Applied Biopharmaceutics & Pharmacokinetics

Applied
Biopharmaceutics &

Pharmacokinetics

Notice

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Applied
Biopharmaceutics &

Pharmacokinetics
Sixth Edition

Leon Shargel, P D, RPh

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

Susanna Wu-Pong, P D, RPh

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

Andrew B.C. Yu, P D, RPh

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

∗ e 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

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
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This book was set in Times by Cenveo Publisher Services.
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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 [email protected].

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



Contents 3. One-Compartment Open Model:
Intravenous Bolus Administration 43
Preface xiii
Glossary xv Elimination Rate Constant 44 53
Apparent Volume of Distribution 45
1. Introduction to Biopharmaceutics and Clearance 48
Pharmacokinetics 1 Practical Focus 50
Clinical Application 53
Drug Product Performance 1 Calculation of k from Urinary Excretion Data
Biopharmaceutics 1 Practice Problem 54
Pharmacokinetics 3 Clinical Application 56
Clinical Pharmacokinetics 4 Chapter Summary 57
Practical Focus 4 Learning Questions 57
Pharmacodynamics 5 Reference 59
Drug Exposure and Drug Response 5 Bibliography 59
Toxicokinetics and Clinical Toxicology 5
Measurement of Drug Concentrations 6 4. Multicompartment Models:
Basic Pharmacokinetics and Intravenous Bolus Administration 61

Pharmacokinetic Models 10 Two-Compartment Open Model 63 79
Chapter Summary 15 Clinical Application 68
Learning Questions 17 Practice Problem 68
References 17 Practical Focus 69
Bibliography 18 Three-Compartment Open Model 77
Determination of Compartment Models
2. Mathematical Fundamentals in Practical Application 84
Pharmacokinetics 19 Chapter Summary 86
Learning Questions 87
Math Self-Exam 19 References 88
Estimation and the Use of Calculators and Bibliography 89

Computers 20 5. Intravenous Infusion 91
Practice Problems 22
Calculus 24 One-Compartment Model Drugs 91
Graphs 26 Infusion Method for Calculating Patient
Units in Pharmacokinetics 31
Measurement and Use of Significant Figures 32 Elimination Half-Life 95
Units for Expressing Blood Concentrations 33
Statistics 33
Practical Focus 34
Rates and Orders of Reactions 35
Chapter Summary 40
Learning Questions 40
References 42
Bibliography 42

vii

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 V from Learning Questions  174
  Infusion Data  100 d References  175
Bibliography  175
Intravenous Infusion of Two-Compartment
  Model Drugs  100   9. Nonlinear Pharmacokinetics  177
Practical Focus  102
Chapter Summary  104 Saturable Enzymatic Elimination Processes  179
Learning Questions  104 Practice Problem  180
Reference  106 Drug Elimination by Capacity-Limited
Bibliography  106   Pharmacokinetics: One-Compartment
  Model, Iv Bolus Injection  181
  6. Drug Elimination and Clearance  107 Clinical Focus   191
Drugs Distributed as One-Compartment
Drug Elimination  107   Model and Eliminated by Nonlinear
The Kidney  108   Pharmacokinetics  191
Renal Drug Excretion  111 Chronopharmacokinetics and Time-Dependent
Clinical Application  114   Pharmacokinetics  193
Practice Problems  114 Bioavailability of Drugs that Follow Nonlinear
Drug Clearance  114   Pharmacokinetics  196
Clearance Models  116 Nonlinear Pharmacokinetics Due to
Renal Clearance  118   Drug–Protein Binding  196
Determination of Renal Clearance  121 Potential Reasons for Unsuspected
Relationship of Clearance to Elimination   Nonlinearity  200
  Half-Life and Volume of Distribution 125 Chapter Summary  200
Chapter Summary  127 Learning Questions  200
Learning Questions  127 References  202
References  129 Bibliography  203
Bibliography  129
10. Physiologic Drug Distribution and
  7. Pharmacokinetics of Oral Protein Binding  205
Absorption  131
Physiologic Factors of Distribution  205
Pharmacokinetics of Drug Absorption  131 Clinical Focus  213
Significance of Absorption Rate Constants  133 Apparent Volume Distribution  213
Zero-Order Absorption Model  133 Practice Problem  216
Clinical Application— Transdermal Protein Binding of Drugs  219
  Drug Delivery  134 Clinical Examples  221
First-Order Absorption Model  134 Effect of Protein Binding on the Apparent
Practice Problem  142   Volume of Distribution  222
Chapter Summary  149 Relationship of Plasma Drug–Protein Binding
Learning Questions  149   to Distribution and Elimination  227
References  150 Determinants of Protein Binding  231
Bibliography  151 Kinetics of Protein Binding  232
Practical Focus  233
  8. Multiple-Dosage Regimens  153 Determination of Binding Constants and
  Binding Sites by Graphic Methods  233
Drug Accumulation  153 Clinical Significance of Drug–Protein
Clinical Example  157   Binding  236
Repetitive Intravenous Injections  158 Modeling Drug Distribution  247
Intermittent Intravenous Infusion  163 Chapter Summary  248
Estimation of k and V of Aminoglycosides Learning Questions  249
  in Clinical Situationds  165 References  250
Multiple-Oral-Dose Regimen  166 Bibliography  251
Loading Dose  168

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

x      CONTENTS 17. Modified-Release Drug Products  469

15. Drug Product Performance, Conventional (Immediate-Release) and
In Vivo: Bioavailability and   Modified-Release Drug Products  469
Bioequivalence  403 Biopharmaceutic Factors  473
Dosage form Selection  475
Drug Product Performance  403 Advantages and Disadvantages of
Purpose of Bioavailability Studies  405   Extended-Release Products  475
Relative and Absolute Availability  406 Kinetics of Extended-Release Dosage Forms  476
Practice Problem  407 Pharmacokinetic Simulation of Extended-Release
Methods for Assessing Bioavailability  407   Products  478
Bioequivalence Studies  413 Clinical Examples  480
Design and Evaluation of Bioequivalence Types of Extended-Release Products  480
  Studies  414 Considerations in the Evaluation of
Study Designs  417   Modified-Release Products  495
Crossover Study Designs  418 Evaluation of Modified-Release Products  497
Clinical Example   422 Evaluation of In Vivo Bioavailability Data  499
Evaluation of the Data  423 Chapter Summary  501
Bioequivalence Example  424 Learning Questions  501
Study Submission and Drug Review References  502
  Process  427 Bibliography  503
The Biopharmaceutics Classification System  431
Generic Biologics (Biosimilar Drug 18. Targeted Drug Delivery ­Systems and
  Products)  433 Biotechnological Products  505
Clinical Significance of Bioequivalence
  Studies  435 Biotechnology  506
Special Concerns in Bioavailability and Drug Carriers and Targeting  514
  Bioequivalence Studies  436 Targeted Drug Delivery  519
Generic Substitution  437 Pharmacokinetics of Biopharmaceuticals  521
Glossary  440 Bioequivalence and Comparability of
Chapter Summary  443   Biotechnology-Derived Drug Products  522
Learning Questions  443 Chapter Summary  523
References  448 Learning Questions  524
Bibliography  449 References  524
Bibliography  525
16. Impact of Drug Product Quality
and Biopharmaceutics on Clinical 19. Relationship Between
Efficacy  451 ­Pharmacokinetics and
Pharmacodynamics  527
Risks From Medicines  451
Drug Product Quality and Drug Product Pharmacodynamics and Pharmacokinetics  527
  Performance  452 Relationship of Dose to Pharmacologic
Pharmaceutical Development  453   Effect  534
Excipient Affect on Drug Product Relationship Between Dose and Duration of
  Performance  455  PraAcctitciveiPtyro(btelfef)m, S  in5g3le6 Iv Bolus Injection  536
Practical Focus  456 Effect of Both Dose and Elimination Half-Life
Quality Control and Quality Assurance  457   on the Duration of Activity  537
Risk Management  459 Effect of Elimination Half-Life on Duration
Scale-Up and Postapproval Changes (Supac)  461   of Activity  537
Product Quality Problems  464 Clinical Examples  539
Postmarketing Surveillance  465 Rate of Drug Absorption and Pharmacodynamic
Glossary  465   Response  541
Chapter Summary  466 Drug Tolerance and Physical Dependency  542
Learning Questions  466 Hypersensitivity and Adverse Response  543
References  466

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

Renal Impairment  617
Pharmacokinetic Considerations  617



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
of bioequivalence as an in vivo measure of drug
The major objective is to provide the reader with product performance and that bioequivalence is
a basic and practical understanding of the principles important in both brand and generic drug product
of biopharmaceutics and pharmacokinetics that can development.
be applied to drug product development and to drug
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-
uct quality and drug product performance.
The primary audience is pharmacy students
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-
book are research and development scientists in phar- • Practical examples and questions are included
maceutics, biopharmaceutics, and pharmacokinetics. to encourage students to apply the principles in
patient care and drug consultation situations.
There are many improvements in this edition.
• Chapter Objectives are added at the beginning of • Active learning and outcome-based objectives are
highlighted.
each chapter
• Chapter Summary at the end of each chapter. Leon Shargel
• Frequently Asked Questions are seeded within each Susanna Wu-Pong

chapter to help the student focus on key concepts. Andrew B.C. Yu
• Most chapters are revised to reflect our current
xiii
understanding of drug disposition, pharmacody-
namics, and drug therapy.



Glossary

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

xvi      GLOSSARY

Cm∞ax 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-
Cm∞in Minimum steady-state drug DL nal tract
concentration; see also Cssmin Dm Loading (initial) dose
Cp Concentration of drug in plasma DNA Maintenance dose
Cp0 DN Deoxyribonucleic acid
Concentration of drug in plasma DP Normal dose
Cp∞ at zero time (t = 0) (equivalent Dt Drug in central compartment
StoteCa0d)y-state plasma drug Du Amount of drug in tissue
C pn concentration (equivalent to CSS) D0 Amount of drug in urine
CSS Last measured plasma drug D0 Dose of drug
concentration Amount of drug at zero time
Cssav Concentration of drug at steady E (t = 0)
state e Pharmacologic effect
Cssmax Average concentration at steady Intercept on y axis of graph
state eGFR relating pharmacologic response
Cssmin Maximum concentration at to log drug concentration
steady state Emax Estimate of GFR based on an
Ct Minimum concentration at E0 MDRD equation
cGMP steady state EC50 Maximum pharmacologic effect
Concentration of drug in tissue Pharmacologic effect at zero
CKD Current good manufacturing ELS drug concentration
ClCr practices ER Drug concentration that pro-
ClD Chronic kidney disease duces 50% maximum pharma-
Clh Creatinine clearance F cologic effect
Clint Dialysis clearance Extended least square
Cl′int Hepatic clearance f Extraction constant (equivalent
Intrinsic clearance to Eh); extraction ratio
Clnr Intrinsic clearance (unbound or fe Fraction of dose absorbed
ClR free drug) fu (bioavailability factor)
ClRu Nonrenal clearance FDA Fraction of dose remaining in
ClT Renal clearance the body
COX-1 Renal clearance of uremic f(t) Fraction of unchanged drug
CRF patient excreted unchanged in urine
CRFA Total body clearance f ′(t) Unbound fraction of drug
Cyclo-oxygenase-1 GFR US Food and Drug
Cv Case report form GI Administration
Cumulative relative fraction GMP Function representing drug
%CV absorbed [I] elimination over time (time is
CYP Drug concentration in venous the independent variable)
D plasma Derivative of f(t)
DA Percent coefficient of variation Glomerular filtration rate
Cytochrome P-450 Gastrointestinal tract
Amount of drug (mass, eg, mg) Good Manufacturing Practice
Amount of drug absorbed [I] is the inhibitor concentration
in an enzymatic reaction

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

Pharmacogenetics

Pharmacokinetics

Patient package insert

Blood flow

Quality assurance

Quality by design

Quality control

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