Clinical Pharmacokineticsand PharmacodynamicsC O N C E P T S A N D A P P L I C A T I O N S

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Clinical Pharmacokineticsand PharmacodynamicsC o n c e p t s a n d A p p l i c a t i o n s

Malcolm Rowland, DSc, PhD

Professor EmeritusSchool of Pharmacy and

Pharmaceutical SciencesUniversity of ManchesterManchester, United Kingdom

F O U R T H E D I T I O N

Thomas N. Tozer, PharmD, PhD

Professor EmeritusSchool of Pharmacy and

Pharmaceutical SciencesUniversity of California, San FranciscoAdjunct Professor of PharmacologySkaggs School of Pharmacy and

Pharmaceutical SciencesUniversity of California San Diego

With Online Simulations byHartmut Derendorf, PhDDistinguished ProfessorGuenther Hochhaus, PhDAssociate ProfessorDepartment of PharmaceuticsUniversity of FloridaGainesville, Florida

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Acquisitions Editor: David B. TroyProduct Manager: Matt HauberMarketing Manager: Allison PowellDesigner: Doug SmockCompositor: Maryland Composition Inc./ASI

Fourth Edition

Copyright © 2011 Lippincott Williams & Wilkins, a Wolters Kluwer business351 West Camden Street 530 Walnut StreetBaltimore, MD 21201 Philadelphia, PA 19106

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9 8 7 6 5 4 3 2 1

Library of Congress Cataloging-in-Publication Data

Rowland, Malcolm.Clinical pharmacokinetics and pharmacodynamics : concepts and applications / Malcolm

Rowland and Thomas N. Tozer. —4th ed.p. ; cm.

Rev. ed. of: Clinical pharmacokinetics. 1995.ISBN 978-0-7817-5009-71. Pharmacokinetics. 2. Chemotherapy. I. Tozer, Thomas N. II. Rowland, Malcolm. Clinical phar-

macokinetics. III. Title.[DNLM: 1. Pharmacokinetics. 2. Drug Therapy. QV 38 R883c 2009]RM301.5.R68 2009615�.7—dc22

2009028928

DISCLAIMER

Care has been taken to confirm the accuracy of the information present and to describe gener-ally accepted practices. However, the authors, editors, and publisher are not responsible for errorsor omissions or for any consequences from application of the information in this book and makeno warranty, expressed or implied, with respect to the currency, completeness, or accuracy of thecontents of the publication. Application of this information in a particular situation remains theprofessional responsibility of the practitioner; the clinical treatments described and recommendedmay not be considered absolute and universal recommendations.

The authors, editors, and publisher have exerted every effort to ensure that drug selection anddosage set forth in this text are in accordance with the current recommendations and practice atthe time of publication. However, in view of ongoing research, changes in government regulations,and the constant flow of information relating to drug therapy and drug reactions, the reader isurged to check the package insert for each drug for any change in indications and dosage and foradded warnings and precautions. This is particularly important when the recommended agent is anew or infrequently employed drug.

Some drugs and medical devices presented in this publication have Food and DrugAdministration (FDA) clearance for limited use in restricted research settings. It is the responsibil-ity of the health care provider to ascertain the FDA status of each drug or device planned for usein their clinical practice.

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To Dawn and Margaretfor their continual love, patience, and tolerance.

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MALCOLM ROWLAND

Malcolm Rowland is Professor Emeritus and former Dean(1998–2001), School of Pharmacy and Pharmaceutical Sciences,University of Manchester, and Adjunct Professor, School ofPharmacy, University of California, San Francisco. He wasPresident of the European Federation of Pharmaceutical Sciences(1996–2000) and Vice-President, International PharmaceuticalFederation (FIP; 2001–2008), the organization that representsand serves pharmacy and pharmaceutical sciences around theglobe. He received his pharmacy degree and PhD from the

University of London, and was on faculty at the School of Pharmacy, University ofCalifornia, San Francisco (1967–1975).

Dr. Rowland, together with Dr. Thomas Tozer, authored the introductory textbook,Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of DrugTherapy. He has authored over 300 scientific articles and chapters. His research interest isprimarily in physiologically-based pharmacokinetics and its application to drug develop-ment and clinical use. In particular, he has pioneered the concept and application ofclearance and developed approaches to the prediction of pharmacokinetics of drugsfrom a combination of physicochemical properties and in vitro information. He was aneditor of the Journal of Pharmacokinetics and Pharmacodynamics (1973–2006), the pre-mier journal dedicated to the subject, and has established workshops for teaching bothbasic- and advanced-level pharmacokinetics. He is an advisor to the pharmaceuticalindustry and sits on various scientific advisory boards.

Dr. Rowland has been awarded honorary doctorate degrees from the University ofPoitiers (France) and Uppsala University (Sweden) as well as Honorary Membership ofthe Royal College of Physicians (London). He received various awards including theDistinguished Investigator Award of the American College of Clinical Pharmacology(ACCP, 2007) and the Millennial Pharmaceutical Scientist Award (FIP BPS, 2000). Hehas been made a fellow of the Academy of Medical Sciences, ACCP (Hon), AmericanAssociation of Pharmaceutical Scientists, the Royal Pharmaceutical Society of GreatBritain, and the Institute of Mathematics.

THOMAS N. TOZER

Dr. Tozer, Professor Emeritus of Biopharmaceutical Sciences andPharmaceutical Chemistry, School of Pharmacy, University ofCalifornia, San Francisco, received his BS, PharmD, and PhD de-grees from the University of California, San Francisco. He is cur-rently an Adjunct Professor of Pharmacology at the University ofCalifornia, San Diego, where he teaches biopharmaceutics andclinical pharmacokinetics at the Skaggs School of Pharmacy andPharmaceutical Sciences. After a 2-year postdoctoral fellowship inthe laboratory of Dr. B. B. Brodie, National Institutes of Health,

ABOUT THE AUTHORS

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Bethesda, Maryland, he joined the Faculty of the School of Pharmacy in San Francisco in1965. Although now in emeritus status, he continues to teach courses and workshops inpharmacokinetics/pharmacodynamics and clinical pharmacokinetics at several institu-tions in the United States and Europe.

Dr. Tozer, together with Dr. Malcolm Rowland, authored Clinical Pharmacokinetics:Concepts and Applications, the title of the first three editions of this textbook. He has pub-lished more than 155 scientific papers on a variety of research topics with emphasis onthe development and application of kinetic concepts in drug therapy. Dr. Tozer’sresearch before retirement was focused in four areas: colon-specific drug delivery, toxico-kinetics, kinetics of potential contrast agents for magnetic resonance imaging, and non-linear pharmacokinetics. Other research included determination of drug disposition indisease states, particularly end-state renal disease. Emphasis here was placed on evaluat-ing and predicting when and how drug administration to renal disease patients shouldbe altered.

Dr. Tozer was a corecipient of the 2000 Meritorious Manuscript Award, AmericanAssociation of Pharmaceutical Scientists, and was a Visiting Professor (1996–1999) at theUniversity of Manchester, Manchester, England. He is a Fellow of the AmericanAssociation of Pharmaceutical Scientists and has served as a consultant to the Food andDrug Administration and to many pharmaceutical companies.

viii ABOUT THE AUTHORS

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uch has happened in the field of our textbook since the last edition was publishedin 1995. First, in recognition that there was a readership that sought a less in-depthtextbook we wrote a companion, entitled Introduction to Pharmacokinetics and

Pharmacodynamics: The Quantitative Basis of Drug Therapy; it was published in 2006. While em-phasizing pharmacokinetics, the widening to include pharmacodynamics as an integralpart of this introductory text reflected the increasing body of knowledge linking the two el-ements that explain the relationship between drug administration and response. We havecontinued this trend of integrating pharmacodynamics with pharmacokinetics in the cur-rent text, which is reflected in the title. Second, in addition to an expanding knowledge ofpharmacodynamics, there has been an explosion in our understanding at the molecularand mechanistic levels of all the processes controlling the pharmacokinetics of drugs. Theavailability of the introductory text has therefore allowed us the opportunity to expand inthis current edition on these new insights for those readers wishing to gain a greater in-depth understanding of the subject. This has required some enlargement over previouseditions, but every attempt has been made to limit the size of the book.

As in our previous three editions, we are committed to developing and applying theconcepts to explain and improve the therapeutic use of drugs. As such, we continue tohave students and practitioners in pharmacy, medicine, pharmacology, and allied profes-sions in mind as our readers. Accordingly, although the principles have wide application,emphasis continues to be at the clinical level. We recognize, however, that pharmacoki-netics and pharmacodynamics are cornerstones in the industrial design, selection, anddevelopment of new drugs, and so believe that this textbook is of equal value to scientistsengaged in all aspects of the pharmaceutical industry, as well as those working in regula-tory agencies evaluating drug applications.

In addition to more detailed consideration of the basic principles compared to the in-troductory text, the current textbook expands greatly on why individuals vary in their re-sponse to drugs, which is central to personalizing drug therapy. Furthermore, there is anincrease in the number of thought-provoking problems at the end of each chapter, withanswers provided in the last appendix. While maintaining the overall structure and or-ganization, there are also significant improvements over the third edition. In particular,we have incorporated advances in our understanding of the role of enzymes and trans-porters in pharmacokinetics, and of genetics in both pharmacokinetics and pharmacody-namics. As briefly mentioned above, we have greatly expanded on pharmacodynamics,which was a single chapter in the specialized topic section of the last edition, and have in-tegrated it throughout the book. We have also incorporated Turnover Concepts andDialysis, which were also previously specialized topics, into the body of the book, recog-nizing that these are fundamental to the subject. We have also added two new chapters.One deals with protein drugs, reflecting the rapid increase in recent years in the numberof such medicines that have become a part of the armamentarium of modern therapeu-tics. The second concerns the prediction of human pharmacokinetics from in vitro andpreclinical data, and subsequent simulation of likely kinetics in patients under a wide va-riety of clinical conditions and situations, which can improve the chances of selectingcompounds that have desirable pharmacokinetic characteristics in planning clinical drugtrials and in ensuring their subsequent optimal use.

PREFACE

ix

M

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PREFACE

We have also updated all chapters and replaced many of the examples and case histo-ries with more modern ones, while providing many new problems with answers. To helpapproach these problems, we have provided at the end of each chapter a summary of keyrelationships. In addition, Drs. Hartmut Derendorf and Guenther Hochhaus, Universityof Florida, have prepared web-based simulations of many of the concepts presentedthroughout the book. The simulations allow the reader to explore the influence ofchanges in parameter values in both pharmacokinetics and pharmacodynamics on drugconcentration and response with time following drug administration. Finally, to conformto the quality of all new figures, of which there are many, we have redrawn or improvedthe figures retained from previous editions.

ACKNOWLEDGMENTS

As with all previous editions, we wish to thank the many students, as well as participants ofvarious workshops that we have taught, and colleagues for helping us shape the fourthedition. Their enthusiasm, commitment, and appreciation continue to be a source ofimmense satisfaction to us. We would also like to thank in particular Joe Balthasar for cri-tiquing the protein drug chapter and Amin Rostami for assistance in the simulation ofpharmacokinetic profiles in virtual patient populations.

It is now 30 years since the first edition of our textbook was published. Throughoutthis period, we have been enormously gratified by the wide and varied readership aroundthe world, sometimes in the most unexpected of places. Our wish has always been to con-tribute to the improved design and more rational use of medicines. We hope that thisfourth edition helps further this aspiration.

Malcolm Rowland, Manchester, UKThomas N. Tozer, San Francisco, California

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Preface ixNonproprietary and Brand Names of Drugs in Text and Illustrations xiiiDefinition of Symbols xix

SECTION I BASIC CONSIDERATIONS

1 Therapeutic Relevance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Fundamental Concepts and Terminology . . . . . . . . . . . . . . . . . . . . . . . . . 17

SECTION II EXPOSURE AND RESPONSE AFTER A SINGLE DOSE

3 Kinetics Following an Intravenous Bolus Dose . . . . . . . . . . . . . . . . . . . . . . 494 Membranes and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1116 Kinetics Following an Extravascular Dose . . . . . . . . . . . . . . . . . . . . . . . . . 1597 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1838 Response Following a Single Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

SECTION III THERAPEUTIC REGIMENS

9 Therapeutic Window . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24510 Constant-Rate Input . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25911 Multiple-Dose Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

SECTION IV INDIVIDUALIZATION

12 Variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33313 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35714 Age, Weight, and Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37315 Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40316 Nonlinearities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44517 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48318 Initiating and Managing Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527

TABLE OF CONTENTS

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xii TABLE OF CONTENTS

SECTION V SUPPLEMENTAL TOPICS

19 Distribution Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56120 Metabolites and Drug Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60321 Protein Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63322 Prediction and Refinement of Human Kinetics from In Vitro,

Preclinical, and Early Clinical Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663

APPENDICES

A. Assessment of AUC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .687B. Ionization and the pH Partition Hypothesis . . . . . . . . . . . . . . . . . . . . . . .691C. Distribution of Drugs Extensively Bound to Plasma Proteins . . . . . . . . . .695D. Plasma-to-Blood Concentration Ratio . . . . . . . . . . . . . . . . . . . . . . . . . . . .703E. Well-stirred Model of Hepatic Clearance . . . . . . . . . . . . . . . . . . . . . . . . . .705F. Absorption Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .709G. Wagner-Nelson Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .713H. Mean Residence Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .717I. Amount of Drug in Body on Accumulation to Plateau . . . . . . . . . . . . . . .723J. Answers to Study Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .727

Index 819

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(For those drugs available only by brand name at time of manuscript submission, thebrand name is provided.)

Abacavir ZiagenAbataceptAbciximab ReoProAcenocoumarolAcetaminophenAcetazolamideAcetylsalicylic acidAcyclovirAdalimumab HumiraAdefovirAgalsidaseAlbendazole AlbenzaAlbuterolAldesleukinAlefacept AmeviveAlemtuzumab CampathAlendronate sodium FosamaxAlfentanilAlglucosidase alfa MyozymeAllopurinolAlprazolamAlprenololAlteplaseAmikacinAmilorideAminosalicylic acidAmiodaroneAmitriptylineAmoxicillinAmpicillinAmprenavir AgeneraseAmrinoneAnakinra KineretAnidulafunginAntipyrineAntihemophilic

Factor (VIII)Antithrombin IIIAprepitant EmendAprotininAscorbic acid

Asparaginase ElsparAspirinAstemizoleAtenololAtorvastatin LipitorAzathioprineAzelastineAzithromycin

BacitracinBarbitalBasiliximab SimulectBenzylpenicillinBethanechol

ChlorideBevacizumab AvastinBivalirudin AngiomaxBosentan TracleerBudesonide Pulmicort

Respules® andEntocort EC

BufurololBumetanideBuprenorphineBupropionBuspironeBusulfan

CaffeineCalcitonin-salmon MiacalcinCapromab pendetide ProstaScint KitCaptoprilCarbamazepineCarbenicillinCarmustineCefamandoleCefazolinCefepimeCefonicidCeforanideCefotaxime

NONPROPRIETARY AND BRAND NAMESOF DRUGS IN TEXT AND ILLUSTRATIONS

xiii

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xiv NONPROPRIETARY AND BRAND NAMES OF DRUGS IN TEXT AND ILLUSTRATIONS

CefprozilCefsulodinCeftazidimeCeftizoximeCeftriaxoneCefuroximeCelecoxib CelebrexCephalexin KeflexCephalothinCephradineCerivastatin BaycolCetirizineCetuximab ErbituxChlordiazepoxideChloroquine AralenChlorothiazideChlorpheniramineChlorpromazineChlorzoxazoneCholestyramineChorionic

gonadotropinCidofovirCilastatin PrimaxinCimetidineCiprofibrateCiprofloxacinCisaprideCitalopram CelexaCladribineClarithromycinClavulanateClobazamClofibric acidClonazepamClonidineClopidogrel PlavixClotting Factor VIIaClotting Factor IXCloxacillinClozapineCocaineCodeineCollagenaseCortisolCosyntropinCrotalidae immune

FabCurareCyclophosphamideCyclosporineCytarabine DepoCyt

Injection

Daclizumab ZenapaxDapsoneDarifenacinDebrisoquineDelavirdine mesylate RescriptorDenileukin diftitox OntakDesflurane SupraneDesipramineDesirudin IprivaskDesloratadine ClarinexDesmopressin acetate DDAVPDextroamphetamineDextromethorphanDiazepamDiclofenacDicloxacillinDicumarolDidanosineDiethylcarbamazepineDiflunisalDigitoxinDigoxinDigoxin immune Fab DigibindDiltiazemDiphenhydramineDipyridamoleDisopyramideDobutamineDolasetron mesylate AnzemetDonepezil AriceptDornase alfa PulmozymeDoxepinDoxorubicinDoxycyclineDraflazineDronabinol MarinolDroperidolDutasteride Avodart

Efalizumab RaptivaEfavirenzEnalaprilEncainideEnfuvirtide FuzeonEnoxacinEpinephrineEpipodophyllotoxinEpoetin alfa EpogenEptifibatide IntegrilinErgonovineErythromycinEsmololEstradiol

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NONPROPRIETARY AND BRAND NAMES OF DRUGS IN TEXT AND ILLUSTRATIONS xv

Etanercept EnbrelEthambutolEthchlorvynolEthinyl estradiolEtonogestrel NuvaRing

(combinedwith ethinylestradiol)

Ezetimibe Zetia (alsocombinedwithsimvastatin[Vytorin®])

Felbamate FamvirFelodipineFenoldopamFentanylFexofenadine AllegraFibrinolysinFilgrastim NeupogenFlecainideFlesinoxanFluconazoleFlumazenil RomaziconFluorouracilFluoxetineFlurazepamFlurbiprofenFluvastatinFluvoxamineFosamprenavir LexivaFurosemide

GabapentinGanciclovir CytoveneGemcitabine GemzarGemtuzumab Mylotarg

ozogamicinGentamicinGladaseGlibenclamideGlyburideGlipizideGlucagonGonadotropin-

releasing hormoneGoserelin ZoladexGriseofulvinGrowth hormone

HalazepamHaloperidol

HalothaneHeparinHepatitis B immune globulinHeptabarbitalHirudinHydralazineHydrocortisoneHydroxyzine

IbandronateIbuprofenImiglucerase CerezymeImipenem PrimaxinImipramineImirestatIndinavir CrixivanIndocyanine greenIndomethacinInfliximab RemicadeInsulinInsulin glargine LantusInterferon Infergen

alfacon-1Interferon Alpha-2b Pegintron

(pegylated)Interferon Beta-1a RebifInterleukin-11

(Oprelvekin) NeumegaIntravenous gamma

globulin GammagardIrbesartan Avalide, AvaproIrinotecan CamptosarIsofluraneIsoniazidIsosorbide dinitrateItraconazole

KetamineKetoconazoleKetoprofenKetorolac

LabetalolLansoprazoleLaronidaseLeflunomide AravaLepirudin RefludanLeucovorinLeuprolide acetateLevodopaLevofloxacinLevonorgestrelLidocaine

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xvi NONPROPRIETARY AND BRAND NAMES OF DRUGS IN TEXT AND ILLUSTRATIONS

LithiumLomefloxacinLomustineLoperamideLopinavir Kaletra

(combinedwith ritonavir)

LorazepamLosartan HyzaarLovastatinLymphocyte

anti-thymocyteimmune globulin

MaprotilineMefloquine ArimaMeloxicamMemantineMenotropins MenopurMeperidineMercaptopurineMesalamineMetforminMethamphetamineMethotrexateMethyldopaMethylphenidateMethylprednisoloneMetoprolol tartrateMetronidazoleMibefradilMidazolamMinocyclineMinoxidilMisonidazoleMisoprostolMontelukast SingulairMorphineMoxalactamMuromomab-CD3

NaloxoneNaproxenNelfinavir mesylate ViraceptNeomycinNesiritideNiacinNicardipineNicotineNicoumaloneNifedipineNitrazepamNitroglycerin

Norelgestromin Ortho Evra(combinedwith ethinylestradiol)

NorepinephrineNorfloxacinNormal immune

globulinNortriptyline

OctreotideOlsalazineOmalizumab XolairOmeprazoleOndansetronOrlistat XenicalOtenzapadOxacillinOxaliplatinOxazepamOxycodoneOxytocin

PaclitaxelPalivizumab SynagisPamidronate ArediaPancuroniumPanitumumab VectibixPara-aminohippuric

acidPancrelipasePantoprazolePapainParoxetinePegvisomantPenciclovir DenavirPenicillin GPentagastrinPentazocine Talwin®

(combinedwithnaloxone)

PentobarbitalPentoxyphyllinePertussis immune

globulinPhenelzinePhenobarbitalPhenprocoumonPhenylbutazonePhenytoinPimozidePiperacillin

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NONPROPRIETARY AND BRAND NAMES OF DRUGS IN TEXT AND ILLUSTRATIONS xvii

PiroxicamPivampicillinPolymyxin

B SulfatePravastatinPrazepamPrednisolonePrednisonePrimaquinePrimidoneProbenecidProcainamideProcarbazineProgesteroneProguanilPromazinePropafenonePropanthelinePropofolPropranololPropylthiouracilProtriptylinePyridostigmine

QuinacrineQuinidine sulfate

Rabies immuneglobulin

Ranibizumab LucentisRanitidineRasburicase ElitekRemifentanil UltivaRho(D) immune

globulinRifampinRitonavir NorvirRituximab Rituxan,

MabtheraRivastigmine ExelonRolipramRosiglitazone AvandiaRosuvastatin Crestor

Salicylic acidSaquinavir mesylate InviraseSaruplaseScopolamineSermorelinSertralineSevoflurane UltaneSildenafil citrate ViagraSimvastatin

Sirolimus RapamuneSomatropinSparteineSt. John’s WortStreptomycinSuccinylcholineSucralfateSufentanilSulfamethazineSulfasalazineSulfinpyrazoneSulindacSumatriptan

TacrolimusTamoxifenTamsulosin FlomaxTaxolTeicoplaninTelithromycin KetekTenecteplase TNKaseTerazosinTerbutalineTerfenadineTeriparatide ForteoTestosteroneTetanus immune

globulinTheophyllineThioguanineThiopentalThyroxineTiclopidine TiclidTimolol maleateTipranavirTirofiban AggrastatTissue-type

plasminogenactivator (t-PA)

TobramycinTolbutamideTolmetinTolterodine tartrate DetrolTositumomab BexxarTrandolapril MavikTrastuzumab HerceptinTriazolamTrimipramine SurmontilTroleandomycinTubocurarine

Urokinase

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xviii NONPROPRIETARY AND BRAND NAMES OF DRUGS IN TEXT AND ILLUSTRATIONS

Vaccinia immuneglobulin

Valganciclovir ValcyteValproic acidValsartan DiovanVancomycinVaricella-zoster Varivax

immune globulinVasopressinVenlafaxine EffexorVerapamil

hydrochloride

VinblastineVincristineViomycinVitamin CVoriconazole

Warfarin

Zafirlukast AccolateZidovudineZileuton ZyfloZoledronic acid Reclast, Zometa

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(Typical units are shown)

A Amount of drug in body, mg or �mol.

Aa Amount of drug at absorption site remaining to be absorbed, mgor �mol.

Aav,ss Average amount of drug in body during a dosing interval at steadystate, mg or �mol.

Ae Cumulative amount of drug excreted in the urine, mg or �mol.

Ae� Cumulative amount of drug excreted in the urine after a singledose to time infinity, mg or �mol.

Ainf Amount of drug in body during a constant-rate infusion, mg or �mol.

A(m) Amount of metabolite in the body, mg or �mol.

Amin The minimum amount of drug in body required to obtain apredetermined level of response, mg or �mol.

Amax,N; Amin,N Maximum and minimum amounts of drug in body after the Nthdose of fixed size and given at a fixed dosing interval, mg or �mol.

AN,t Amount of drug in body at time t after the Nth dose, mg or �mol.

Ass Amount of drug in body at steady state during constant-rateadministration, mg or �mol.

Amax,ss; Amin,ss Maximum and minimum amounts of drug in body during a dosinginterval at steady state on administering a fixed dose at a fixeddosing interval, mg or �mol.

AUC Area under the plasma drug concentration-time curve. Total areafrom time 0 to infinity is implied unless the local context indicatesa specific time interval (e.g., a dosing interval), mg-hr/L or �M-hr.

AUCb Area under the blood concentration-time curve, mg-hr/L or �M-hr.

AUC(m) Area under the plasma metabolite concentration-time curve, mg-hr/L or �M-hr.

AUCss Area under the plasma concentration-time curve within a dosinginterval at steady state, mg-hr/L or �M-hr.

AUMC Total area under the first moment-time curve, mg-hr2/L or �M-hr2.

BMI Body mass index, kg/m2.

BSA Body surface area, m2.

C Concentration of drug in plasma (or reservoir), mg/L or �M.

C50 Concentration giving one-half the maximum effect, mg/L or �M.

C(0) Initial plasma concentration obtained by extrapolation to timezero, after an intravenous bolus dose, mg/L or �M.

CA Drug concentration in arterial blood, mg/L or �M.

DEFINITIONS OF SYMBOLS

xix

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xx DEFINITIONS OF SYMBOLS

Cav,ss Average drug concentration in plasma during a dosing interval atsteady state on administering a fixed dose at equal dosing intervals,mg/L or �M.

Cinf Concentration of drug in plasma during a constant-rate infusion,mg/L or mM.

Cb Concentration of drug in blood, mg/L or �M.

CL Total clearance of drug from plasma, L/hr or mL/min.

CLb Total clearance of drug from blood, L/hr or mL/min.

CLb,H Hepatic clearance of drug from blood, L/hr or mL/min.

CLcr Renal clearance of creatinine, mL/min or L/hr.

CLD Clearance by dialysis procedure, L/hr or mL/min.

CLH Hepatic clearance of drug from plasma, L/hr or mL/min.

CLint Intrinsic clearance of drug in organ of elimination (well-stirredmodel), L/hr or mL/min.

CLR Renal clearance of drug from plasma, L/hr or mL/min.

CLu Clearance of unbound drug, L/hr or mL/min.

Clower, Cupper Lower and upper bounds of the therapeutic window of plasmaconcentrations, mg/L or �M.

Cmax Highest drug concentration observed in plasma afteradministration of an extravascular dose, mg/L or �M.

Cmax,ss, Cmin,ss Maximum and minimum concentrations of drug in plasma atsteady state on administering a fixed dose at equal dosing intervals,mg/L or �M.

C(m) Concentration of a metabolite in plasma, mg/L or �M.

C(m)ss Concentration of a metabolite in plasma at steady state during aconstant-rate infusion of a drug, mg/L or �M.

Cmin Concentration of drug in plasma required to give the minimumeffect, mg/L or �M.

Cout Concentration leaving the extractor in the reservoir model, mg/Lor �M.

Css Concentration of drug in plasma at steady state during constant-rate administration, mg/L or �M.

CT Average concentration of drug in tissues outside plasma, mg/L or �M.

Cu Unbound drug concentration in plasma, mg/L or �M.

CuH Unbound drug concentration within hepatocytes, mg/L or �M.

CV Concentration of drug in venous blood, mg/L or �M.

DL Loading (or priming) dose, mg.

DM Maintenance dose given every dosing interval, mg

DM,max Largest maintenance dose that will keep systemic exposure withinthe therapeutic window, mg.

E Extraction ratio, no units.

In pharmacodynamics, E means “effect,” which may be either clini-cally desirable or adverse. Units are those of response measured.

EH Hepatic extraction ratio, no units.

Emax Maximum effect, units of response measurement.

ER Renal extraction ratio, no units.

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DEFINITIONS OF SYMBOLS xxi

F Bioavailability of drug, no units.

fD Fraction of total elimination occuring by dialysis, no units.

fe Fraction of drug systemically available that is excreted unchangedin urine, no units.

Fev Bioavailability of drug after extravascular administration, no units.

FEV1 Forced expiratory volume in one second, L.

FF Fraction of an oral dose that enters the gut wall, no units.

FG Fraction of drug entering the gut that passes on to the portalcirculation, no units.

FH Fraction of drug entering the liver that escapes elimination onsingle passage through the organ, no units.

fm Fraction of drug systemically available that is converted to ametabolite, no units.

Fm Fraction of administered dose of drug that enters the generalcirculation as a metabolite, no units.

FR Fraction of filtered and secreted drug reabsorbed in the renaltubule, no units.

fu Ratio of unbound and total drug concentrations in plasma, no units.

fub Ratio of unbound and whole blood concentrations available forbinding, no units.

fuP Ratio of unbound and total sites on a plasma protein, no units.

fuR Apparent fraction unbound in intracellular fluids, no units.

fuT Ratio of unbound and total drug concentrations in tissues (outsideplasma), no units.

� Steepness of concentration–response relationship, no units.

GFR Glomerular filtration rate, mL/min or L/hr.

k Elimination rate constant, hr�1.

ka Absorption rate constant, hr�1.

Ka Association equilibrium constant, L/mol.

Kd Dissociation constant for saturable binding, mg/L.

KI Inhibition equilibrium constant, mg/L or �M.

Km Michaelis-Menten constant, mg/L or �M.

Kp Equilibrium distribution ratio of drug between tissue and plasma,no units.

Kp,b Equilibrium distribution ratio of drug between tissue and blood, nounits.

KT Constant for saturable transport model, mg/L.

kt Fractional turnover rate, hr�1.

kT Fractional rate at which drug leaves a tissue, hr�1.

�1, �2 Exponential coefficients, hr�1

m Slope of the relationship between response and the log of theplasma concentration (between 20 and 80% of maximumresponse), units of the response.

MRT Mean residence time of a drug molecule within the body, hr.

n A unitless number.

N Number of doses, no units.

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xxii DEFINITIONS OF SYMBOLS

P Permeability coefficient, cm/sec.

PT Total concentration of binding protein in plasma, mM.

Q Blood flow, L/min or L/hr.

QH Hepatic blood flow (portal vein plus hepatic artery), L/min or L/hr.

QR Renal blood flow, L/min or L/hr.

Rac Accumulation ratio (index), no units.

Rd Ratio of unbound clearance of an individual patient with renalfunction impairment to that of a typical patient, no units.

RF Renal function in an individual patient as a fraction of renalfunction in a typical patient, no units.

Rinf Rate of constant intravenous infusion, mg/hr.

Rsyn Rate of synthesis or input of a substance into the body, mg/hr or�g/hr

Rt Turnover rate, mg/hr.

SA Surface area, m2.

� Dosing interval, hr.

tmax Maximum dosing interval to remain within the limits of Clower andCupper, hr.

t Time, hr.

tD Duration of response, hr

tinf Duration of a constant-rate infusion, hr.

Tm Maximum rate of drug transport, mg/hr.

tmax Time at which the highest drug concentration occurs afteradministration of an extravascular dose, min or hr.

tt Turnover time, hr.

t1/2 Elimination half-life, hr.

t1/2,a Half-life of systemic absorption, hr.

V Volume of distribution (apparent) based on drug concentration inplasma, L.

V1 Initial dilution space or volume of central compartment in a two-compartment model, L.

Vb Volume of distribution (apparent) based on drug concentration inwhole blood, L.

VB Blood volume, L.

Vm Maximum rate of metabolism by a given enzymatic reaction, mg/hror �mol/hr.

V(m) Volume of distribution (apparent) of a metabolite based on itsplasma concentration, L.

VP Plasma volume, L.

VR Aqueous volume of intracellular fluids, L.

Vss Volume of distribution (apparent) under steady state conditionsbased on drug concentration in plasma, L.

VT Physiologic volume outside plasma into which drug appears to dis-tribute, L.

Vu Unbound volume of distribution, L.

W Body weight, kg.

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