51. Clinical Pharmacoklnehcs
`2}
`Concepts and Applications
`2];
`ll:
`third edition
`"I?
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`1.:
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`Apotex v. Novartis
`|PR2017—00854
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`NOVARTIS 2050
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`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2050
`
`1
`
`

`

`Clinical Pharmacokinetics
`
`Concepts and Applications
`
`2
`
`

`

`',1._I
`
`- ::~~ ,.
`, . •,
`~ ·, .. • ·
`
`Clinical Pharmacokinetics
`
`Concepts and Applications
`
`third edition
`
`MALCOLM ROWLAND, Ph.D.
`Department of Pharmacy
`
`University of Manchester
`
`Manchester, England
`
`THOMAS N . TOZER, Ph.D.
`School of Pharmacy
`University of Cal ifornia
`
`San Francisco, California
`
`A Lea & Febiger Book
`
`,~ LIPPINCOTT WILLIAMS & WILKINS
`•
`A Wolters Kluwer Company
`Philadelphia • Baltimore • New York • London
`Buenos Aires • Hong Kong • Sydney • Tokyo
`
`-
`
`3
`
`

`

`Executive Editor: Donna Balado
`Developmental Editors: Frances Klass, Lisa Stead
`Production Manager: Laurie Forsyth
`Project Editor: Robert D. Magee
`
`Copyright© 1995
`Lippincott Williams & Wilkins
`530 Walnut Street
`Philadelphia, Pennsylvania 19106-362 1 USA
`
`All rights reserved . This book is protected by copyright. No part of this book may be reproduced in any
`form or by any means, including photocopying, or utilized by any information storage and retrieval system
`without written permissio n from the copyright owner.
`
`Accurate indications, adverse reactions, and dosage schedules for drugs are provided in this book, but it is
`possible they may change. The reader is urged to review the package information data of the manufacturers
`of the medications mentioned .
`
`Printed in the United States of America
`
`First Edition 1980
`
`· Library of Congress Cataloging-in-Publication Data
`
`I. Tozer, Thomas N.
`
`Rowland, Malcolm.
`Clinical Pharmacokinetics : concepts and applications / Malcolm
`Rowland, Thomas N. Tozer. - 3rd ed.
`p.
`cm.
`"A Lea & Febiger Book."
`Includes bibliographical references and index.
`ISBN 0-68.3-07404-0
`1. Pharmacokinetics. 2. Chemotherapy.
`II . Title.
`[DNLM: 1. Pharmacokinetics.
`RM301.5.R68
`1994
`615.7-dc20
`DNLM/ DLC
`for Library of Congress
`
`2. Drug Therapy.
`
`QV 38 R883c 1994]
`
`94-26305
`CIP
`
`The Publishers have made every ejfort to trace the copyright holders for borrowed material. lf they have in(cid:173)
`advertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity.
`
`04
`7 8 9 10
`
`------------------------------------------------ ..
`
`4
`
`

`

`To Margaret and Dawn
`To Margaret and Down
`
`5
`
`

`

`PREFACE
`
`PURPOSE OF TEXT
`The third edition, in keeping with the first two editions, is a primer in pharmacokinetics
`with an emphasis on clinical applications. The book should be useful to any student, prac(cid:173)
`titioner, or researcher who is interested or engaged in the development, evaluation, or use
`of medicines. Such persons include pharmacists, physicians, veterinarians, pharmaceutical
`scientists, toxicologists, analytical chemists, biochemists, and clinical chemists. It is an in(cid:173)
`troductoiy text and therefore presumes that the reader has little or no experience or knowl(cid:173)
`edge in the area. Previous exposure to certain aspects of physiology and pharmacology
`would be helpful, but it is not essential. Some knowledge of calculus is also desirable.
`Our intent is to help the reader learn to apply pharmacokinetics in therapeutics. To this
`end, we emphasize concepts through problem solving with only the essence of required
`mathematics. In this respect, the book is a programmed learning text. At the beginning of
`each chapter, objectives are given to identify the salient points to be learned. To further
`aid in learning the material, examples are worked out in detail in the text. At the end of
`each chapter, except the first, there are problems that allow the reader to grasp the concepts
`of the chapter and to build on material given in previous chapters. The order of the prob(cid:173)
`lems in each chapter reflects consideration of both difficulty and how well the problems
`apply to chapter principles. The questions start with the less difficult ones and those that
`emphasize the principles.
`
`OR GANIZATI ON AND CONTENT
`As in the second edition, the book is divided into five sections: Absorption and Disposition
`Kinetics, Therapeutic Regimens, Physiologic Concepts and Kinetics, Individualization, and
`Selected Topics. Those wishing to gain a general overview of the subject need only study
`Sections One and Two, together with Chapter 13, Variability, and Chapter 18, Monitming.
`Section Three deals with the physiologic concepts relevant to an understanding of the
`processes of absorption, distribution, and elimination. This section forms the basis for an
`appreciation of the material in Section Four, which is concerned with the identification,
`description, and accounting of variability in patients' responses to drugs. Covered here are
`general aspects of variability, followed by considerations of genetics, age and weight, dis(cid:173)
`ease, interacting drugs, and monitoring of drug concentrations.
`Section Five contains selected topics. These are intended for those readers who wish to
`gain a more detailed insight into various aspects of clinical pharmacokinetics. The topics
`are distribution kinetics, pharmacologic response, metabolite kinetics, dose and time de(cid:173)
`pendencies, turnover concepts, and dialysis. Each topic is generally self-contained; they
`have not been arranged in any particular sequence.
`
`CHANGES IN THIRD EDITION
`The 6-year gap between this third edition and the second, published in 1989, is shorter
`than the 9 years between the second and first editions. This shortening of the time span
`
`6
`
`

`

`l
`
`I
`
`,;o'•
`
`.. ~,.
`•·1~'~'~·
`
`CONTENTS
`
`......... .. ... .............. .... .. ........................ , .. ,., .. .. .. .. ... . xi
`Definitions of Symbols
`l. Why Clinical Pharmacokinetics?
`... ...... ....... .. .. .. ........ .. ..... .. ... ...... ...... ..... .. .. 1
`
`SECTION I. ABSORPTION AND DISPOSITION KINETI CS
`2. Basic Considerations
`.... ....... ........ ..... ...... ....... .... ... ..... .. .... ..... .... ......... 11
`3.
`Intravenous Dose . _ ........ ......... ...... ......... ... _ .. ___ .. .... ....... _ ..... ...... .... ... __ . _ l 8
`4. Extravascular Dose
`.... ..... ...... .. ........ _ ... ..... _ .......... ....... ....... ................. 34
`
`SE CTION II. THERAPEUT IC REGIMENS
`5. Therapeutic Response and Toxicity ... .............................. ....... ....... ......... 53
`6. Constant-Rate Regimens ....... .................... .. , ........... ..... ......... ............ ... 66
`7. Multiple-Dose Regimens .. ......... ..... _ .. .. ......... .. _. _ ... ................... .... .. .... . _. 83
`
`SECTION Ill. PHYSIOLOGI C CONCEPTS AND KINETICS
`8. Movement Through Membranes
`..... ... .............. ................... .... .. ..... ..... l 09
`9. Absorption ....... ........ .... ..... ...... ........... ....... .. ..... .......... .... ............... .. 119
`l 0. Distribution
`....... ............. ......... , ... ...... .. .. ........ .... ........ ....... ......... ..... 137
`11. Elimination .. ............. .... ...... ... ...... ....... ....................... ..... , ........ .. ... .. 156
`12. Integration With Kinetics .... ................ ..... , ..... ... ...... .... __ .. ..... ........... .. 184
`
`INDIVIDUALIZATION
`. SE CTI ON IV.
`13. Variability ......... .............. ... .. .... . _ ......... .. ....... ..... ..... .............. ..... ... __ 203
`14. Genetics
`................. ... ............. .................... ...... ..... ..... ............. ..... 220
`15. Age and Weight
`............. ......... ....... .... .......... ..... ... .. ..... .. ........ ... ... .. 230
`16. Disease ........ ........ .......... ..... .... ...... ... ..... .............................. ... .. .... . 248
`17. Interacting Drugs ....... ....... ..... ................. ......... .......... ...... ...... ..... ..... 267
`18. Concentration Monitoring
`................... .............. ..... ...... ..... ............... . 290
`
`SECTION V. SELECTED TOPICS
`19. Distribution Kinetics .... ... ... , .... ..... ....... .... ................................ ...... ... .. 313
`20. Pharmacologic Response _ ............ ................. .. _ ..... .. . __ . _ .. .... __ . _ ........... 340
`21. Metabolite Kinetics ........... ....... .... ..... .. ........ .. ....... ...... .. ............ .. ..... 367
`22. Dose and Time Dependencies .. ......... .. ..... ....... ................. ... .... .. .. ..... 394
`23. Turnover Concepts
`............. ..... ..... .................. ................. ... ... .. ........ 424
`24. Dialysis . ...... ...... .. ......... ............ .......... ... ..... __ .... ... .... ................... _ .. 443
`
`SELECTED READING
`
`..... .... ... ..... ... . .. ...... .. __ . _. _. _ ....... ......... , .... ... ..... , _ ..... ..... .... 463
`
`APPENDIX I. ADDITIONAL CONCEPTS AND DERIVATIONS
`
`A. Assessment of AUC ............... .... .... ... ............................... > ............. 469
`B. Estimation of Elimination Half-life From Urine Data
`) ix
`
`, .... ..... ...... ....... ........ .. . 473
`
`7
`
`

`

`X
`
`CONTENTS
`
`. .... : .. ... . 478
`C. Estimotion of Absorption Kinetics From Plasma Concentration Data
`D. Mean Residence Time -·-··- ···-·- ·-···-·-·- ··· ·· .. · ··· ·· ·· ·· .. · ·· ·· .. · ·· ··· ··· ·· ·· · ·-- ·-·· .485
`E. Amount of Drug in Body on Accumulation to Plateau
`.. . .. .. .. ... .......... . ... .. .. .490
`F. Distribution of Drugs Extensively Bound to Plasma Proteins
`. .......... .. .. . ... .. ... 494
`G. Blood to Plasma Concentration Ratio ...... .......... .. .. . ..... .. .. .. .... .. .... . .. . .. ... 502
`H. Estimation of Creatinine Clearance Under Nonsteady-State Conditions ....... 504
`
`APPENDIX II. ANSWERS TO PROBLEMS
`
`.. .. .. .. .... . .. .. . .. , .. .. .. ... ... . , . ... .. .... .. ... ..... .. 507
`
`INDEX
`
`·· -- ·-· ·--··- ·· -- ··· ··--·--··-· ·-- ·-- ·-- ·-· ··· ··· ··· ··· ···· ·· .... -... ..... ... .. .. .. ... .. .. ... .. .... ...... 586
`
`J
`
`l
`
`l
`
`8
`
`

`

`WHY CLINICAL PHARMA COKINETIC S?
`
`Those patients who suffer from chronic ailments such as diabetes and epilepsy may have
`to take drugs every day for the rest of their lives. At the other extreme are those who take
`a single dose of a drug to relieve an occasional headache. The duration of drug therapy is
`usually between these extremes. The manner in which a drug is taken is called a dosage
`regimen. Both the duration of drug therapy and the dosage regimen depend on the ther(cid:173)
`apeutic objectives, which may be either the cure, the mitigation, or the prevention of
`disease. Because all drugs exhibit undesirable effects, such as drowsiness, dryness of the
`mouth, gastrointestinal irritation, nausea, and hypotension, successful drug therapy is
`achieved by optimally balancing the desirable and the undesirable effects. To achieve op(cid:173)
`timal therapy, the appropriate "drug of choice" must be selected. This decision implies an
`accurate diagnosis of the disease, a knowledge of the clinical state of the patient, and a
`sound understanding of the pharmacotherapeutic management of the disease. Then the
`questions How much? How often? and How long? must be answered. The question How
`much? recognizes that the magnitudes of the therapeutic and toxic responses are functions
`of the dose given. The question How often? recognizes the importance of time, in that the
`magnitude of the effect eventually declines with time following a single dose of drug. The
`question How long? recognizes that a cost (in terms of side effects, toxicity, economics) is
`incurred with continuous drug administration. In practice, these questions cannot be di(cid:173)
`vorced from one another. For example, the convenience of giving a larger dose less fre(cid:173)
`quently may be more than offset by an increased incidence of toxicity.
`In the past, the answers to many important therapeutic questions were obtained by trial
`and error. The dose, interval between doses, and route of administration were selected,
`and the patient's progress followed. The desired effect and any signs of toxicity were care(cid:173)
`fully noted, and if necessary, the dosage regimen was adjusted empirically until an accept(cid:173)
`able balance between the desired effect and toxicity was achieved. Eventually, after con(cid:173)
`siderable experimentation on a large number of patients, reasonable dosage regimens were
`established (Table 1-1), but not without some regimens producing excessive toxicity or
`proving ineffective. Moreover, the above empirical approach left many questions unan(cid:173)
`swered. Why, for example, does tetracycline have to be given every 6 to 8 hours to be
`effective, while digoxin can be given once daily? Why must oxytocin be infused intrave(cid:173)
`nously? Why is morphine more effective given intramuscularly than when given orally?
`Furthermore, this empirical approach contributes little, if anything, toward establishing a
`safe, effective dosage regimen of another drug. That is, our basic understanding of drugs
`has not been increased.
`To overcome some of the limitations of the empirical approach and to answer some of
`the questions raised, it is necessary to delve further into the events that follow drug ad(cid:173)
`ministration. In vitro and in vivo studies show that the magnitude of the response is a
`function of the concentration of drug in the fluid bathing the site(s) of action. From these
`observations the suggestion might be made that the therapeutic objective can be achieved
`by maintaining an adequate concentration of drug at the site(s) of action for the duration
`
`9
`
`

`

`2
`
`WHY CLINICAL PHARMACOKINETICS?
`
`CHAPTER l
`
`of therapy. However, rarely is a drug placed at its site of action. Indeed, most drugs are
`given orally, and yet they act in the brain, on the heart, at the neuromuscular junction, or
`elsewhere. A drug must therefore move from the site of administration to the site of action.
`Simultaneously, however, the drug distributes to all other tissues including those organs,
`notably the liver and the kidneys, that eliminate it from the body.
`Figure l ~l illustrates the events occurring after a dose of drug is administered orally.
`The rate at which drug initially enters the body exceeds its rate of elimination; the con(cid:173)
`centrations of drug in blood and other tissues rise, often sufficiently high to elicit the desired
`therapeutic effects and sometimes even to produce toxicity. Eventually, the rate of drug
`elimination exceeds the rate of its absorption, and thereafter, the concentration of drug in
`both blood and tissues declines and the effect(s) subsides. To administer drugs optimally,
`therefore, knowledge is needed not only of the mechanisms of drug absorption, distribu(cid:173)
`tion, and elimination but also of the kinetics of these processes, that is, pharmacokinetics.
`The application of pharmacokinetic principles to the therapeutic management of patients
`is clinical pharmacokinetics.
`
`Table 1-1 • Empirically Derived Usual Adult Dosage Regimens of Some
`Representative Drugs Before the Introduction of Cllnical Pharmacokinetlcs0
`
`DRUG
`
`Tetracycline
`
`Digoxin
`
`INDICATED USE
`
`Treatment of Infections
`
`Amelioration of congestive
`cardiac failure
`
`ROUTE
`
`Oral
`
`Oral
`
`Oxytocin
`
`Morphine sulfate
`
`Induction and maintenance
`of labor
`Relief of severe pain
`
`Intravenous
`
`Intramuscular
`
`Oral
`
`DOSAGE REGIMEN
`
`250 mg every 6-8 hr
`
`l .5-2 mg initially over 24
`hr, thereafter 0.25-0.5
`mg once a day
`
`0.2-4 milliunits/min by
`infusion
`l O mg when needed
`Not recommended because
`of reduced effectiveness
`
`<7faken from American Medical Association: Drug Evaluations. 2nd Ed., Publishers Science Group, Acton, MA, 1973.
`
`Fig. 1-1. Plasma concentration of
`theophylline in a subject following an
`oral dose of a 600-mg controlled-re(cid:173)
`lease formulation. Before the peak is
`reached, the rate of absorption ex(cid:173)
`ceeds that of elimination. At the
`peak, the two rates are equal; there(cid:173)
`after, the rate of elimination exceeds
`that of absorption. (Redrawn from
`. Sauter, R., Steinijans, V.W., Diletti,
`E., Bohm, A., and Schulz, H.U.:
`Presentation of results in bioequival(cid:173)
`ence studies. Int. J. Clin. Pharmacol.
`Ther. Toxicol., 30:57-30, 1992.)
`
`6
`
`5
`
`:§ ,g, 4
`">, E
`..c -
`CL C:
`a3 .2 3 -
`.= '§
`Cs:l-
`E ~
`(.) 2
`~ §
`-
`0.. 0
`
`U)
`
`0
`
`0
`
`12
`
`24
`Hours
`
`36
`
`48
`
`10
`
`

`

`CHAPTER l
`
`WHY CLINICAL PHARMACOKINETICS?
`
`3
`
`The events following drug administration can be divided into two phases, a pharmaco(cid:173)
`kinetic phase, in which the adjustable elements of dose, dosage form, frequency, and route
`of administration are related to drug level-time relationships in the body, and a pharma(cid:173)
`codynamic phase, in which the concentration of drug at the site(s) of action is related to
`the magnitude of the effect(s) produced (Fig. 1-2). Once both of these phases have been
`defined, a dosage regimen can be designed to achieve the therapeutic objective. Despite
`the greater amount of information required with this approach, it has several advantages
`over the empirical approach. First, and most obvious, distinction can be made between
`pharmacokinetic and pharmacodynamic causes of an unusual drug response. Second, the
`basic concepts of pharmacokinetics are common to all drugs; information gained about the
`pharmacokinetics of one drug can help in anticipating the pharmacokinetics of another.
`Third, understanding the pharmacokinetics of a drug often explains the manner of its use;
`occasionally such an understanding has saved a drug that othe1wise may have been dis(cid:173)
`carded or has suggested a more appropriate dosage regimen. Lastly, lmowing the phar(cid:173)
`macokinetics of a drug aids the clinician in anticipating the optimaj dosage regimen for an
`individual patient and in predicting what may happen when a dosage regimen is changed.
`A basic tenet of clinical pharmacokinetics is that the magnitudes of both the desired
`response and toxicity are functions of the drug concentration at the site(s) of action. Ac(cid:173)
`cordingly, therapeutic failure results when either the concentration is too low, giving in(cid:173)
`effective therapy, or is too high, producing unacceptable toxicity. Between these limits of
`concentration lies a region associated with therapeutic success; this region may be regarded
`as a "therapeutic window." Rarely can the concentration of the drug at the site of action
`be measured directly; instead the concentration is measured at art alternative and more
`accessible site, the plasma.
`Based on the foregoing considerations, an optimal dosage regimen might be defined as
`one that maintains the plasma concentration of a drug within the therapeutic window. For
`many drugs, this therapeutic objective is met by giving an initial dose to achieve a plasma
`concentration within the therapeutic window and then maintaining this concentration by
`replacing the amount of drug lost with time. One popular and convenient means of main(cid:173)
`tenance is to give a dose at discrete time intervals. Figure 1-3 illustrates the basic features
`associated with this approach by depicting the concentrations that follow the administration
`of two regimens, A and B. The dosing interval is the same but the dose given in regimen
`B is twice that given in regimen A. Because some drug always remains in the body from
`preceding doses, accumulation occurs until, within a dosing interval, the amount lost equals
`the dose given; a characteristic saw-toothed plateau is then achieved. With regimen A,
`
`Pharmacokinetics
`
`Plasma
`Dosage
`Concen-
`Regimen ~
`tration
`
`Pharmacodynam ics
`.--------
`Site
`of
`I Action
`
`Effects
`
`I
`I
`I
`I
`
`I , ________ -
`
`+
`..... ____________ /
`
`I
`
`I
`I
`I
`I
`I
`
`I
`I
`I
`I
`I
`..... _ - - - - _ ..... - - - __ 1
`
`Fig. 1-2. An approach to the design of a dosage regimen. The pharmacokinetics and the pharmacodynamics of
`the drug are first defined. Then, either the plasma drug concentration-time data or the effects produced are used
`via pharmacokinetics as a feedback (dashed lines) to modify the dosage regimen to achieve optimal therapy.
`
`11
`
`

`

`4
`
`WHY CLINICAL PHARM4COKINETICS?
`
`CHAPTER l
`
`several doses had to be given before drug accumulation. was sufficient to produce a ther(cid:173)
`apeutic concentration. Had therapy been stopped before the,n, the drug might have been
`thought ineffective and perhaps abandoned prematurely. Alternatively, larger doses might
`have been tried, e.g., regimen B. Although a therapeutic response would have been
`achieved fairly promptly, toxicity would have ensued with continued administration when
`the concentration exceeded the upper limit of tl1e therapeutic window.
`The synthetic antimalarial agent, quinacrine, developed during World War II to substi(cid:173)
`tute for the relatively scarce quinine, is an example. Quinacrine was either ineffective
`acutely against malaria or eventually produced unacceptable toxicity when a dosing rate
`sufficiently high to be effective acutely was maintained. Only after its pharmacoldnetics
`had been defined was this drug used successfully. Quinacrine is eliminated slowly and
`accumulates extensively with repeated daily administration. The answer was to give large
`doses over the first few days to rapidly achieve therapeutic success, followed by small daily
`doses to maintain the plasma concentration within the therapeutic window.
`The plateau situation in Fig. 1-3 shows that both the width of the therapeutic window
`and the speed of drug elimination govern the size of the maintenance dose and the fre(cid:173)
`quency of administration. When the window is narrow and the drug is eliminated rapidly,
`small doses must be given often to achieve therapeutic success. Both cyclosporine and
`digoxin have a narrow therapeutic window, but because cyclosporine is eliminated much
`more rapidly than digoxin, it has to be given more frequently. Oxytocin is an extreme
`example; it also has a narrow therapeutic window but is eliminated within minutes. The
`only means of adequately ensuring a therapeutic concentration of oxytocin therefore is to
`infuse it at a precise and constant rate directly into the blood. This degree of control is not
`possible with other modes of administration. Besides, had oxytocin been given orally, this
`polypeptide hormone would have been destroyed by the proteolytic enzymes in the gas(cid:173)
`trointestinal fluids. Morphine, given orally, is also destroyed substantially before entering
`the general circulation, but for a reason different from that of oxytocin. Morphine is ex(cid:173)
`tensively metabolized on passage through the liver, an organ lying between the gastroin(cid:173)
`testinal tract and the general circulation.
`Awareness of the benefits of understanding pharmacokinetics and concentration-re(cid:173)
`sponse relationships has led in recent years to the extensive application of such information
`by the pharmaceutical industry to drug design, selection, and development. For example,
`a potent compound found to be poorly and unreliably absorbed and intended for oral
`administration may be shelved in favor of a somewhat less potent but more extensively and
`reliably absorbed compound. Also, many of the basic processes controlling both pharma(cid:173)
`cokinetics and response are similar across mammalian species such that data can be ex(cid:173)
`trapolated from animals to predict quantitatively the likely behavior in humans. This quan-
`
`Fig. 1-3. When a drug is given in
`a fixed dose and at fixed time inter(cid:173)
`vals (denoted by the arrows), it ac(cid:173)
`cumulates within the body until a
`plateau is reached. With regimen A,
`therapeutic success is achieved al(cid:173)
`though not initially. With regimen B,
`the therapeutic objective is achieved
`more quickly, but the plasma drug
`concentration is ultimately too high.
`
`C:
`0
`~ Regimen B
`
`1-------~
`
`,~--+ + ¥
`
`Therapeutic
`Failure
`
`Therapeutic
`Success
`
`}
`
`Therapeutic
`Failure
`
`..... -----· ... --- .-----
`
`Time
`
`12
`
`

`

`CHAPTER l
`
`WHY CLINICAL PHARMACOKINETICS?
`
`5
`
`titative framework improves the chances of selecting not only the most prom1smg
`compounds but also the correct range of safe doses to first test in humans. Incorporation
`of a pharmacokinetic element with these early Phase I studies, usually in healthy subjects,
`together with assessment of any side effects produced, helps to define candidate dosage
`forms and regimens for evaluation in Phase II studies conducted in a small number of
`patients. These Phase II studies are aimed at defining the most likely safe and efficacious
`dosage regimens for use in the subsequent larger Phase III clinical trials, often involving
`many thousands of patients. Ultimately, some compounds prove to be of sufficient benefit
`and safety to be approved for a particular clinical indication by drug regulatory authorities.
`Even then the drug undergoes virtually continuous postmarketing surveillance to further
`refine its pharmacotherapeutic profile. This sequence of events in drug development and
`evaluation is depicted schematically in Fig. 1-4.
`Figure 1-5 illustrates an important problem identified during drug development and
`therapy, variability. There is a wide range of daily dose requirements of the oral antico-
`
`PRECLINICAL
`TESTING
`
`CLINICAL (HUMAN) TESTING
`Dose (Cone)
`Population PK/PD
`Response Trials
`Characteristics in
`Large Efficacy Trials
`<=
`=>
`PK/PD in Special
`Populations
`
`Post(cid:173)
`Marketing
`Surveillance
`
`L'.:r=v PK-guided ?7 ~ ~
`
`Efficacy
`Dose escalation
`In vitro PK/PD
`Safety ~ Dosage
`Animal PK/PD
`C::::;7 Assessment
`Selection
`
`Toxicity
`
`Animal Testing
`
`,____P_ha_s_e _I _ )
`
`Patient Variables
`
`)
`Phase II
`~ - -~ , ~ -P-ha_s_e1_11_ )
`
`Fig. 1-4. The development and subsequent marketing of a drug. The prehuman data helps to identify promising
`compounds and to suggest useful doses for testing in humans. Phases I, II, and III of human assessment generally
`correspond to the first administration to humans, early evaluation in selected patients, and the larger trials,
`respectively. Pharmacokinetic (PK) and pharmacodynamic (PD) data gathered during all phases of drug devel(cid:173)
`opment help to efficiently define safe and effective dosage regimens for optimal individual use. Postmarketing
`surveillance helps to refine the PK/PD information.
`
`Fig. 1-5. The daily dose of warfarin required to produce similar
`prothrombin times in 200 adult patients va1ies widely. (1 mg/L =
`3.3 µM). (Redrawn from Koch-Weser, J.: The serum level ap(cid:173)
`proach to individualization of drug dosage. Eur. J. Clin. Pharma(cid:173)
`col. 9:1-8, 1975.)
`
`(/) 25
`C
`0
`~ 20
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`
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`
`13
`
`

`

`6
`
`WHY CLINICAL PHARMACOKINETICS?
`
`CHAPTER l
`
`agulant warfarin needed to produce a similar prothrombin time (an index of blood coag(cid:173)
`ulability). Sources of variability in drug response include the patient's age, weight, degree
`of obesity, type and degree of severity of the disease, the patient's genetic makeup, other
`drugs concurrently administered, and environmental factors. The re.sult is that a standard
`dosage regimen of a drug may prove therapeutic in some patients, ineffective in others,
`and toxic in still others. The need to adjust the dosage regimen of a drug for an individual
`patient is evident; this need is clearly greatest for drugs that have a narrow therapeutic
`window, that exhibit a steep concentration-response curve, and that are critical to drug
`therapy. Examples are digoxin, used to treat some cardiac disorders; phenytoin, used to
`prevent epileptic convulsions; theophylline, used to diminish chronic ahway resistance in
`asthmatics; and cyclosporine, an immunosuppressant used in organ transplantation. With
`these drugs, and with many others, variability in pharmacokinetics is a major source of total
`variability in drug response.
`It is becoming increasingly common to gain as much information on variability as pos(cid:173)
`sible during drug development by gathering, albeit limited, individual plasma concentration
`and response data in a large population of patients during Phase III clinical trials. Attempts
`are then made to account for this variability in terms of such patient characteristics as age
`and weight. These population pharmacokinetic/pharmacodynamic studies form a basis for
`dosage regimen recommendations in clinical practice.
`Coadministration of several drugs to a patient, prevalent in clinical practice, can pose
`problems. Although the response produced by each drug alone may be predictable, that
`produced by the combination may be less certain and occasionally unpredictable. Keto(cid:173)
`conazole, for example, devoid of immunosuppressant activity, potentiates the effect of
`cyclosporine. Possible causes of this kind of effect are many. In this instance, as in many
`others, the interaction involves a change in pharmacokinetics. Some drugs stimulate drug-
`
`Fig. 1-6. Although the average plateau plasma
`concentration of phenytoin tends to increase with
`the dosing rate, there is considerable variation in
`the individual values. (One mg/L = 3.97 µM.) (Re(cid:173)
`drawn from Lund, L.: Effects of phenytoin in pa(cid:173)
`tients with epilepsy in relation to its concentration
`in plasma. In Biological Effects of Drugs in Relation
`to Their Plasma Concentration. Edited by D.S. Da(cid:173)
`vies and B.N.C. P1ichard, Macmillan, London and
`Basingstoke, 1973, pp. 227- 238.)
`
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`E -C
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`
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`
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`
`5
`10
`Daily Dose (mg/kg)
`
`15
`
`14
`
`

`

`CHAPTER l
`
`WHY CLINICAL PHARMACOKINETICS?
`
`7
`
`metabolizing enzymes and hasten drug loss; others inhibit these enzymes and slow elimi(cid:173)
`nation. Still others interfere with drug absorption. Such interactions are graded; the change
`in the pharmacokinetics of a drug varies continuously with the plasma concentration of the
`interacting drug and hence with time. Indeed, given in sufficiently high doses, almost any
`drug can interact with another. It is always a question of degree. Understanding the quan(cid:173)
`titative elements of interactions ensures the more rational use of drugs that may need to
`be coadministered.
`Figure 1-6 illustrates a situation in which monitoring of the drug concentration may be
`beneficial. Over the narrow range of the daily dose of the antiepileptic drug phenytoin, the
`plateau plasma drug concentration varies markedly within the patient population. Yet the
`therapeutic window ofphenytoin is narrow, 7 to 20 mg/L; beyond 20 mg/L, the frequency
`and the degree of toxicity increase progressively with concentration. Here again, pharma(cid:173)
`cokinetics is the major source of variability. A pragmatic approach to this problem would
`be to adjust the dosage until the desired objective is achieved. Control on a dosage basis
`alone, however, has proved difficult. Control is achieved more readily and accurately when
`plasma drug concentration data and the pharmacokinetics of the drug are known.
`Drug selection and therapy have traditionally been based solely on observations of the
`effects produced. In this chapter, the application of pharmacokinetic principles to decision
`making in drug therapy has been illustrated. Both approaches are needed to achieve optimal
`drug therapy. This book emphasizes the pharmacokinetic approach. It begins with a con(cid:173)
`sideration of kinetic concepts basic to pharmacokinetics and ends with a section containing
`selected topics.
`
`I
`.~
`
`i I
`I
`I I
`I
`I
`
`15
`
`

`

`', L·~;:~·:
`.......... , . ~ .. ~
`
`2
`
`BASIC CONSIDERATIONS
`
`OBJECTIVES
`
`The reader will be able to:
`
`l. Define the follow ing terms:
`Pharmacokinetics, intravascular and extravascular administration, absorption, dispo·
`sition , distribution , metabolism, excretion, first-pass effect, enterohepatic cycling, com(cid:173)
`partment
`
`2 . Discuss the limitations to interpretation of pharmacokinetic data imposed by assays that fa il
`to distinguish between compounds administered (e.g ., R- and S·isomers) or between drug
`and metabolite.
`
`3. Show the general contribution of mass balance concepts to drug absorption and drug and
`metabolite disposition.
`
`Pharmacoldnetics has many use