third edition
`
`Concepts and Applications
`
`
`
`MALCOLM ROWLAND
`
`THOMAS N. TOZER
`
`Apotex v. Novartis
`lPR2017-00854
`
`NOVARTIS 2105
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2105
`
`1
`
`

`

`
`
`Clinical Pharmacokinetics
`
`Concepts and Applications
`
`third edition
`
`MALCOL/Vl ROWLAND, Ph . D.
`
`Department of Pharmacy
`
`University of Manchester
`
`Manchester, England
`
`THOMAS N. TOZER, PhD.
`
`School of Pharmacy
`
`University of California
`
`San Francisco, California
`
`A Lea & Febiger Book
`
`fib LIPPINCOTT WILLIAMS e \X/lLKlNS
`' A Wolten Kluwer Company
`Philadelphia . Baltimore . New York - London
`Buenos Alres . Hong Kong . Sydney . Tokyo
`
`2
`
`

`

`AV;V
`
`V '
`
`-
`‘
`do
`.
`Executne Editor. Donna Bala
`Developmental Editors: Frances Klass. Lisa Stead
`qer: Laurie Forsyth
`Production Mona
`Project Editor.- Robert D. Magee
`
`Copyright © 1995
`Lippincott Williams & \Vllkins
`530 Walnut Street
`Philadelphia, Pennsylvania 19106-3621 USA
`
`
`
`pyright. No part of this book may be reproduced in any
`All rights reserved. This book is protected by CO or utilized by any information storage and retrieval system
`form or by any means, including photocopying,
`without written permission 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
`
`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 0-683-07404-0
`1. Pharmacokinetics
`11. Title.
`[DNLM-. 1. Pharmacokinetics
`RM301.5.R68
`1994
`615.7—dc20
`DNLM/DLC
`
`~
`
`-
`2 Chemoth
`
`.
`
`e a
`r W
`
`1- Tozer. Thomas N.
`
`2
`
`'
`
`"Drug Therapy'
`
`QV 38 R883c1994]
`
`for Library of Congress
`
`94-26505
`CIP
`
`7799 Publishers have m d
`adve
`a e every effort to trace the copyright holdersfor borrow d
`l f b
`b
`.
`e materia . I t ey We m—
`tb/
`l
`I
`.
`over oo/eed any hey w be 0 eased 0 make be necessary arrangements (1
`e
`75
`rten
`
`i
`
`04
`
`78910
`
`3
`
`

`

`
`
`CONTENTS
`
`............................................................................ xi
`Definitions of Symbols
`1 . Why Clinical Pharmacokinetics?
`............................................................... 1
`
`SECTION I. ABSORPTION AND DISPOSITION KINETICS
`2. Basic Considerations
`......................................................................... 1 1
`3.
`Intravenous Dose ............................................................................... 18
`4. Extravascular Dose ............................................................................ 34
`
`SECTION II.
`THERAPEUTIC REGIMENS
`5. Therapeutic Response and Toxicity ........................................................ 53
`(D. Constant-Rate Regimens ...................................................................... ()0
`7. Multiple-Dose Regimens ...................................................................... 83
`
`PNYSIOLOGIC CONCEPTS AND KINETICS
`SECTION III.
`8. Movement Through Membranes
`......................................................... 109
`9. Absorption ..................................................................................... 119
`10. Distribution
`.................................................................................... 137
`1 1. Elimination ..................................................................................... 156
`12.
`Integration With Kinetics
`................................................................... 184
`
`INDIVIDUALIZATION
`SECTION IV.
`13. Variability ...................................................................................... 203
`14. Genetics
`....................................................................................... 220
`15. Age and Weight
`............................................................................ 230
`16. Disease ......................................................................................... 248
`17.
`Interacting Drugs
`............................................................................. 267
`18. Concentration Monitoring ................................................................. 290
`
`SELECTED TOPICS
`SECTION V.
`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 Hall-lite From Urine Data .................................. 473
`
`ix
`
`4
`
`

`

`x
`
`CONTENTS
`
`......i...... 478
`C. Estimation 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 ll. ANSWERS T0 PROBlEMS ......................................................... 507
`
`INDEX ......................................................................................................... 58b
`
`5
`
`

`

`as...
`
`..
`
`f
`
`‘(
`
`WHY CLINICAL PHARMACOKINETICS?
`
`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-
`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—
`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-
`vorced from one another. For example, the convenience of giving a larger dose less fre-
`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 fOIIOWed. The desired effect and any signs of toxicity were care-
`fully noted, and if necessary, the dosage regimen was adjusted empirically until an accept—
`able balance between the desired effect and toxicity was achieved. Eventually, after con—
`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-
`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-
`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-
`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
`
`6
`
`

`

`WHY CtINICAL PHARMACOKINETICS
`
`2
`
`CHA
`
`PTER I
`
`1e
`
`1
`
`'
`
`-
`
`'
`
`'
`
`ration to the site 0 .
`
`_
`
`.
`
`nnu aneo .
`
`. .
`
`.
`
`'
`
`'
`
`'
`
`'
`
`m the bod .
`
`at its site of action. Indeed, most drugs are
`.
`_
`'
`.
`-
`l
`laced
`of therapy. However. rarely is atldl'tlfr-En on the heart, at the neuromuscular lunchon, 0r
`‘ t thev act in
`,
`'
`'
`'
`'
`glven orally. and ye
`J
`l
`l
`A dru must therefore move from the Slte Ofladfiltnslfltes includjng thOSefGale“.
`3881:ere- uslv filowever
`the dmg distributes to all 0t ler lS
`Organs,
`notably the liver and the kidneys, that elunmate 1t frod se of drylg is administered or 11
`Figure 1—1 illustrates the events occurring after a 0
`a y_
`,
`.
`.
`.
`bod exceeds its rate of elimination; the Con.
`ElirhfiznZtof’lllfilgiglohndilhlcllyoillgrtl5:131;as;oftenStifficieéitlylligijllto(5111?:thedFsired
`therapeutic effects and sometimes even to produce tonglty. thfgolicefitrafio:(if: drug
`elimination exceeds the rate of its absorption, and therea ter,
`d _
`. t
`d
`.I’Ug In
`both blood and tissues declines and the efffecltfsl Sllb}::i:-m:00: deIgHZESI‘or-Stliisnogfifiggl
`32::eigfellllrllllzliggnefiitn:1; ofthe lantics ofthese processes: that IS, phamcpkmetics.
`'
`dednot on
`o t emec
`.
`.
`-
`,
`
`The application of pharmacokinetic principles to the therapeutic management 0 Patlents
`is clinical phamwcokinetics.
`
`Table 1-1 . Empiricully Derived Usual Adult Dose 0 ll. imons of Some
`Roprosonlullvo Drugs Before "l0 Inmduciion of C inica Pharmacokinolics-
`DRUG
`INDICATED USE
`ROUTE
`DOSAGE REGIMEN
`Tetracycline
`Treatment of infections
`Oral
`250 mg every 6-8 hr
`Digoxin
`Amelioration of congestive
`Oral
`l .5—2 mg initially over 24
`cardiac failure
`hr, thereafter 025-05
`mg once a day
`Intravenous
`induction and maintenance
`0.2-4 milliunits/min by
`of labor
`infusion
`Intramuscular
`Relief of severe pain
`lO mg when needed
`OFGl
`Not recommended because
`0 reduced effectiveness
`”Taken from American Medical Association: Drug Evaluations. 2nd Ed, Publishers Science Group, Acton MA 1973
`
`Oxyiocin
`Morphine sulfate
`
`6
`
`5
`
`Fig. 1—1. Plasma concentration of
`theophylline in a subject following an
`oral dose of a GOO-mg controlled-re-
`lease formulation. Before the peak is
`reached, the rate of absorption ex-
`ceeds that of elimination. At the
`a) A
`peak, the two rates are equal; there- E S,
`after, the rate ofelimination exceeds 3 E
`that of absorption. (Redrawn from
`8" E
`Sauter, R., Steinijans, V.W., Diletti, 3 log
`E., Bohm, A., and Schulz, H.U.:
`'— g
`Presentation ofresults in bioequival-
`E 5
`ence studies. Int. ], Clin. Pharmacol.
`g g 2
`Ther. Toxicol., 305740, 1992.)
`CT- 8
`
`4
`
`3
`
`l
`
`0
`
`0
`
`12
`
`24
`Hours
`
`36
`
`43
`
`7
`
`

`

`CHAPTER 1
`
`WHY CLINICAL PHARMACOKINETICS?
`
`3
`
`The events following drug administration can be divided into two phases, a pharmaco-
`kinetlc 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-
`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 otherwise may have been dis-
`carded or has suggested a more appropriate dosage regimen. Lastly, knowing the phar—
`macokinetics of a drug aids the clinician in anticipating the optimal 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-
`cordingly, therapeutic failure results when either the concentration is too low, giving in—
`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 an 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—
`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
`
`Pharmacodynamics
`
`Dosage
`
`Plasma
`Concen-
`tration
`
`Regimen
`
`Fig. 1—2. An approach to the design of a dosage regimen. The phammcokinetics and the phamlacodmamics of
`the drug are first defined. Then, either the plasma drug concentration-time data or the effects produced are used
`via phannacoldnetics as a feedback (dashed hues) to modify the dosage regimen to achieve optimal therapy.
`
`8
`
`

`

`4
`
`WHY CLINICAL PHARMACOKINET
`
`ICSZ
`
`CHAR“)
`
`I
`
`- nt to produCe a th J
`.
`ulatlon was suffime
`.
`Cr.
`several doses had to be given before drug accum
`then, the drug mlght have been
`ed before
`-
`apeutic concentrationaHadltherZIIZZ’IIEJSSSeZtZIgmaturely. AltematJvely, larger doses might
`thought ineffective an per laps
`'
`onse would haVe b
`.
`h a therapeutlc resp
`.
`.
`.
`66“
`if
`e. “ re men BI Althoug
`‘
`tinued admlnlstratlonW
`Ezhfievlefiefaillyegromitly, gxicitv would have ensued W'ltll con
`hen
`.
`.
`/ a
`the concentration exceeded the upper 'hmlligfatld:$l:rped during World War II to substi-
`The synthetic antimalarial agent, qumac
`,
`.
`-
`was either ineffecti
`I
`’
`‘
`'
`z
`example. Qulnacrme
`Ve
`.
`th
`relatlvel
`scarce quinine, IS in
`.
`.
`h n a
`_
`tute for
`?
`al y or eventually produced unacceptable tox101ty w e
`dOSIng rate
`acutely against m aria
`ned. Only after its pharmacokmetics
`‘
`'
`as maintai
`.
`.
`'
`sufficrently high to be effective acutely W
`Quinacl‘ine is ehmmated slowly and
`'
`full
`.
`h d b
`d fined was this drug used success
`.
`'
`.y
`adcumzelgteseextensively with repeated daily admimstratlon. 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 ther-aIEEUtfi$132:- eutic
`. d
`The plateau situation in Fig. 1—3 shows that both the w1d . 0
`e
`d P
`d :th fpw
`and the speed of drug elimination govern the size of the maintenance l.Os'e and e. e-
`quency of administration. When the window is narrow and the drug IS e 1m11nate
`rapidly,
`small doses must be given often to achieve therapeutic success. .Both cyc osporine and
`digoxin have a narrow therapeutic window, but because cyclosporine lS 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 mthln mlnutes. The
`only means of adequately ensuring a therapeutic concentration of oxytocm 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-
`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-
`tensively metabolized on passage through the liver, an organ lying between the gastroin-
`testinal tract and the general circulation.
`Awareness of the benefits of understanding pharmacokinetics and concentration—r6-
`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.
`
`concentration is ultimately too high.
`
`Fig. 1-3. When a drug is given in
`a fixed dose and at fixed time inter-
`vals (denoted by the arrows), it ac-
`cumulates within the body until a
`plateau is reached. With regimen A
`therapeutic success is achieved al:
`though not initially. With regimen B
`the therapeutic objective is achieved
`more quickly, but the plasma dmg
`
`9
`
`

`

`CHAPTER I
`
`WHY CLINICAL PHARMACOKINETICS?
`
`5
`
`titative framework improves the chances of selecting not only the most promising
`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
`
`Toxicity
`
`
`CLINICAL (HUMAN) TESTING
`Dose (Conc)
`Population PK/PD
`Post-
`Response Trials
`Characteristics in
`Large Efficacy Trials
`.
`4:9 PK-guided fl [LIII
`<2 Market“
`In vitro PK/PD
`Dose escalation
`Efficacy
`:> Surveillance
`Animal PK/PD
`Safety
`Dosage
`Q37 Assessment
`Selection
`Patient Variables
`
`IZZ>
`PK/PD in Special
`POpulatlons
`
`Animal Testing
`
`I
`
`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 1, 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-
`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 ofwarfarin required to produce similar
`prothrombin times in 200 adult patients varies widely. (1 mg/L =
`3.3 pM). (Redrawn from Koch-Weser, ].: The serum level ap-
`proach to individualization of drug dosage. Eur. ]. Clin. Pharma-
`co]. 9:1—8, 1975.)
`
`
`
`Qééwémmmwmm
`VT??? Twweg
`NC‘OV‘LD nobdaéA
`
`Daily Dose (mg)
`
`10
`
`m 25
`g
`1g 20
`E
`§ 15
`
`O “
`
`5 10
`
`5
`
`E e
`
`a.)
`m
`
`10
`
`

`

`5
`
`WW am am “Vii/Hf]? 57632
`
`ME? 1
`
`agulant warfarin needed to roducc a similar prothromhin time/an, index of hlood mag.
`ulabilitv). Sources of variability in dmg resptmsc include the patient 3 age, Wight degree
`of obesity. tvpe and degree of severity of the disease. the patient 3 genetic rlrli
`eup, 0th“
`drugs concurrently administered, and environmental factms. The resnlt 13 t at a standaJ-d
`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 indmdUa]
`patient is evident; this need is clearly greatest for drugs that have a narrow Ithe‘W’GUtic
`window, that exhibit a steep concentratitm—resymse curve, and that are critical to drug
`therapy. Examples are digoxin, used to treat some cardiac disorders; W011! used to
`prevent epileptic convulsions; theophylline, used to diminish chronic airway resistance in
`asthmatics; and cyclosporine, an immunosuppressant used In organ transplantation With
`these drugs, and with many others, variability in pharmacoldnetlcs Is a major source of total
`variabilityindru re
`use.
`'
`..
`It is becoming in:ll')(:)asingly common to gain as much information on vanablllty as P05-
`sible during drug development by gathering, albeit limited, individual plasma concentratio“
`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 phannacoldnetidphannacodynamic 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 ocmsionally unpredictable. Ketc—
`conazole, for example, devoid of immunosuppressant activitv, 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 pharmacoldnetics. 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 pM.) (Re-
`drawn from Lund. L: Eflects of phenytoin in pa-
`tients with epilepsy in relation to its concentration
`in plasma. In Biological Eflects of Drugs in Relation
`to Their Plasma Concentration. Edited by D.S, Da-
`vies and B.;\’.C. Prichard. Macmillan, London and
`Basingstoke, 1973, pp. 227—238.)
`
`11
`
`50
`
`‘5
`
`(mg/L)
`
`
`PlasmaPhenytoinConcentration
`
`B8
`
`_s 0
`
`11
`
`

`

`WHY CLINICAL PHARMACOKINETICS?
`
`7
`
`be coadministered.
`Figure]: 10—6 lllufitrates a Situation in which monitoring of the drug concentration may be
`bene C1
`' vert e narrow range 0f the daily dose of the antiepileptic drug phenytoin, the
`plateau plasma drug concentration varies markedly within the patient population. Yet the
`therapeuth WlndOW of phenytoin is narrow, 7 to 20 mg/L; beyond 20 mg/L, the frequency
`and the. degree 0f tOXiCity increase progressively with concentration. Here again, pharma-
`cokinetlcs 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-
`sideration of kinetic concepts basic to pharmacokinetics and ends with a section containing
`selected topics.
`
`12
`
`12
`
`

`

`
`
`THERAPEUTIC RESPONSE AND TOXICITY
`
`OBJECTIVES
`
`The reader will be able to:
`
`I . Explain why effect (desired or toxic) of a drug is often better correlated with plasma con'
`centration than with dose.
`
`2. Define the terms: graded response, all-or-none response, therapeutic concentration range,
`utility curve, and tolerance.
`3. List the range of plasma concentrations associated with therapy for any of the drugs given
`in Table 5—2.
`
`4. Discuss briefly situations in which poor plasma drug concentration—response relationships
`are likely to occur.
`5. Explain briefly why modality of administration of a given daily dose can affect therapeutic
`outcome.
`
`The rational design of safe and efficacious dosage regimens is now examined. In this section,
`fundamental aspects of dosage regimens are covered primarily from the point of view of
`treating a patient population with a given disease. It is realized, of course, that individuals
`vary in their responses to drugs, and subsequently, in Section Four, focus is turned toward
`the establishment of dosage regimens in individual patients.
`A therapeutic dosage regimen is basically derived from the kinds of information shown
`in Table 5—1. One consideration includes those factors that relate to both efficacy and
`safety of the drug, that is, its pharmacodynamics and toxicology. Another consideration is
`how the body acts on the drug and its dosage form, the essence of pharmacokinetics. A
`third consideration is that of the clinical state of the patient and his or her total therapeutic
`regimen. A fourth category includes all other factors such as genetic differences, tolerance,
`and drug interactions. All of these determinants are, of course, interrelated and interde—
`pendent.
`Dosage regimens are designed to produce a therapeutic objective. This objective may
`be achieved by various modalities of drug administration, extending from a single occasional
`dose to continuous and constant input. An example of the former is the use of aspirin to
`treat an occasional headache; the continuous iv. infusion of heparin to maintain a desired
`degree of anticoagulation is an example of the latter. More commonly, drugs are admin-
`istered repeatedly in discrete doses. The frequency and duration vary with the condition
`being treated. Some drugs are administered relatively infrequently, producing large fluc—
`tuations in the plasma concentration. Reasons for this approach include the development
`of tolerance to the drug and the need to produce high concentrations for short periods of
`time, as occurs in some antibiotic and anticancer chemotherapies. In other situations, main—
`
`53
`
`13
`
`13
`
`

`

`54
`
`THERAPEUTIC RESPONSE AND
`
`IOXILH Y
`
`C H
`
`“Pitts
`
`Pts are
`
`eded. In all cases, attem
`'
`.
`‘ tion of drug ‘5 ne
`‘neffectlve thera
`.
`' el
`(30115“:Int concentra
`23:32:: Omfihirriliivungesirable and toxic effects and prevent l
`py
`lasma concentr
`,
`‘
`'
`Evidence exists that response is often better correlated With P
`at1011 than
`.
`-
`to be most appropriate to aPpl
`with dose administered. Accordingly, 't would seerrrthens. Thus, given pharmacokineli phat
`macoldnetic principles to the design ofdos:g:fi1:nglor amount of drug in the body fol]
`.
`_
`1 d e, the lasma concen
`$30525;:(lllllirie(:m be egtimated. Ultimately, however, thce; vaél‘tiie1:);:ngfglfi reglmen
`0 nehcs fa.
`must be assessed by the therapeutic and toxic responses pro uc
`.
`‘
`cilitates the achievement of an approprlate dosage reglmen and se
`useful
`mEans
`of evaluatin existin dosa e regimens.
`.
`.
`.
`In this chapter gariousg elements of the concentration—response relationship are ex-
`plored. Principles for attaining and maintaining a therapeutic level 0f drug in the body are
`discussed in the subsequent two chapters of this SCCUOH-
`
`(Min
`.
`
`g
`
`.
`rves as a
`
`RESPONSE AND CONCENTRATION
`
`Response may be as vague as a general feeling of improvement or as prec15e as a lowering
`of the diastolic blood pressure by 30 mm Hg.
`.
`.
`Information relating concentration to response is obtained at three levels: m mtro ex-
`periments, animal studies, and investigations in human volunteers and patients. The last
`level is the most relevant to human drug therapy but, unfortunately, only limited infor-
`mation is often obtainable here about the nature of the drug—receptor interaction. In vitro
`experiments, which include studies of the action of drugs on enzymes, receptors, micro-
`organisms, and isolated tissues and organs, serve this purpose best. However, in isolating
`the variables, many of the complex interrelationships that exist in vivo are destroyed. An-
`imal studies bridge much of the gap between in vitro experimentation and human inveS-
`tigation. Studies in animals introduce both the variable time, with all that it connotes, and
`
`Table 5-1 . Dolomincnh of a Dos-go Regimen
`
`ACTTVTWOXTCIW
`PHARMACOKINET‘CE
`Therapeutic window
`Absorption
`glde ifeds
`Distribution
`OXICI
`Metabolism
`Concentration—response relationships
`Excretion
`
`
`
`CllNlCAl FACTORS
`
`MANAGEMENT
`STATE OF PATIENT
`OF THERAPY
`
`A e, we,- h,
`. W
`anditiongbein treated
`MUlhple~drug therapy
`R
`t
`t d '
`islration
`E .
`t
`t
`Convenience ot regimen
`oueo 0 min
`hQ d'
`XlS ence a at er
`Isease states
`Compliance of patient
`golsage Loam
`d
`ce
`epen en
`oeranc
`PhcrmOCogenetics-idiosyncroSY
`DrUg interactions
`
`14
`
`14
`
`

`

`CHAPTER 5
`
`THERAPEUTIC RESPONSE AND TOXICITY
`
`55
`
`the elements of absorption and disposition as well as the feedback control systems that
`operate to maintain homeostasis. Animal studies are often most useful for evaluating the
`pliannacologic spectrum of activity of a potential therapeutic agent and for determining
`aspects 0f its tOXiCity profile. Irrespective of the level of information, however, the conclu-
`sion is the same: A relationship, although sometimes complex, exists between the concen-
`tration of active agent at the site of measurement and the response.
`The majority of drugs used clinically act reversibly in that the effect is reversed upon
`reducing concentration at the site of action. Many responses produced are graded, so called
`because the magnitude of the response can be scaled or graded. An example of a graded
`response, shown in Fig. 5—1, is the improvement of pulmonary function produced by the
`bronchodilator terbutaline, after its s.c. administration. The intensity of the response varies
`with the drug concentration in plasma. Many other pharmacologic and toxic responses do
`not occur on a continuous basis; these are known as quantal or all-or-none responses. An
`obvious but extreme example is death. Another is the suppression of an arrhythmia. The
`arrhythmia either is or is not suppressed. Sometimes, a limit is set on a graded response
`below which an effect is said not to occur clinically. For example, a potentially toxic effect
`of antihypertensive therapy is an excessive lowering of blood pressure. The lowering of .
`blood pressure produced by the antihypertensive agents is a graded response, but hypo—
`tensive toxicity is said to occur only if the blood pressure falls to too low a value. Here the
`clinical endpoint is all-or-none, but the pharmacologic response is graded.
`Returning to terbutaline, Fig. 5~1 is a plot of the fo