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Applied

Biopharmaceutics &
Pharmacokinetics

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Applied
Biopharmaceutics &
Pharmacokinetics Sixth Edition

Leon Shargel, PhD, RPh


Applied Biopharmaceutics, LLC
Raleigh, North Carolina
Affiliate Associate Professor, School of Pharmacy
Virginia Commonwealth University, Richmond, Virginia
Adjunct Associate Professor, School of Pharmacy
University of Maryland, Baltimore, Maryland

Susanna Wu-Pong, PhD, RPh


Associate Professor
Director, Pharmaceutical Sciences Graduate Program
Department of Pharmaceutics
Medical College of Virginia
Virginia Commonwealth University
Richmond, Virginia

Andrew B.C. Yu, PhD, RPh


Registered Pharmacist
Gaithersburg, Maryland
Formerly Associate Professor of Pharmaceutics
Albany College of Pharmacy
Albany, New York
Present Affiliation: CDER, FDA∗
Silver Spring, Maryland

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

New York Chicago San Francisco Lisbon London Madrid Mexico City
Milan New Delhi San Juan Seoul Singapore Sydney Toronto

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Applied Biopharmaceutics & Pharmacokinetics, Sixth Edition

Copyright © 2012 by The McGraw-Hill Companies, Inc. All rights reserved. Printed in the United States of America.
Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or
distributed in any form or by any means, or stored in a data base or retrieval system, without the prior written permission
of the publisher.

Previous editions copyright © 2005 by The McGraw-Hill Companies, Inc.; © 1999, 1993 by Appleton & Lange; © 1985,
1980 by Appleton-Century-Crofts.

1  2  3  4  5  6  7  8  9  0  DOC/DOC   17  16  15  14  13  12

ISBN 978-0-07-160393-5
MHID 0-07-160393-X

This book was set in Times by Cenveo Publisher Services.


The editors were Michael Weitz and Christie Naglieri.
The production supervisor was Sherri Souffrance.
The production manager was Harleen Chopra, Cenveo Publisher Services.
The design was by Elise Lansdon; the cover design was by Barsoom Design, with cover art © Gregor Schuster/Corbis.
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This book is printed on acid-free paper.

Library of Congress Cataloguing-in-Publication Data

Shargel, Leon, 1941-


  Applied biopharmaceutics & pharmacokinetics/Leon Shargel, Andrew
B.C. Yu, Susanna Wu-Pong.—6th ed.
     p. ; cm.
   Applied biopharmaceutics and pharmacokinetics
   Includes bibliographical references and index.
   ISBN-13: 978-0-07-160393-5 (hardcover : alk. paper)
   ISBN-10: 0-07-160393-X (hardcover : alk. paper)
   1.  Biopharmaceutics.  2.  Pharmacokinetics.  I.  Yu, Andrew B. C., 1945-
   II.  Wu-Pong, Susanna.  III.  Title.  IV.  Title: Applied biopharmaceutics and pharmacokinetics.
  [DNLM:  1.  Biopharmaceutics.  2.  Models, Chemical.  3.  Pharmacokinetics.  QV 38]
  RM301.4.S52 2012
  615’.7—dc23
011020446

McGraw-Hill books are available at special quantity discounts to use as premiums and sales promotions, or for use in cor-
porate training programs. To contact a representative please e-mail us at bulksales@mcgraw-hill.com.

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About the Authors

Dr. Leon Shargel has over 30 years experience in Austin and her PhD from the University of California
both academia and the pharmaceutical industry. He at San Francisco (USCF), and postdoctoral training
has been a member or chair of numerous national in metabolism and dermatology also at UCSF. She is
committees involved in state formulary issues, bio- the recipient of the AAPS Young Investigator Award
pharmaceutics and bioequivalence issues, institutional and the AACP Grant for New Investigators. She has
review boards, and a member of the USP Biophar- been an NIH and NSF Study Section Reviewer, and
maceutics Expert Committee. Dr. Shargel received a reviewer for numerous scientific journals. She has
a BS in pharmacy from the University of Maryland published over 60 scientific papers, books, chapters, and
and a PhD in pharmacology from the George Wash- abstracts, including Biopharmaceutial Drug Design
ington University Medical Center. He is a registered and Development, Vol. 2. In addition, Dr. Wu-Pong
pharmacist and has over 150 publications includ- is a 2005 graduate of the Grace E. Harris Leadership
ing several leading textbooks in pharmacy. He is a Institute and a fellow of the 2010–11 AACP Academic
member of various professional societies including Fellow Leadership Program.
the American Association Pharmaceutical Scien-
tists (AAPS), American Pharmacists Association Dr. Andrew Yu has over 30 years of experience
(APhA), and the American Society for Pharmacol- in academia, government, and the pharmaceutical
ogy and Experimental Therapeutics (ASPET). industry. Dr. Yu received a BS in pharmacy
from Albany College of Pharmacy and a PhD in
Dr. Susanna Wu-Pong is Associate Professor and pharmacokinetics from the University of Connecticut.
Director of the Pharmaceutical Sciences Graduate He is a registered pharmacist and has over 30
Program at Virginia Commonwealth University publications and a patent in novel drug delivery. He
(VCU). She has been a faculty member at VCU had lectured internationally on pharmaceutics and
School of Pharmacy for 18 years. She received her drug delivery.
BS in pharmacy from the University of Texas at

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Contents
Preface xiii
Glossary xv

1. Introduction to Biopharmaceutics and 3. One-Compartment Open Model:


Pharmacokinetics 1 Intravenous Bolus Administration 43
Drug Product Performance 1 Elimination Rate Constant 44
Biopharmaceutics 1 Apparent Volume of Distribution 45
Pharmacokinetics 3 Clearance 48
Clinical Pharmacokinetics 4 Practical Focus 50
Practical Focus 4 Clinical Application 53
Pharmacodynamics 5 Calculation of k from Urinary Excretion Data 53
Drug Exposure and Drug Response 5 Practice Problem 54
Toxicokinetics and Clinical Toxicology 5 Clinical Application 56
Measurement of Drug Concentrations 6 Chapter Summary 57
Basic Pharmacokinetics and Learning Questions 57
Pharmacokinetic Models 10 Reference 59
Chapter Summary 15 Bibliography 59
Learning Questions 17
References 17
Bibliography 18
4. Multicompartment Models:
Intravenous Bolus Administration 61
2. Mathematical Fundamentals in Two-Compartment Open Model 63
Pharmacokinetics 19 Clinical Application 68
Practice Problem 68
Math Self-Exam 19 Practical Focus 69
Estimation and the Use of Calculators and Three-Compartment Open Model 77
Computers 20 Determination of Compartment Models 79
Practice Problems 22 Practical Application 84
Calculus 24 Chapter Summary 86
Graphs 26 Learning Questions 87
Units in Pharmacokinetics 31 References 88
Measurement and Use of Significant Figures 32 Bibliography 89
Units for Expressing Blood Concentrations 33
Statistics 33
Practical Focus 34
5. Intravenous Infusion 91
Rates and Orders of Reactions 35 One-Compartment Model Drugs 91
Chapter Summary 40 Infusion Method for Calculating Patient
Learning Questions 40 Elimination Half-Life 95
References 42
Bibliography 42

vii

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viii      CONTENTS

Loading Dose Plus IV Infusion—One- Dosage Regimen Schedules  169


  Compartment Model  96 Practice Problems  171
Practice Problems  98 Chapter Summary  173
Estimation of Drug Clearance and Vd from Learning Questions  174
  Infusion Data  100 References  175
Intravenous Infusion of Two-Compartment Bibliography  175
  Model Drugs  100
Practical Focus  102
Chapter Summary  104
  9. Nonlinear Pharmacokinetics  177
Learning Questions  104 Saturable Enzymatic Elimination Processes  179
Reference  106 Practice Problem  180
Bibliography  106 Drug Elimination by Capacity-Limited
  Pharmacokinetics: One-Compartment
  6. Drug Elimination and Clearance  107   Model, Iv Bolus Injection  181
Clinical Focus   191
Drug Elimination  107 Drugs Distributed as One-Compartment
The Kidney  108   Model and Eliminated by Nonlinear
Renal Drug Excretion  111   Pharmacokinetics  191
Clinical Application  114 Chronopharmacokinetics and Time-Dependent
Practice Problems  114   Pharmacokinetics  193
Drug Clearance  114 Bioavailability of Drugs that Follow Nonlinear
Clearance Models  116   Pharmacokinetics  196
Renal Clearance  118 Nonlinear Pharmacokinetics Due to
Determination of Renal Clearance  121   Drug–Protein Binding  196
Relationship of Clearance to Elimination Potential Reasons for Unsuspected
  Half-Life and Volume of Distribution 125   Nonlinearity  200
Chapter Summary  127 Chapter Summary  200
Learning Questions  127 Learning Questions  200
References  129 References  202
Bibliography  129 Bibliography  203

  7. Pharmacokinetics of Oral 10. Physiologic Drug Distribution and


Absorption  131 Protein Binding  205
Pharmacokinetics of Drug Absorption  131 Physiologic Factors of Distribution  205
Significance of Absorption Rate Constants  133 Clinical Focus  213
Zero-Order Absorption Model  133 Apparent Volume Distribution  213
Clinical Application— Transdermal Practice Problem  216
  Drug Delivery  134 Protein Binding of Drugs  219
First-Order Absorption Model  134 Clinical Examples  221
Practice Problem  142 Effect of Protein Binding on the Apparent
Chapter Summary  149   Volume of Distribution  222
Learning Questions  149 Relationship of Plasma Drug–Protein Binding
References  150   to Distribution and Elimination  227
Bibliography  151 Determinants of Protein Binding  231
Kinetics of Protein Binding  232
Practical Focus  233
  8. Multiple-Dosage Regimens  153 Determination of Binding Constants and
Drug Accumulation  153   Binding Sites by Graphic Methods  233
Clinical Example  157 Clinical Significance of Drug–Protein
Repetitive Intravenous Injections  158   Binding  236
Intermittent Intravenous Infusion  163 Modeling Drug Distribution  247
Estimation of k and Vd of Aminoglycosides Chapter Summary  248
  in Clinical Situations  165 Learning Questions  249
Multiple-Oral-Dose Regimen  166 References  250
Loading Dose  168 Bibliography  251

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CONTENTS      ix

11. Drug Elimination and Hepatic 13. Physiologic Factors Related to Drug


Clearance  253 Absorption  321
Route of Drug Administration and Extrahepatic Drug Absorption and Design of a Drug
  Drug Metabolism  253   Product  321
Practical Focus  255 Route of Drug Administration  321
Hepatic Clearance  255 Nature of Cell Membranes  324
Enzyme Kinetics  257 Passage of Drugs Across Cell Membranes  326
Clinical Example  261 Oral Drug Absorption During Drug Product
Practice Problem  263   Development  333
Anatomy and Physiology of the Liver  265 Drug Interactions in the Gastrointestinal
Hepatic Enzymes Involved in the   Tract  334
  Biotransformation of Drugs  267 Oral Drug Absorption  336
Drug Biotransformation Reactions  269 Methods for Studying Factors that Affect
Pathways of Drug Biotransformation  270   Drug Absorption  348
First-Pass Effects  282 Clinical Examples  351
Hepatic Clearance of a Protein-Bound Drug: Effect of Disease States on Drug Absorption  351
  Restrictive and Nonrestrictive Clearance Miscellaneous Routes of Drug
  from Binding  287   Administration  353
Effect of Changing Intrinsic Clearance and/or Chapter Summary  355
  Blood Flow on Hepatic Extraction and Learning Questions  356
  Elimination Half-Life after Iv and Oral References  357
  Dosing  288 Bibliography  359
Biliary Excretion of Drugs  289
Role of Transporters in Hepatic Clearance
  and Bioavailability  292
14. Biopharmaceutic Considerations in
Chapter Summary  293 Drug Product Design and in Vitro
Learning Questions  294 Drug Product Performance  361
References  296
Bibliography  298 Biopharmaceutic Factors Affecting Drug
  Bioavailability  361
Rate-Limiting Steps in Drug Absorption  363
12. Pharmacogenetics  301 Physicochemical Nature of the Drug  366
Polymorphism  303 Formulation Factors Affecting Drug
Pharmacogenomics  306   Product Performance   368
Adverse Drug Reactions Attributed Drug Product Performance, In Vitro: Dissolution
  to Genetic Differences  308   and Drug Release Testing  370
Genetic Polymorphism in Drug Metabolism: Compendial Methods of Dissolution  374
  Cytochrome P-450 Isozymes  310 Alternative Methods of Dissolution Testing  376
Genetic Polymorphism in Drug Transport: Meeting Dissolution Requirements  378
  Mdr1 (P-Glycoprotein) and Multidrug Problems of Variable Control in Dissolution
  Resistance  311   Testing  379
Genetic Polymorphism in Drug Targets  312 Performance of Drug Products: In Vitro–In Vivo
Relationship of Pharmacokinetics/   Correlation  380
  Pharmacodynamics and Pharmacogenetics/ Dissolution Profile Comparisons  386
  Pharmacogenomics  313 Drug Product Stability  386
Clinical Example  315 Considerations in the Design of a Drug
Summary  316   Product  387
Glossary  316 Drug Product Considerations  389
Abbreviations  317 Clinical Example  394
References  317 Chapter Summary  398
Bibliography  318 Learning Questions  399
References  399
Bibliography  401

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x      CONTENTS

15. Drug Product Performance, 17. Modified-Release Drug Products  469


In Vivo: Bioavailability and Conventional (Immediate-Release) and
Bioequivalence  403   Modified-Release Drug Products  469
Biopharmaceutic Factors  473
Drug Product Performance  403 Dosage form Selection  475
Purpose of Bioavailability Studies  405 Advantages and Disadvantages of
Relative and Absolute Availability  406   Extended-Release Products  475
Practice Problem  407 Kinetics of Extended-Release Dosage Forms  476
Methods for Assessing Bioavailability  407 Pharmacokinetic Simulation of Extended-Release
Bioequivalence Studies  413   Products  478
Design and Evaluation of Bioequivalence Clinical Examples  480
  Studies  414 Types of Extended-Release Products  480
Study Designs  417 Considerations in the Evaluation of
Crossover Study Designs  418   Modified-Release Products  495
Clinical Example   422 Evaluation of Modified-Release Products  497
Evaluation of the Data  423 Evaluation of In Vivo Bioavailability Data  499
Bioequivalence Example  424 Chapter Summary  501
Study Submission and Drug Review Learning Questions  501
  Process  427 References  502
The Biopharmaceutics Classification System  431 Bibliography  503
Generic Biologics (Biosimilar Drug
  Products)  433
Clinical Significance of Bioequivalence 18. Targeted Drug Delivery ­Systems and
  Studies  435 Biotechnological Products  505
Special Concerns in Bioavailability and
  Bioequivalence Studies  436 Biotechnology  506
Generic Substitution  437 Drug Carriers and Targeting  514
Glossary  440 Targeted Drug Delivery  519
Chapter Summary  443 Pharmacokinetics of Biopharmaceuticals  521
Learning Questions  443 Bioequivalence and Comparability of
References  448   Biotechnology-Derived Drug Products  522
Bibliography  449 Chapter Summary  523
Learning Questions  524
References  524
16. Impact of Drug Product Quality Bibliography  525
and Biopharmaceutics on Clinical
Efficacy  451 19. Relationship Between
Risks From Medicines  451 ­ harmacokinetics and
P
Drug Product Quality and Drug Product Pharmacodynamics  527
  Performance  452
Pharmaceutical Development  453 Pharmacodynamics and Pharmacokinetics  527
Excipient Affect on Drug Product Relationship of Dose to Pharmacologic
  Performance  455   Effect  534
Practical Focus  456 Relationship Between Dose and Duration of
Quality Control and Quality Assurance  457   Activity (teff), Single Iv Bolus Injection  536
Risk Management  459 Practice Problem  536
Scale-Up and Postapproval Changes (Supac)  461 Effect of Both Dose and Elimination Half-Life
Product Quality Problems  464   on the Duration of Activity  537
Postmarketing Surveillance  465 Effect of Elimination Half-Life on Duration
Glossary  465   of Activity  537
Chapter Summary  466 Clinical Examples  539
Learning Questions  466 Rate of Drug Absorption and Pharmacodynamic
References  466   Response  541
Drug Tolerance and Physical Dependency  542
Hypersensitivity and Adverse Response  543

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CONTENTS      xi

Drug Distribution and Pharmacologic General Approaches for Dose Adjustment


  Response  544   in Renal Disease  618
Pharmacodynamic Models  545 Measurement of Glomerular Filtration Rate  621
Drug Exposure-Pharmacologic Response Serum Creatinine Concentration and Creatinine
  Relationships  558   Clearance  622
Chapter Summary  559 Practice Problems  624
Learning Questions  560 Dose Adjustment for Uremic Patients  627
References  561 Extracorporeal Removal of Drugs  638
Bibliography  563 Clinical Examples  642
Effect of Hepatic Disease on
  Pharmacokinetics  645
20. Application of Pharmacokinetics to Chapter Summary  651
Clinical Situations  565 Learning Questions  652
Medication Therapy Management  565 References  653
Individualization of Drug Dosage Regimens  566 Bibliography  655
Therapeutic Drug Monitoring  567
Clinical Example  574 22. Physiologic Pharmacokinetic Models,
Design of Dosage Regimens  576 Mean Residence Time, and Statistical
Conversion from Intravenous Infusion
  to Oral Dosing  578 Moment Theory  657
Determination of Dose  579 Physiologic Pharmacokinetic Models  658
Practice Problems  580 Mean Residence Time  670
Effect of Changing Dose and Dosing Statistical Moment Theory  674
  Interval on C∞max, C∞min, and C∞av  580 Selection of Pharmacokinetic Models  687
Determination of Frequency of Drug Chapter Summary  689
  Administration  581 Learning Questions  689
Determination of Both Dose and Dosage References  690
  Interval  582 Bibliography  691
Determination of Route of Administration  583
Dosing of Drugs in Infants and Children  584
Dosing of Drugs in the Elderly  585 Appendix A  Statistics  693
Dosing of Drugs in the Obese Patient  588
Pharmacokinetics of Drug Interactions  590
Inhibition of Drug Metabolism  594 Appendix B Applications of Computers in
Inhibition of Monoamine Oxidase (Mao)  595 Pharmacokinetics  707
Induction of Drug Metabolism  596
Inhibition of Drug Absorption  596
Inhibition of Biliary Excretion  596 Appendix C Solutions to Frequently
Altered Renal Reabsorption Due to Asked Questions (FAQs) and
  Changing Urinary ph  596 Learning Questions  717
Practical Focus  597
Effect of Food on Drug Disposition  597
Adverse Viral Drug Interactions  597 Appendix D Guiding Principles for
Population Pharmacokinetics  597 Human and Animal
Regional Pharmacokinetics  608 Research  761
Chapter Summary  609
Learning Questions  610
References  613 Appendix E Popular Drugs and
Bibliography  614 Pharmacokinetic
Parameters  767
21. Dose Adjustment in Renal and Hepatic
Index  773
Disease  617
Renal Impairment  617
Pharmacokinetic Considerations  617

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Preface

The publication of this sixth edition of Applied Biop- • The growing importance of drug transporters,
harmaceutics and Pharmacokinetics represents over CYP enzymes, and influence of pharmacogenet-
30 years in print. We are grateful to our readers for ics on long-term drug response and other rel-
their loyalty and helpful suggestions throughout the evant topics have been updated to reflect current
years. As with the previous editions, we want to con- knowledge and application of pharmacokinetic/
tinue to maintain our original scope and objectives. pharmacodynamics to drug therapy.
This text integrates basic scientific principles • Chapter 15 is expanded and re-titled, Drug
with drug product development and clinical phar- Product Performance, In Vivo: Bioavailability
macy practice. and Bioequivalence, to reflect the consideration
The major objective is to provide the reader with of bioequivalence as an in vivo measure of drug
a basic and practical understanding of the principles product performance and that bioequivalence is
of biopharmaceutics and pharmacokinetics that can important in both brand and generic drug product
be applied to drug product development and to drug development.
therapy. This revised and updated edition of the text • Chapter 16 is now titled, Impact of Drug Product
remains unique in teaching basic concepts that may Quality and Biopharmaceutics on Clinical
be applied to understanding complex issues associ- Efficacy. This chapter describes the types of
ated with in vivo drug delivery that are essential for safety and efficacy risks and various means for
safe and efficacious drug therapy. preventing them including the roles of drug prod-
The primary audience is pharmacy students uct quality and drug product performance.
enrolled in pharmaceutical science courses in phar- • In addition, the concept of quality-bydesign (QbD)
macokinetics and biopharmaceutics. This text fulfills may be applied to improve critical quality attributes
course work offered in separate or combined courses essential for drug product safety and efficacy
in these subjects. Secondary audiences for this text- • Practical examples and questions are included
book are research and development scientists in phar- to encourage students to apply the principles in
maceutics, biopharmaceutics, and pharmacokinetics. patient care and drug consultation situations.
• Active learning and outcome-based objectives are
There are many improvements in this edition. highlighted.
• Chapter Objectives are added at the beginning of
each chapter Leon Shargel
• Chapter Summary at the end of each chapter. Susanna Wu-Pong
• Frequently Asked Questions are seeded within each Andrew B.C. Yu
chapter to help the student focus on key concepts.
• Most chapters are revised to reflect our current
understanding of drug disposition, pharmacody-
namics, and drug therapy.

xiii

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Glossary

A, B, C Preexponential constants for AUMC Area under the (first) moment–


three-compartment model time curve
equation BA Bioavailability
a, b, c Exponents for three-compartment BCS Biopharmaceutics classification
model equation system
a, b, g Exponents for three-compartment BDDCS Drug disposition classification
model equation (equivalent to a, system
b, c above) BE Bioequivalence
l1, l2, l3 Exponents for three- BLA Biologic license application
compartment-type exponential BM Biomarker
equation (equivalent to a, b, c BMI Body mass index
above; more terms may be added BRCP Breast cancer-resistance protein
and indexed numerically with λ (an ABC transporter)
subscripts for multiexponential BUN Blood urea nitrogen
models) C Concentration (mass/volume)
Ab Amount of drug in the body of Ca Drug concentration in arterial
time t; see also DB plasma
Ab∞ Total amount of drug in the body C∞av Average steady-state plasma
ABC ABC transport protein drug concentration; see also
AE Adverse event Cc or Cp Concentration of drug in the
ANDA Abbreviated New Drug Applica- central compartment or in
tion; see also NDA plasma
ANOVA Analysis of variance CCr Serum creatinine concentration,
API Active pharmaceutical ingredient usually expressed as mg%
AUC Area under the plasma CE Clinical endpoint
level–time curve Ceff Minimum effective drug
Area under the plasma concentration
[ AUC]∞0
level–time curve extrapolated to CGI Concentration of drug in gastro-
infinite time intestinal tract
Area under the plasma level– CI Confidence interval
[ AUC]t0
time curve from t = 0 to last Cm Metabolite plasma concentration
measurable plasma drug concen- Cmax Maximum concentration of drug
tration at time t

xv

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xvi      GLOSSARY


Cmax Maximum steady-state drug DB Amount of drug in body
concentration; see also Cssmax DE Drug eliminated
Cmin Minimum concentration of drug DGI Amount of drug in gastrointesti-

Cmin Minimum steady-state drug nal tract
concentration; see also Cssmin DL Loading (initial) dose
Cp Concentration of drug in plasma Dm Maintenance dose
Cp0 Concentration of drug in plasma DNA Deoxyribonucleic acid
at zero time (t = 0) (equivalent DN Normal dose
to C0) DP Drug in central compartment
Cp∞ Steady-state plasma drug Dt Amount of drug in tissue
concentration (equivalent to CSS) Du Amount of drug in urine
Cp Last measured plasma drug D0 Dose of drug
n
concentration D0 Amount of drug at zero time
CSS Concentration of drug at steady (t = 0)
state E Pharmacologic effect
Cssav Average concentration at steady e Intercept on y axis of graph
state relating pharmacologic response
Cssmax Maximum concentration at to log drug concentration
steady state eGFR Estimate of GFR based on an
Cssmin Minimum concentration at MDRD equation
steady state Emax Maximum pharmacologic effect
Ct Concentration of drug in tissue E0 Pharmacologic effect at zero
cGMP Current good manufacturing drug concentration
practices EC50 Drug concentration that pro-
CKD Chronic kidney disease duces 50% maximum pharma-
ClCr Creatinine clearance cologic effect
ClD Dialysis clearance ELS Extended least square
Clh Hepatic clearance ER Extraction constant (equivalent
Clint Intrinsic clearance to Eh); extraction ratio
Cl′int Intrinsic clearance (unbound or F Fraction of dose absorbed
free drug) (bioavailability factor)
Clnr Nonrenal clearance f Fraction of dose remaining in
ClR Renal clearance the body
ClRu Renal clearance of uremic fe Fraction of unchanged drug
patient excreted unchanged in urine
ClT Total body clearance fu Unbound fraction of drug
COX-1 Cyclo-oxygenase-1 FDA US Food and Drug
CRF Case report form Administration
CRFA Cumulative relative fraction f(t) Function representing drug
absorbed elimination over time (time is
Cv Drug concentration in venous the independent variable)
plasma f ′(t) Derivative of f(t)
%CV Percent coefficient of variation GFR Glomerular filtration rate
CYP Cytochrome P-450 GI Gastrointestinal tract
D Amount of drug (mass, eg, mg) GMP Good Manufacturing Practice
DA Amount of drug absorbed [I] [I] is the inhibitor concentration
in an enzymatic reaction

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GLOSSARY      xvii

IBW Ideal body weight MDR1 p-Glycoprotein, ABCB1


IVIVC In vitro–in vivo correlation MDRD MDRD equation used to esti-
k Overall drug elimination rate mate of GFR
constant (k = ke + km); first-order MDT Mean dissolution time
rate constant, similar to ke1 MEC Minimum effective concentra-
Ka Association binding constant tion
ka First-order absorption rate miRNA MicroRNA
constant MLP Maximum life-span potential
Kd Dissociation binding constant MRP Multidrug resistance-associated
ke Excretion rate constant (first proteins
order) MRT Mean residence time
kel Excretion rate constant (first MRTc Mean residence time from the
order) central compartment
ke0 Transfer rate constant out of the MRTp Mean residence time from the
effect compartment peripheral compartment
kI Inhibition constant: = k-I/kI+ MRTt Mean residence time from the
KM Michaelis–Menten constant tissue compartment (same as
km Metabolism rate constant (first MRTp)
order) MTC Minimum toxic concentration
kN Normal elimination rate constant μ0 Area under the zero moment
(first order) curve (same as AUC)
N
kNR Nonrenal elimination constant of μ1 Area under the first moment
normal patient curve (same as AUMC)
U
kNR Renal elimination constant of NDA New Drug Application
uremic patient
NONMEN Nonlinear mixed-effect model
ku Uremic elimination rate constant
(first order) NTI Narrow therapeutic index; see
kon First-order association rate also critical dose drug
constant OTC Over-the-counter drugs
koff First-order dissociation constant OATP Organic anion transporting
k0 Zero-order absorption rate polypeptide
constant OAT Organic anion transporter
kle Transfer rate constant from the P Amount of protein
central to the effect PD Pharmacodynamics
compartment PEG Polyethylene glycol
k21 Transfer rate constant (from the P-gp p-Glycoprotein, MDR1, ABCB1
tissue to the central compart- PGt Pharmacogenetics
ment); first-order transfer rate PK Pharmacokinetics
constant from compartment 2 to
PPI Patient package insert
compartment 1
Q Blood flow
LBW Lean body weight
m Slope (also slope of E versus QA Quality assurance
log C) QbD Quality by design
Mu Amount of metabolite excreted QC Quality control
in urine
mAbs Monoclonal antibodies
MAT Mean absorption time

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xviii      GLOSSARY

R Infusion rate; ratio of Cmax after t0 Initial or zero time


n dose to Cmax after one dose t1/2 Half-life
(see Chapter 8) (accumulation τ Time interval between doses
ratio); pharmacologic response USP United States Pharmacopeia
(see Chapter 19) V Volume (L or mL)
r Ratio of mole of drug bound to v Velocity
total moles of protein Vapp Apparent volume of distribution
Rmax Maximum pharmacologic (binding)
response VC Volume of central compartment
RLD Reference-listed drug VD Volume of distribution
RNA Ribonucleic acid Ve Volume of the effect
RNAi RNA interference compartment
SD Standard deviation Vi Vi and V are the reaction
siRNA Small inhibitory RNA velocity with and without
SNP Single-nucleotide polymorphism inhibitor, respectively
t Time (hours or minutes); Vmax Maximum metabolic rate
denotes tissue when used as a Vp Volume of plasma (central
subscript compartment)
teff Duration of pharmacologic Vt Volume of tissue compartment
response to drug (VD)exp Extrapolated volume of
tinf Infusion period distribution
tlag Lag time (VD)SS or Steady-state volume of
tmax Time of occurrence for maxi- VDSS distribution
mum (peak) drug concentration

Shargel_FM.indd 18 3/5/12 12:56:44 PM