell Laboratories. S-Plus is an extension of this statistical language produced
by the StatSci Division of MathSoft in Seattle. The software is used extensively by many pharmacokinetics
and statisticians for model analysis.
MATHCAD
www.mathcad.com
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 boundary-value problems both at the
command line and in Solve blocks that use natural notation to specify the differential equations and
constraints.
CYBER PATIENT
Cyber Patient is a Windows-based multimedia pharmacokinetic simulation program that can be used for
development and presentation of problem-solving case studies from Michael B. Bolger, USC School of
Pharmacy. This program is suitable for simulations in pharmacy courses and research in development of
pharmacokinetic drug models.
GASTROPLUS
GastroPlus is a computer simulation program that predicts the rate and extent of drug absorption from the
gastrointestinal tract. This innovative program was developed by a team of scientist-programmers under
the direction of Dr. Michael B. Bolger at Simulations Plus, Inc., in collaboration with Dr. Gordon L. Amidon.
INSTRUCTIONAL PROGRAMS
The Modern Biopharmaceutics Version 6 Computer Based Training Software provides a complete
information base for both university biopharmaceutics courses and continuing education courses. The
program teaches both basic principles and important applications. Course material is available in modules on
CD for individualized learning. For more information see www.tsrlinc.com/mbindex.htm or www.simulations-
plus.com.

Other Pharmacokinetic Programs


ACSL BioMed Software based on the ACSL language that is used to simulate clinical trials of drugs.
Pharsight Corporation, www.pharsight.com.
BIOPAK A pharmacokinetic program for bioavailability/bioequivalence studies, available from SCI
Software.
BOOMER/MULTI-FORTE A simulation program by D. W. A. Bourne, College of Pharmacy, University of
Oklahoma.
PCDCON A convolution/deconvolution program by W. R. Gillespie ().
FUNFIT A parameter estimation regression program.
Kinetica 4.0 A pharmacokinetic/pharmacodynamic analysis and simulation program that supports
nonlinear mixed-effect model fitting. Available at www.innaphase.com.
LAGRAN A parameter estimation regression program.
MATLAB A powerful program that handles complex models, mostly in chemical engineering but found
useful in pharmacokinetics.
NCOMP An Excel-based program for noncompartmental analysis of pharmacokinetic data, by Paul B.
Laub. For integration of AUC and other uses, with choice of splines obtained from Lagrange polynomials
or the hybrid method recommended by . J Pharm Sci 85:393–395, 1996.
NPEM A nonparametric expectation maximization program by . It is part of the USC*PACK collection
(see above).
Pharsight Trial Simulator A comprehensive computer-assisted trial simulation software system by
Pharsight Corporation, www.pharsight.com/products/prod_pts_home.php.
PDx-Pop Integrates with NONMEM and other software to expedite population modeling and analysis.
UNIX version published by GloboMax LLC.
SAAM A program for pharmacokinetics and other biological models that was developed at the National
Institutes of Health (NIH).
SAAM/CONSAM Performs nonlinear regression in batch (SAAM) or conversational mode (CONSAM). The
SAAM/CONSAM programs are provided by the NIH. Available from L. A. Zech and P. C. Greif, Laboratory
of Mathematical Biology, NIH, zech@ncifcrf.gov.
P-PHARM A population pharmacokinetic-dynamic data modeling program from InnaPhase,
science@innaphase.com.
PK-Sim A whole-body physiology-based pharmacokinetic (PBPK) simulation software by Bayer
Technology Services GmbH, www.pk-sim.com.
PopKinetics A population pharmacokinetics analysis program. It is a companion application to SAAM II
that uses parametric algorithms, Standard Two-Stage and Iterated Two-Stage, to compute population
parameters. Available from the SAAM Institute, info@saam.com.
TOPFIT A PC-based pharmacokinetic program with both data fitting and clinical application, available
from Gustav Fischer ().
WinNonMix A program for nonlinear mixed-effects modeling provided in an interactive and easy-to-use
Windows application. By Pharsight Corporation, www.pharsight.com.
WinSAAM A Windows version of the original interactive biological modeling program, CONSAAM,
developed in 1980 at the NIH. WinSAAM adds Windows features and enhances application environment
and is maintained by Peter C. Grief.

ELECTRONIC SPREADSHEETS
For general computation, many programs, such as electronic spreadsheets, are very adaptable to
calculation and pharmacokinetic curve plotting. Spreadsheet software programs such as Quattro and
Microsoft Excel are easy to use. Data are entered in columns (referred to alphabetically as A, B, C, . . .) and
rows (referred to numerically as 1, 2, 3, . . .). Manuals are generally displayed on screen and can be
selected by moving the arrow keys followed by pressing the Return or Enter key. An example of a Microsoft
Excel worksheet used to generate time-versus-concentration data after n doses of a drug given orally
according to a one-compartment model is given in . The parameter inputs are in column B, time is in
column D, and concentration is in column E.

Figure B-2.

Example of a Microsoft Excel spreadsheet used to calculate time–concentration data according to an oral
one-compartment model after n doses.

Example 1
From a series of time–concentration data (, rows A and B), determine the elimination rate constant using
the regression feature of MS Excel.
Figure B-3.

A sample spreadsheet showing a set of time–concentration data (Time and Conc) being analyzed to
obtain the slope or the elimination constant. Note: Only four points from the terminal part of the curve
were regressed [t versus ln (conc)].

Solution
a. Type in the time and concentration data shown in columns A and B ().
b. Convert in column C all concentration data to ln concentration. Data point #1 may be omitted because
ln of zero cannot be determined.
c. From the main menu, select Insert:
Select function
SLOPE
Y data range (select last 4 value)
X data range (select last 4 value)
The slope, given in is –0.1. In this case, the ln concentration is plotted versus time, and the slope is
simply the elimination rate constant.
Note: To check this result, students may be interested in simulating the data with dose = 10,000 g/kg, V D
= 1000 mL/kg, k a = 0.8 hr– 1, and k = 0.1 hr– 1.

Example 2
Generate some data for a two-compartment model using two differential equations. Initial conditions are
dose = 1, V = 1, and k 12 = 0, k 21 = 1, and k = 3.
Solution
The data may be generated with MathCAD (). Note that k 12 is abbreviated as k 1, k 21 is abbreviated as k
2, and k is abbreviated at k 3 in the program for simplicity. Also, dC p/dt = F(t, x, y); x = C p; y = C t; t =
time; and dC t/dt = G(t, x, y).

Figure B-4.
A sample of the MathCAD application program used to solve the two-differential equation for a two-
compartment model after IV bolus dose. (The first 10 data points are shown.)

Model Fitting
An example of a set of oral plasma data was fitted to a one-compartment model by RSTRIP (). The
software makes an initial estimate as well as a final parameter after several iterations. An example of some
oral plasma data was generated with PCNonlin (, , ).

Figure B-5.
Sample output from RSTRIP pharmacokinetic software showing a good fit of the theoretical data to actual
data (columns 2 and 3). The parameters estimated are given in the top right-hand corner.

Figure B-6A.
Sample output from PCNONLIN showing data fitted to Model 3, a one-compartment model with first-order
absorption and first-order elimination.
Figure B-6B.

Sample output from PCNONLIN.

Figure B-6C.
Sample output from PCNONLIN.

Example 3
After a drug is administered orally, a series of plasma drug concentration–time data may be fitted to a one-
compartment model, to estimate the absorption rate constant, elimination rate constant, and volume of
distribution. Other pharmacokinetic parameters of interest may also be calculated using the NONLIN
program, as shown in , , . Three parameters were estimated—V, k 01, and k 10—representing volume of
distribution, k a, and k (see model). Initial estimates were derived from either curve stripping or feathering.
Dose is CON (1). In this case, NOBS = 9, showing that there are 9 data points. There is only one function
that describes the model FUNC 1. S(1) represents the calculation of AUC, S(2) the calculation of
absorption, and S(3) the calculation of elimination half-life.

REFERENCES
Charles BG, Duffull SB: Pharmacokinetic software for the health sciences: Choosing the right package for
teaching purposes. Clin Pharmacokinet 40(6):395–403, 2001

D'Argenio DZ, Schumitzky A: ADAPT II User's Guide. Los Angeles, Biomedical Simulation Resource,
University of Southern California, 1992

Heatherington AC, Vicini P, Golde H: A pharmacokinetic/pharmacodynamic comparison of SAAM II and


PC/WIN Nonlin Modeling software. J Pharm Sci 87:1255–1263, 1998 [PMID: 9758686]

Jelliffe RW, Schumitzky A, Van Guilder M, Jiang F: User Manual for Version 10.7 USC*PACK Collection of PC
Programs. USC Laboratory of Applied Pharmacokinetics, University of Southern California, 1995

Karol M, Gillespie WR, Veng-Pederson P: AAPS Short Course: Convolution, Deconvolution and Linear
Systems, Washington, DC, AAPS (1991)

Schumitzky A: Nonparametric EM algorithms for estimating prior distributions. Appl Math Comput
45:143–157, 1991

Tanswell P, Koup J: Int J Clin Pharmacol Ther Toxicol 31(10):514–420, 1993

BIBLIOGRAPHY

Bourne DWA: Mathematical modeling of pharmaceutical data. In Swarbrick J, Boylan JC (eds), Encyclopedia
of Pharmaceutical Technology, Vol 9. New York, Marcel Dekker, 1994

Gabrielsson J, Wiener D: Pharmacokinetics and Pharmacodynamic Data Analysis: Concepts and


Applications, 2nd ed. Swedish Pharmaceutical Press, 1998

Gex-Fabry M, Balant LP: Consideration on data analysis using computer methods and currently available
software for personal computers. In Welling PG, Balant LP (eds), Handbook of Experimental
Pharmacology, Vol 110, Pharmacokinetics of Drugs, Berlin, Springer-Verlag, 1994

Maronda R (ed): Clinical applications of pharmacokinetics and control theory: Planning, monitoring, and
adjusting dosage regiments of aminoglycosides, lidocaine, digoxitin, and digoxin. In Jelliffe RW (ed),
Selected Topics in Clinical Pharmacology. New York, Springer-Verlag, 1986, chap 3

The NONMEM Project Group: NONMEM User Manuals I–VI. San Francisco, University of California, San
Francisco, www.micromath.com, 1995

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Applied Biopharmaceutics & Pharmacokinetics > Appendix D: Guiding Principles for Human and
Animal Research* >

ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING


HUMAN SUBJECTS
The Declaration of Helsinki, first published in 1964 by the World Medical Association, established
recommendations guiding medical doctors in biomedical research involving human subjects
(www.wma.net/e/policy/b3.htm). The Declaration governs international research ethics and defines rules for
"research combined with clinical care" and "non-therapeutic research." The Declaration of Helsinki has been
revised periodically and is the basis of Good Clinical Practices used today. A copy of the latest revision is
reproduced in this Appendix. The Declaration of Helsinki addressed the following issues:
"Medical research is subject to ethical standards that promote respect for all human beings and protect
their health and rights."
Research protocols should be clearly formulated into an experimental protocol and reviewed by an
independent committee prior to initiation.
Informed consent from all research participants is necessary.
Research should be conducted by medically/scientifically qualified individuals.
Risks should not exceed benefits.
The Belmont Report, Ethical Principles and Guidelines for the Protection of Human Subjects of Research,
was published by the National Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research on April 18, 1979 (http://www.nihtraining.com/ohsrsite/guidelines/belmont.html). The
Belmont Report identifies three principles, or general prescriptive judgments, that are relevant to research
involving human subjects.

Boundaries between Practice and Research


1. Practice refers to interventions that are designed solely to enhance the well-being of an individual
patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral
practice is to provide diagnosis, preventive treatment, or therapy to particular individuals.
2. Research designates an activity designed to test an hypothesis, permit conclusions to be drawn, and
thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories,
principles, and statements of relationships). Research is usually described in a formal protocol that sets
forth an objective and a set of procedures designed to reach that objective.
3. Experimental is when a clinician departs in a significant way from standard or accepted practice. The
fact that a procedure is "experimental," in the sense of new, untested, or different, does not
automatically place it in the category of research.

Basic Ethical Principles


1. Respect for Persons
2. Beneficence
3. Justice

Applications
1. Informed Consent
2. Assessment of Risks and Benefits
3. Selection of Subjects
The United States' Code of Federal Regulations (CFR) publishes regulations for the protection of human
subjects. Title 45 Code of Federal Regulations Part 46 (45CFR46) contains federal regulations which directly
apply to most of human research done in the United States and are intended to protect all human
subjects. 45CFR46 does the following:
Defines activities that are subject to regulation
Details the composition and function of an Institutional Review Board (IRB)
Describes expedited review procedures
Lists the criteria for review of research
Provides a detailed description of the informed concent process, including waivers
Describes the process for documenting consent, including waivers
There are three subparts of the regulations that include additional protections for vulnerable
populations:
Pregnant women, fetuses, and neonates
Prisoners
Children
Various resources concerning ethics involving human subjects research and Institutional Review Boards
(IRBs) have been collected by the National Institutes of Health (www.nih.gov/sigs/bioethics/IRB.html).
*From Guide for the Care and Use of Laboratory Animals, DHEW publ. no. (NIH) 80-23, revised 1978,
reprinted 1980. Bethesda, MD, Office of Science and Health Reports, DDR/NIH.

GUIDING PRINCIPLES IN THE CARE AND USE OF ANIMALS


Animal experiments are to be undertaken only with the purpose of advancing knowledge. Consideration
should be given to the appropriateness of experimental procedures, species of animals used, and number
of animals required.
Only animals that are lawfully acquired shall be used in the laboratory, and their retention and use shall be
in every case in compliance with federal, state, and local laws and regulations and in accordance with the
NIH Guide.
Animals in the laboratory must receive every consideration for their comfort; they must be properly
housed, fed, and their surroundings kept in a sanitary condition.
Appropriate anesthetics must be used to eliminate sensibility to pain during all surgical procedures. Where
recovery from anesthesia is necessary during the study, acceptable technique to minimize pain must be
followed. Muscle relaxants or paralytics are not anesthetics and they should not be used alone for surgical
restraint. They may be used for surgery in conjunction with drugs known to produce adequate analgesia.
Where use of anesthetics would negate the results of the experiment, such procedures should be carried
out in strict accordance with the NIH Guide. If the study requires the death of the animal, the animal must
be killed in a humane manner at the conclusion of the observations.
The postoperative care of animals shall be such as to minimize discomfort and pain, and in any case shall be
equivalent to accepted practices in schools of veterinary medicine.
When animals are used by students for their education or the advancement of science, such work shall be
under the direct supervision of an experienced teacher or investigator. The rules for the care of such
animals must be the same as for animals used for research.

DECLARATION OF HELSINKI
World Medical Association Declaration of Helsinki
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964; amended by the 29th WMA
General Assembly, Tokyo, Japan, October 1975; 35th WMA General Assembly, Venice, Italy, October 1983;
41st WMA General Assembly, Hong Kong, September 1989; 48th WMA General Assembly, Somerset West,
Republic of South Africa, October 1996, and the 52nd WMA General Assembly, Edinburgh, Scotland,
October 2000
A. Introduction
1. The World Medical Association has developed the Declaration of Helsinki as a statement of ethical
principles to provide guidance to physicians and other participants in medical research involving human
subjects. Medical research involving human subjects includes research on identifiable human material or
identifiable data.
2. It is the duty of the physician to promote and safeguard the health of the people. The physician's
knowledge and conscience are dedicated to the fulfillment of this duty.
3. The Declaration of Geneva of the World Medical Association binds the physician with the words, "The
health of my patient will be my first consideration," and the International Code of Medical Ethics declares
that, "A physician shall act only in the patient's interest when providing medical care which might have
the effect of weakening the physical and mental condition of the patient."
4. Medical progress is based on research which ultimately must rest in part on experimentation involving
human subjects.
5. In medical research on human subjects, considerations related to the well-being of the human subject
should take precedence over the interests of science and society.
6. The primary purpose of medical research involving human subjects is to improve prophylactic,
diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of
disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be
challenged through research for their effectiveness, efficiency, accessibility and quality.
7. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic
procedures involve risks and burdens.
8. Medical research is subject to ethical standards that promote respect for all human beings and protect
their health and rights. Some research populations are vulnerable and need special protection. The
particular needs of the economically and medically disadvantaged must be recognized. Special attention is
also required for those who cannot give or refuse consent for themselves, for those who may be subject
to giving consent under duress, for those who will not benefit personally from the research and for
those for whom the research is combined with care.
9. Research Investigators should be aware of the ethical, legal and regulatory requirements for research
on human subjects in their own countries as well as applicable international requirements. No national
ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections
for human subjects set forth in this Declaration.
B. Basic principles for all medical research
10. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of
the human subject.
11. Medical research involving human subjects must conform to generally accepted scientific principles,
be based on a thorough knowledge of the scientific literature, other relevant sources of information, and
on adequate laboratory and, where appropriate, animal experimentation.
12. Appropriate caution must be exercised in the conduct of research which may affect the environment,
and the welfare of animals used for research must be respected.
13. The design and performance of each experimental procedure involving human subjects should be
clearly formulated in an experimental protocol. This protocol should be submitted for consideration,
comment, guidance, and where appropriate, approval to a specially appointed ethical review committee,
which must be independent of the investigator, the sponsor or any other kind of undue influence. This
independent committee should be in conformity with the laws and regulations of the country in which the
research experiment is performed. The committee has the right to monitor ongoing trials. The
researcher has the obligation to provide monitoring information to the committee, especially any serious
adverse events. The researcher should also submit to the committee, for review, information regarding
funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for
subjects.
14. The research protocol should always contain a statement of the ethical considerations involved and
should indicate that there is compliance with the principles enunciated in this Declaration.
15. Medical research involving human subjects should be conducted only by scientifically qualified
persons and under the supervision of a clinically competent medical person. The responsibility for the
human subject must always rest with a medically qualified person and never rest on the subject of the
research, even though the subject has given consent.
16. Every medical research project involving human subjects should be preceded by careful assessment
of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others.
This does not preclude the participation of healthy volunteers in medical research. The design of all
studies should be publicly available.
17. Physicians should abstain from engaging in research projects involving human subjects unless they
are confident that the risks involved have been adequately assessed and can be satisfactorily managed.
Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if
there is conclusive proof of positive and beneficial results.
18. Medical research involving human subjects should only be conducted if the importance of the
objective outweighs the inherent risks and burdens to the subject. This is especially important when the
human subjects are healthy volunteers.
19. Medical research is only justified if there is a reasonable likelihood that the populations in which the
research is carried out stand to benefit from the results of the research.
20. The subjects must be volunteers and informed participants in the research project.
21. The right of research subjects to safeguard their integrity must always be respected. Every
precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's
information and to minimize the impact of the study on the subject's physical and mental integrity and
on the personality of the subject.
22. In any research on human beings, each potential subject must be adequately informed of the aims,
methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher,
the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject
should be informed of the right to abstain from participation in the study or to withdraw consent to
participate at any time without reprisal. After ensuring that the subject has understood the information,
the physician should then obtain the subject's freely-given informed consent, preferably in writing. If the
consent cannot be obtained in writing, the non-written consent must be formally documented and
witnessed.
23. When obtaining informed consent for the research project the physician should be particularly
cautious if the subject is in a dependent relationship with the physician or may consent under duress. In
that case the informed consent should be obtained by a well-informed physician who is not engaged in
the investigation and who is completely independent of this relationship.
24. For a research subject who is legally incompetent, physically or mentally incapable of giving consent
or is a legally incompetent minor, the investigator must obtain informed consent from the legally
authorized representative in accordance with applicable law. These groups should not be included in
research unless the research is necessary to promote the health of the population represented and this
research cannot instead be performed on legally competent persons.
25. When a subject deemed legally incompetent, such as a minor child, is able to give assent to
decisions about participation in research, the investigator must obtain that assent in addition to the
consent of the legally authorized representative.
26. Research on individuals from whom it is not possible to obtain consent, including proxy or advance
consent, should be done only if the physical/mental condition that prevents obtaining informed consent
is a necessary characteristic of the research population. The specific reasons for involving research
subjects with a condition that renders them unable to give informed consent should be stated in the
experimental protocol for consideration and approval of the review committee. The protocol should state
that consent to remain in the research should be obtained as soon as possible from the individual or a
legally authorized surrogate.
27. Both authors and publishers have ethical obligations. In publication of the results of research, the
investigators are obliged to preserve the accuracy of the results. Negative as well as positive results
should be published or otherwise publicly available. Sources of funding, institutional affiliations and any
possible conflicts of interest should be declared in the publication. Reports of experimentation not in
accordance with the principles laid down in this Declaration should not be accepted for publication.
C. Additional principles for medical research combined with medical care
28. The physician may combine medical research with medical care, only to the extent that the research
is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is
combined with medical care, additional standards apply to protect the patients who are research
subjects.
29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of
the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of
placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method
exists.
30. At the conclusion of the study, every patient entered into the study should be assured of access to
the best proven prophylactic, diagnostic and therapeutic methods identified by the study.
31. The physician should fully inform the patient which aspects of the care are related to the research.
The refusal of a patient to participate in a study must never interfere with the patient–physician
relationship.
32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not
exist or have been ineffective, the physician, with informed consent from the patient, must be free to
use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's judgement
it offers hope of saving life, reestablishing health or alleviating suffering. Where possible, these measures
should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new
information should be recorded and, where appropriate, published. The other relevant guidelines of this
Declaration should be followed.

Copyright ©2007 The McGraw-Hill Companies. All rights reserved.


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