`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
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`
`
`Clinical Pharmacokinetics
`Concepts and Applications
`
`third edition
`
`MA.LCOLM ROWLAND, Ph.D.
`Department of Pharmacy
`University of Manchester
`Manchester, England
`
`THOMAS N. TOZER, Ph.D.
`School of Pharmacy
`University of California
`San Francisco, California
`
`A Lea & Febiger Book
`
`Williams & Wilkins
`
`BALIIMORE • PHilADELPHIA • HONG KONG
`lONDON • MUNICH • SYDNEY • TOKYO
`A WAVE RLY COMPANY
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`Executive Editw·: Donna Balado
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`Project Editor: Robert D. Magee
`
`Copyright © 1995
`Williams & Wilkins
`Rose Tree Corporate Center
`1100 North Providence Road
`Building IT, Suite 5025
`Media, PA 19063-2043 USA
`
`All rights reserved. This book is protected by copyright. No patt 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 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 n:~ader 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 an d applications I Malcolm
`Rowland, Thomas N. Tozer. - 3rd eel.
`em.
`p.
`"A Lea & Fcbiger Book."
`Includes bibliographical references and index.
`ISBN 0-683-07104-0
`1. Phannacokinetics. 2. Chemotherapy.
`ll. Title.
`IDNL.l\1: 1. Pharmacokinetics. 2. Drug Therapy.
`RM301.5.R68
`1994
`615.7-clc20
`DmM/ DLC
`for Library of Congress
`
`I. Tozer, Thomas
`
`QV 38 R883c 1991]
`
`94-26305
`ClP
`7be Publishers have made every ef!ort to trace the copyright holders for borrowed material. If they have in-
`advertently overlooked any, they will be pleased to make tbe necessmy an·angemenls at the .first opportunity.
`
`Reprints of cl1apters may be purchased from Williams & Wilkins in quantities of 100 or more. Call
`Isabella Wise, Special Sales Department, (BOO) 358-3583.
`
`96 97 98
`2 3 4 5 6 7 8 9 10
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`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 exb·eme are those who take
`a single dose of a drug to relieve ao occasional headache. The duration of drug therapy i'>
`usually between these exhemes. The manner in which a drug is taken is called a dosage
`regim.en. 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 appropliate "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 djsease. Then the
`questions How much? How often? and How long? must be answered. The question Hm.v
`much? recognizes that the magnitudes of the therapeutic and toxic responses m·e 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 m1other. 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 tlial
`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-
`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 expe1irn.entation on a large number of patients, reasonable dosage regimens \·Ver e
`established (Table 1-1), but not without some regimens producing excessive toxicity or
`proving ineflective. Moreover, the above empirical approach left many questions unan-
`S\Vered. Why, for example, docs 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? vVhy 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 batl1ing the site(s) of action. From these
`observations the suggestion might be made that tl1e therapeutic objective can be achieved
`by maintaining an adequate concentration of drug at the site(s) of action for the duration
`
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`CHAPTER l
`
`WHY CLINICAL PHARMACOKINETICS?
`
`2
`of therapy. However, rarely is a drug placed at its site of action. IndeP.d, 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 1-1 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-
`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 tl1ereafter, the concentration of dmg in
`both blood and tissues declines and the effect(s) subsides. To administer drugs optimally,
`d1erefore, knowledge is needed not only of the rnecbanisms of drug absorption, distribu-
`tion, and elimination but also of the kinetics of these processes, that is, pharmacokinetics.
`The application of pharmacokinetic principles to tl1e therapeutic management of patients
`is clinical pharmacokinetics.
`
`DRUG
`Tetracycline
`Digoxin
`
`ROUTE
`Oral
`Oral
`
`Intravenous
`
`lntra muscula·
`Oral
`
`Table 1-1. Empirically Derived Usual Adult Dosage Regimens of Some
`Representative Drugs Before the Introduction of Clinical Pharmacokineticsa
`DOSAGE REGIMEN
`INDICA TED USE
`25 0 mg every 6-8 hr
`Treatment of Infections
`1.5-2 mg initially over 24
`Amelioration of congestive
`hr, thereafter 0. 25-0.5
`cardiac failure
`mg once a day
`0.2-4 milliunits/min by
`infusion
`1 0 mg when needed
`Not recommended because
`of reduced effectiveness
`"Token from American Medical Association: Drug Evoluolions. 2nd Ed .• Publishers Science Group, Acton, 11/\A, 1973.
`
`O xytocin
`
`Morphine sulfate
`
`Ind uction and maintenance
`of labor
`Relief of severe pain
`
`Fig. 1-l. Pla~ma concentratio n of
`theophylline in a subjectfollowing an
`oral dose of a 600-mg controlled-re-
`lease formu lation. Before the peak is
`reached , the rate of absorption ex-
`ceed s that of e limination. At the
`peak, the two rates arc eCJual; the re-
`after, the rate of elimination exceed~
`that of absorption. (Redrawn f1·om
`Sauter, R., Steinijans, V.W., D iletti,
`E., Bt'l lu.n, A., and Sch ulz, H.U.:
`P resentation of results in b ioequival-
`ence studies. Int . J. Clin. Pharmacal.
`Ther. Toxicol., 30:57-30, 1992.)
`
`6
`
`Q ) -
`
`5
`·= ~ 4
`3
`
`>-E
`.c--
`C..c
`0
`0
`Q) · -
`~"§
`ct:l +-'
`E li5 U ) u
`~§ o..o
`
`2
`
`1
`
`0
`
`0
`
`12
`
`36
`
`48
`
`24
`Hours
`
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`CHAPTER l
`
`W HY CLINICAL PrARMACOKINETICS?
`
`3
`
`The events following drug administration can be divided into two phases, a pharnwco-
`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 pharnw-
`codynarnic phase, in which the concentration of drug at the site(s) of action is related to
`the magnitude of the effect(s) produced (Fig. l-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 seveml advantages
`over the empilical approach. First, and most obvious, distinction can be made between
`pharmacok:inetic 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, knovving 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. Betw·een 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 dmgs, this therapeutic objective is met by giving an initial dose to achieve a plasma
`concentration witllin 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 l-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. \Vith regimen A,
`
`Pharmacokinetics
`
`Pharmacodynamics
`
`Dosage
`Regimen
`
`Plasma
`Concen-
`tration
`
`,...-------
`I
`Site
`I
`I
`of
`I
`I Action
`[ ________
`I
`
`Effects
`
`+ l
`+ l
`...... ___________ _
`-------------
`Fig. 1-2. An approach to tbe design of a dosage regimen. The pharmacokinetics and the pharmacodynamics of
`the dmg 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 rttoclil)r the dosage regimen to achieve optimal therapy.
`
`l
`/
`
`I
`I
`I
`
`I
`/
`
`I
`I
`I
`
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`4
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`WHY CUNICAL PHARMACOKINETICS?
`
`CHAPTER l
`
`several doses had to be given before drug accumulation was sufficient to produce a ther-
`apeutic concentration. Had therapy been stopped before then, the drug might have been
`thought ineffective and perhaps abandoned prematw-ely. 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 adminisb·ation when
`the concentration exceeded the upper limit of the therapeutic window.
`The synthetic antimala1ial agent, quinacrine, developed during World vVar II to substi-
`tute for the relatively scarce quinine, is an example. Quinacline was either inefTective
`acutely against malalia or eventually produced unacceptable toxicity when a dosing rate
`sufficiently high to be eflective acutely vvas maintained. Only after its phannacokinetics
`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 tl1erapeutic success, followed by small daily
`doses to maintain the plasma concenb·ation within the therapeutic window.
`The plateau situation in Fig. l-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-
`quency of administration. \Vhen the window is nan-ow and tl1e dmg 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-
`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 metaLollL.ed on passage through the liver, an organ lying between thP- gastroin-
`testinal tract and tb.e general circulation.
`Awareness of the benefits of understanding pharmacokinetics and concentration-re-
`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-
`cokinetics and response are similar across mammalian species such that data can be ex-
`b"apolated froin animals to predict quantitatively the likely behavior in humans. This quan-
`
`F ig. 1-3. When a drug is given in
`a fixed dose and at fixed lime inter-
`vals (denoted by the arrows), it ac-
`cumulates within the body until a
`plateau is reached. With mgimen A,
`therapeutic success is achjeved al-
`though not initially. With regimen B,
`th.e therapeutic objective is acllievcd
`more quickly, but the plasma drug
`concentration is ulti111ately too high.
`
`c:
`0
`
`~ -c:
`
`Q)
`
`(.) c:
`0
`(.)
`0>
`,_
`:::l
`Cl
`m
`E en
`m
`Q..
`
`Regimen B
`
`- ---- ------ ----
`
`+
`
`+
`
`+ + +
`Time
`
`Therapeutic
`Failure
`
`Therapeutic
`Success
`
`}
`
`Therapeutic
`Failure
`
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`CHAPTER 1
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`WHY CLINICAL PHARMACOKINETICS?
`
`5
`
`titative framework improves the chances of selecting not only the most prmmsmg
`compounds but also the correct range of safe doses to first test in humans. Incorporation
`of a pharmacokinetic element vvith 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 dming drug development and
`therapy, variability. There is a wide range of daily dose requirements of the oral antico-
`
`PRECLINICAL
`TESTING
`
`G=v PK-guided ? D .Q,
`
`CLINICAL (HUMAN) TESTING
`Population PK/PD
`Dose (Cone)
`Characteristics in
`Response Trials
`Large Efficacy Trials
`¢=::1
`c::::>
`PK/PD in Special
`Populations
`
`Post-
`Marketing
`Surveillance
`
`Efficacy
`Dose escalation
`In vitro PK/PD
`Safety ~ Dosage
`Animal PK/PD
`Selection
`~Assessment
`Patient Variables
`
`Toxicity
`I Animal Testing)
`
`I
`
`Phase I
`
`> Phase II
`
`)
`~----~ ~~ -P-h-as-e-11-1~)
`
`Fig. l-4. The development and subsequent marketing of a drug. The prehmnan data helps to identify promising
`compounds and to suggest usefill doses for testing in humans. Phases I, II, and III of human assessment generally
`correspond to the first administration to hmnaus, early evaluation in selected patients, and the hu·ger trials,
`respectively. l)hannacokinetic (P K) 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. l'ostrnarketing
`smveillance helps to refine the PK/PD information.
`
`(/)
`
`(/) 25
`c
`0
`~ 20
`:;:::::;
`> ..... Q) 15
`0 - 10
`.c
`0 ...... c
`Q) 5
`..... Q) a.. 0
`
`(..)
`
`Fig. l -5. The daily dose of warfarin required to produce similar
`prothrombin times in 200 adult patients vaJies widely. (J mg!L =
`3.3 J.tM). (Redrawn from Kocb-\~1eser, J.: The serum level ap-
`proach to individualization of drug dosage. Eur. J. Clin. Pharrna-
`col. 9:1- 8, 1975.)
`
`-
`
`-
`
`1-
`
`,.--
`
`-_ 1-
`
`-
`
`-
`
`r--
`
`1-
`
`NO">O">O'>O'>O'>O'>O'>O'>O'>O'>
`. . . . . . . . . .
`V NC"J'<:j"L.(')C.OI"-000'>00
`I
`I
`I
`I
`I
`I
`I
`I T""T""
`NC"J-::I"L.(')C.OI"-OOO'>c!,/\
`
`Daily Dose (mg)
`
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`6
`
`WHY CUNICAL PHARMACOKINETICS?
`
`CHAPTER I
`
`agulant warfm·in needed to produce a similar prothrombin time (an index of blood coag-
`ulability). Sources of vruiability 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 result is that a standard
`dosage regimen of a drug may prove therapeutic in some patients, ineffective in otl1ers,
`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 arc digoxin, used to treat some cardiac disorders; phenytoin, used to
`prevent epileptic convulsions; theophylline, used to diminish chronic airway resistance in
`asthmatics; and cyclosporine, an immunosuppressant used in organ transplantation. \Vitl1
`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 vru·iabiJity as pos-
`sible during drug development by gathering, albeit }jmited, individual plasma concentration
`and response data in a large population of patients during Phase III cliillcal trials. Attempts
`are then made to account for this variability in terms of such patient characte1istics as age
`and weight. These population phannacokinetic/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-
`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
`t.he dosing rate, there is considerable variation in
`the individual values. (One mg!L = 3.97 J.1M.) (Re-
`drawn from Lund, L.: EH'ects of phenytoin in pa-
`tients with epilepsy in relation to its concentration
`in plasma. In Biological Effects ofDmgs in Hclation
`to Their Plasma Concentration. Edited by D.S. Da-
`vies and B.N.C. Prichard, Macmillan, London and
`Basingstoke, 1973, pp. 227- 238.)
`
`50
`
`40
`
`c::
`0
`~ 30
`,._..
`c::
`<P
`(..) c::
`0 <.:>
`c::
`0 20
`>, c::
`<P .c a..
`E
`~ 10
`([
`
`~
`
`0
`
`0
`
`•
`
`•
`• • •
`•
`.........
`• • ••
`• •
`•
`••••••
`..........
`••
`• •
`• •
`• ••••••••
`. ,·:ft-'~···
`•
`•• -··1
`..... a ....
`\~:\.
`. . :,. :-·~( ~.
`••
`fO:i• ••
`
`•
`
`• •
`
`10
`5
`Daily Dose (mg/kg)
`
`15
`
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`CHAPTER l
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`WHY CLINICAL PHARMACOKINETICS2
`
`7
`
`metabolizing enzymes and hasten drug loss; others inhibit these enzymes and slow elimi-
`nation. Still others interfere with drug absorption. Such interactions are graded; the change
`in the pharmacokinetics of a drug varies continuously vv:ith 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-
`titative elements of interactions ensures the more rational use of drugs tl1at may need to
`be coadministered.
`Figure l-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 tl1.e patient population. Yet the
`therapeutic window of phenytoin is narrow, 7 to 20 mg/L; beyond 20 mg/L, the frequency
`and the degree of toxicity increase progressively witl1 concentration. Here again, pharma-
`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. Contwl 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 tl1e drug are known.
`Dmg 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 pharmacoki.nctic approach. It begins with a con-
`sideration ofldnetic concepts basic to pharmacokinetics and ends with a section containing
`selected topics.
`
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`--
`--
`
`'L
`
`2
`
`BASIC CONSIDERATIONS
`
`OBJECTIVES
`The reader w ill be able to:
`l . Define the following terms:
`Pharmacokinetics, intravascular and extravascular administration, absorption, d ispo-
`sition, distribution, metabolism, excretion, first-pass effect, enterohepatic cycling, com-
`partment
`2. Discuss the limitations to interpretation of pharmacokinetic data imposed by assays that fail
`to distinguish between compounds administered (e.g., R-and $-isomers) or between drug
`and metabolite.
`3. Show the general contribution of mass balance concepts to drug absorption and drug and
`metabolite disposition.
`
`Pharmacokinetics has many useful applications that stem from basic concepts. These con-
`cepts are developed in this section of the book. This chapter specifically defines terms and
`describes a basic model for drug absorption and disposition.
`
`ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS
`Measurement of a drug in the body is limited usually to blood or plasma. Nonetheless, the
`information obtained has proved very useful. Such usefulness can be ex-plained by anatomic
`and physiologic features that affect a drug following its administration.
`Blood or plasma, in addition to being a practical and convenient site of measurement,
`is the most logical one for determining drug in the body. Blood receives drug from the site
`of' administration as well as carries it to all the organs, including those in which the drug
`acts and those in which it is eliminated. This movement of drug is depicted schematically
`in Fig. 2-1. This scheme forms a basis for physiologic 1nodeling in pharrnacoki·netics. Such
`modeling has applications not only in clinical pharmacokinetics but in drug development,
`veterinary medicine, and in assessing risk associated with exposures to environrnental and
`occupational substances.
`
`Sites of Administration
`There are several sites at which drugs are commonly administered. These sites may be
`classified as either intravascular or extravascular. Intravascular admi.njstration refers to the
`placement of a drug directly into the blood, either intravenously or intra-arterially.
`Extravascular modes of administration include the oral, sublinguaL buccal, intranms-
`cular, subcutaneous, dermal, pulmonary, and rectal routes. To enter the blood, drug ad-
`
`11
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`12
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`BASIC CONSIDERATIONS
`
`CHAPTER2
`
`ministered extravascularly must be absorbed: No absorption step is required when a drug
`is administered intravascularly.
`Drug may also be administered regionally, e.g., into the pleural or peritoneal cavities or
`into the cerebrospinal fluid. Regional administration includes intra-arterial injection into
`the vesselleadin.g to a tissue to be treated, e.g., one containing a cancerous tumor. It is a
`potential means of gaining a selective therapeutic advantage. This advantage, in comparison
`with other routes of administration, comes about by increasing drug exposure locally, where
`it is needed, and decreasing or producing little or no change in exposure throughout the
`rest of the body, where it is not wanted.
`
`Disposition
`Once absorbed, a drug is distributed to the various organs of the body. Distribution is
`influenced by how well each organ is perfused with blood, organ size, binding of drug
`within blood and in tissues, and permeability of tissue membranes.
`The two principal organs of elimination, the liver and the kidneys, are shown separately
`in Fig. 2-l. The kidneys are the primary site for excretion of the chemically unaltered, or
`unchanged, drug. The liver is the usual organ for drug metabolism; however, the kidneys
`and other organs can also play an important metabolic role for certain drugs. The metab-
`olites so formed are either further metabolized or excreted unchanged. The liver may also
`secrete unchanged drug into the bile. The lungs are, or may be, an important route for
`
`Fig. 2-1. Once absorbed from any of the many sites
`of administration, drug is conveyed by blood to aU sites
`within the body including the eliminating organs. Sites
`of admiojstration include: a, artery; b, peripheral vein;
`c, muscle and subcutaneous tissue; d, lung; and e, gas-
`lrointestiual tract. The dark- and light-colored lines
`V\~th arrows refer to the mass movement of dm g in
`blood and in bile, respectively. The movemc11t of vir-
`tually any drug can be followed from site of adininis-
`tration to site of elimination.
`
`* Site of Administration
`D Enterohepatic Cycle
`
`•
`
`Route of Elimination
`
`* d
`
`-
`
`-
`
`Tissues
`
`* b
`
`+
`
`CB Heart D
`C o~:,
`....
`· c;J
`
`'0
`0
`0
`a:J
`en
`:::J
`0
`c
`C1) >
`
`J
`
`Renal Excretion
`Gut
`Wall
`
`* e
`Gut Q Lumen
`
`Fecal Excretion Metabolism
`and Decomposition
`
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`IPR2018-00943
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`
`CHAPTER 2
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`BASIC CONSIDERATIONS
`
`13
`
`eliminating volatile substances, for example, gaseous anesthetics. Another potential route
`of eHmination is via a mother's milk. Although an insignificant route of elimination in the
`mother, drug in the milk may be consumed in sufficient quantity to affect the suckling
`infant.
`
`CHEMICAL PURITY AND ANALYTIC SPECIFICITY
`
`A general statement needs to be made about the chemical purity of prescribed medicines
`and the specificity of chemical assays.
`Over the years, a major thrust of the pharmaceutical industry has been to produce
`therapeutic agents that are not only as safe and eflective as possible but also arc well
`characte1izcd to ensure reproducible quaHties. The majority of administered drugs today
`are therefore essentially pure mate1ials, and coupled with specific analytic techniques for
`their determination in biologic :Buids, definitive information about their pharmacokinetics
`can be gained. However, a large number of drug substances are not single chemical entities
`but rather mixtures. This particularly appHcs to stereoisomers and proteins. The most
`common stcrcoisomers found together in medicines are optical isomers, or compounds for
`which their structures are mirror images; the drug substance is usually a racemate, a 50:.50
`mixture of the R- and S-isomers. Some dmg substances contain geometric isomers, and
`still others, especially proteins of high molecular weight derived from natural products or
`through fermentation, may be a mixture of structurally related, but chemically distinct,
`compounds. Each chemical entity within the drug substance can have a different phar-
`macologic, toxicologic, and pharmacokjnetic profile. Sometimes these differences are small
`and inconsequential, other times the differences can be therapeutically important. For
`example, dextroamphetamine (S-isomer) is a potent central nervous stimulant, whereas the
`R-enantiomer is almost devoid of such activity. Despite such differences, many commonly
`employed chemical assays do not distinguish between stereoisomers. Obviously, under
`these circumstances, attempting to quantifY the various processes and to relate plasma
`concentration to response has many problems with no simple solutions. Notwithstanding
`these problems, specific information about each chemical entity should be sought whenever
`possible. Increasingly, stereoisomers are being produced as single chemical entities, such
`as S-naproxyn, which avoid these problems. In contrast, many new protein and polypeptide
`drugs are being introduced that may, in many instances, lack purity. Fmthermore, these
`substances arc often measured by assays that lack specificity.
`An added problem exists following drug administration, namely, the formation of me-
`tabolites. To be of value, an analytic procedure must distinguish between drug and mctab-
`olite(s). Today, most assays have this desired specificity, except for some of those used to
`measure many proteins and polypeptides.
`A potential problem exists vvhen