Concepts and Applications
`
`third edition
`
`Clinical Pharmacokinetics
`
`
`
`MALcoiM ROWLAND
`: THOMAS N. 102ch
`
`'
`
`DRL EXHIBIT 1022 PAGE 1
`
`DRL EXHIBIT 1022 PAGE 1
`
`

`

`--~~~~~------------------------------------------------
`
`C I i n i c o I P h o r m o c o k i n e ·t i c s
`
`Coricepts 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 California
`
`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
`
`DRL EXHIBIT 1022 PAGE 2
`
`

`

`F.xecutive Editor: Donna Balado
`Developmental Editors: Frances Klass, Lisa Stead
`Production Manager: Laurie Forsy th
`Project Editor: Robert D. Magee
`
`Copyright© 1995
`Lippincott W ill iams & Wi lkins
`530 Walnut Street
`Philadelphia, Pe nnsylvania l 9 l 06-362 l USA
`
`All rights reserved. This book is protected by copyright. No part of this book may be re produced in any
`form or by any means, including photocopying, or utilized by any information storage and retrieval system
`without w ritten pe rmissio n from the copyright owner.
`
`Accurate indications , adverse reactions, and dosage schedules fo r 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 I Malcolm
`3rd ed.
`Rowland, Tho mas N. Tozer. -
`p .
`cm.
`"A Lea & Febiger Book. "
`Includes b ibliographical references and index.
`ISBN 978-0-683-07404-8
`ISBN 0-683-07404-0
`1. Pharmacokinetics. 2. Chemothe rapy.
`II. Title.
`[DNLM: 1. Pharmacokinetics.
`RM301.5 R68
`1994
`615 7-<lc20
`DNLM/ DLC
`fo r Library of Congress
`
`7be Publishers have made every effort to trace the copyright holders for borrowed material. If they have in(cid:173)
`advertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity .
`
`l l l 2 13 14 15 16 17 18 19 20
`
`94-26305
`CIP
`
`I. Tozer, Thomas N.
`
`2. Drug Therapy.
`
`QV 38 R883c 1994]
`
`DRL EXHIBIT 1022 PAGE 3
`
`

`

`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(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 t1ial
`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)
`fu lly noted, and if necessary, the dosage regimen was adjusted empi1ically 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 we re
`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?
`Fmihermore, 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 th at 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 ach ieved
`by maintaining an adequate concentration of drug at the site(s) of action for the duration
`
`DRL EXHIBIT 1022 PAGE 4
`
`

`

`2
`
`WHY CLINICAL PHARtv\ACOKINETICS2
`
`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 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(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 Clinical Pharmacoklnetics•
`
`DRUG
`
`Tetracycline
`
`Digoxin
`
`INDICATED USE
`
`Treatment of Infections
`Amelioration of congestive
`cardioc failure
`
`ROUTE
`
`Oral
`
`Oro!
`
`DOSAGE REGIMEN
`
`250 mg every 6-8 hr
`
`l 5- 2 mg initiolly over 24
`hr, thereafter 0.25-0.5
`mg once a day
`
`0 2-4 milliunits/ min by
`infusion
`
`Oxytocin
`
`Morphine sulfate
`
`Induction a nd mo intenance
`of labor
`Relief of severe pain
`
`Intravenous
`
`Intramuscular
`
`l 0 mg when needed
`
`Oral
`
`Not recommended because
`of reduced effectiveness
`
`"Token from American Medical Associolon. Drug Evoluolrons. 2nd Ed., Publishers Science Group, Acton , MA. 1973.
`
`Fig. 1-1. Plas!lla concentration of
`theophylline in a subject following an
`oral dose of a 600-!llg controlled-re(cid:173)
`lease forlllulation. Before the peak is
`reached, the rate of absorption ex(cid:173)
`cee ds that of eli lll in ati on. At the
`peak, the two rates are equal ; there(cid:173)
`after, the rate of elilllination exceeds
`that of absorption. (Redrawn from
`Sauter, R. , Steinijans, V.W., Oiletti ,
`E .. Bohlll , A. , and Sc hul z, H.U.:
`Presentation of results in bioequival(cid:173)
`ence studies. Int. J. Clin. Phar!llacol.
`The r. Toxicol. , .30:S7-30, 1992. )
`
`6
`
`5
`
`4
`
`3
`
`2
`
`Q) - - -
`
`c: ~ = en
`>- E
`..c: -
`Cl.. c:
`0
`0
`Q) · (cid:173)
`I- e
`..c: -
`~-E §3
`CJ)
`(.)
`~ c
`-
`0
`a.. u
`
`0
`
`0
`
`12
`
`24
`Hours
`
`36
`
`48
`
`DRL EXHIBIT 1022 PAGE 5
`
`

`

`CHAPTER l
`
`WHY CLINICAL PHARMACOKINETICS?
`
`3
`
`The events following drug administration can be divided into two phases, a pharrnaco(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 pharrna(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 otherwise may have been dis(cid:173)
`carded or has suggested a more appropriate dosage regimen. Lastly, knowing the phar(cid:173)
`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(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 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(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
`
`Pharmacodynamics
`
`Dosage
`Regimen
`
`Plasma
`Concen-
`tration
`
`.-- --- ---
`I
`Site
`I
`I
`of
`I
`I Action
`[ ________
`
`I
`
`Effects
`
`.)
`
`+
`...... ___ ____ ___ __ ;
`
`\
`
`I
`I
`I
`I
`I
`
`+
`...... ____ ________ ;
`
`F ig. 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
`i ia pharm acoki netics as a feedback (dashed lines) to modify the dosage regimen to achieve optimal therapy.
`
` DRL EXHIBIT 1022 PAGE 6
`
`

`

`4
`
`W HY CLINICAL PHARMACOKINETICS2
`
`CHAPTER l
`
`several doses had to be given before drug accumulation was sufficient to produce a ther(cid:173)
`apeutic concentration. Had therapy bee n stopped before then, the drug might have been
`thought ineffective and perhaps abandoned prematurely. Alternatively, larger doses might
`have been tried, e.g., regimen B. Although a therape utic response would have been
`achieved fairly promptly, toxicity would have ensued with continued administration when
`the concentration exceeded the upper limit of the 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 pharmacokinetics
`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-
`
`Regimen B
`
`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)
`cumu lates 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.
`
`Therapeutic
`Failure
`
`Therapeutic
`Success
`
`}
`
`Therapeutic
`Failure
`
`--- -------- --- -
`
`Time
`
`·-=-------------------------------------
`
`DRL EXHIBIT 1022 PAGE 7
`
`

`

`CHAPTER 1
`
`WHY CLINICAL PHARMACOKINETICS?
`
`s
`
`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 regulat01y 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
`/----; (';. n
`Large Efficacy Trials
`G==:v PK-guided ~ U v ~ <=
`Efficacy ~ =>
`In vitro PK/PD
`Dose escalation
`PK/PD in Special
`Safety ~ Dosage
`Animal PK/PD
`Populations
`~ Assessment
`Selection
`Patient Variables
`
`Toxicity
`I Animal Testing)
`
`I Phase I
`
`)
`.
`
`~P_h_ase_ll ~> l~P_hase_l_ll __.)
`
`Post(cid:173)
`Marketing
`Surveillance
`
`Fig. 1-4. The development and subseque nt marketing of a drug. The prehuman data helps to ide ntify promising
`compounds and to suggest useful doses for testing in humans. Phases I, II , and III of human assess ment gene rally
`correspond to the first adm inistration to hum ans, early evaluation in selected patients, and the larger trials,
`respectively. Pharmacokinetic (PK ) and pharmacodynamic (PD ) data gathered du1ing all phases of drug devel(cid:173)
`opment help to efficiently de fin e safe and effective dosage regimens for optimal individual use. Postmarke ting
`surveillance helps to refin e the PK/PD information .
`
`(/) 25
`c
`0
`:;::::; 20
`~ > '-
`CV 15
`
`(/)
`..0
`
`0 - 10
`
`0
`.......
`c
`CV 5
`(.;)
`'-
`CV
`CL 0
`
`Fig. 1-5. The daily dose of warfarin required to produce si milar
`prothrombin times in 200 adult patients varies 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.)
`
`N O'l O'l O'l O'l O'l O'l O'l O'l O'l O'l
`
`V N c0 -.:t ir:i c.O ,.....: a:i m ci ci
`I
`I
`I
`I
`I
`I
`I
`I ..--..-(cid:173)
`-.::t" UJ C.0 f'- 00 O'l 6 f\
`N M
`
`Daily Dose (mg)
`
`DRL EXHIBIT 1022 PAGE 8
`
`

`

`6
`
`WHY CLINICAL PHARfv\ACOKINETICS?
`
`CHAPTER l
`
`agulant warfa1in 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 result 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 airway 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 pharmacokinetidpharmacodynamic 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-
`
`F ig. 1- 6. Although the average plateau plasma
`concentration of phenytoin tends to increase with
`the dosing rate, the re 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 \vith 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.)
`
`E
`c
`0
`
`__J --0>
`~ ...... -c
`
`Q.)
`
`'-' c
`0 u
`c
`0
`>.,
`c
`Q.)
`..c
`D._
`
`50
`
`40
`
`30
`
`20
`
`•
`
`•
`
`•
`
`•
`• •
`• • • •
`• •
`
`•
`•
`
`• •
`
`~
`
`E
`~ 10
`
`D._
`
`0
`
`0
`
`10
`5
`Daily Dose (mg/kg)
`
`15
`
`DRL EXHIBIT 1022 PAGE 9
`
`

`

`CHAPTER 1
`
`WHY CLINICAL PHARtv\ACOKINETICS?
`
`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 of phenytoin 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 pharrnacokinetics 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 pharrnacokinetic 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 pharrnacokinetics and ends with a section containing
`selected topics.
`
`DRL EXHIBIT 1022 PAGE 10
`
`

`

`(
`
`.. '
`
`':'--
`
`-~··
`~ ' ..
`
`'
`
`.
`
`4
`
`EXTRAVASCULAR DOSE
`
`OBJECTIVES
`
`The reader will be able to:
`l . Describe the characteristics of, and the differences between, first-order and zero-order ab(cid:173)
`sorption processes .
`
`2. Determine w hether absorption or disposition rate limits drug elimi nation, given plasma con(cid:173)
`centration-time data following different dosage forms or routes of administration.
`
`3. Anticipate the effect of altering rate of absorption , extent of absorption , clearance, or volume
`of distribution on the plasma concentration and amount of drug in the body following extra(cid:173)
`vascular administration.
`
`4. Estimate the bioavailability of a drug, given ei ther plasma concentration or urinary excretion
`data following both extravascular and intravascular administration.
`
`5 . Estimate the relative bioavailability of a drug , given either plasma concentration or urinary
`excretion data following different dosage forms or routes of administration .
`
`6. Estimate the renal clearance of a drug from plasma concentration and urinary excretion
`data following extravascular administration.
`
`For systemically acting drugs , absorption is a prerequisite for therapeutic activity when
`they are administered extravascularly. The factors that influence drug absorption are con(cid:173)
`sidered in Chap. 9, Absorption. In this chapter the following aspects are examined: the
`impact of rate and extent of absorption on both plasma concentration and amount of drug
`in the body; the effect of alterations in absorption and disposition on body level-time
`relationships; and the methods used to assess pharmacokinetic parameters from plasma
`and urinary data following extravascular administration.
`The term bioavailability is commonly applied to both rate and extent of drug input into
`the systemic circulation. Throughout this book the term will be limited to the extent of
`drug input and can be considered as the fraction, or percent, of the administered dose
`absorbed intact.
`
`KINETICS OF ABSORPTION
`
`The oral absorption of drugs often approximates first-order kinetics, especialiy when given
`in solution. The same holds true for the absorption of drugs from many other extravascular
`sites including subcutaneous tissue and muscle. Under these circumstances, absorption is
`characterized by an absorption rate constant, ka , and a corresponding half-life. The half(cid:173)
`lives for the absorption of drugs administered orally in solution or in a rapidly disintegrating
`dosage form usually range from 15 min to 1 hr. Occasionally, they are longer.
`
`34
`
`DRL EXHIBIT 1022 PAGE 11
`
`

`

`CHAPTER 4
`
`EXTRAVASCUlAR DOSE
`
`35
`
`Sometimes, a drug is absorbed at essentially a constant rate. The absorption kinetics are
`then called zero order. Differences between zero-order and first-order kinetics are illus(cid:173)
`trated in Fig. 4-1. For zero-order absorption, a plot of amount remaining to be absorbed
`against time yields a straight line, the slope of which is the rate of absorption (Fig. 4-lA).
`Recall from Chap. 3 that the fractional rate of decline is constant for a first-order process;
`the amount declines linearly with time when plotted semilogarithmically. In contrast, for
`a zero-order absorption process, the fractional rate increases with time, because the rate
`is constant but the amount remaining decreases. This is reflected in an ever-increasing
`gradient with time in a semilogarithmic plot of the amount remaining to be absorbed (Fig.
`4-lB ). A graphical method of examining the kinetics of absorption from plasma data fol(cid:173)
`lowing extravascular administration is given in Appendix 1-C.
`For the remainder of this chapter, and for much of the book, absorption is assumed to
`be first order. If absorption is zero order, then the equations developed in Chap. 6 (Con(cid:173)
`stant-Rate Regimens ) apply.
`
`A. Regular Plot
`
`8. Sem ilogarithmic Plot
`
`-0 100
`Q.)
`.....
`..Cl
`0 en
`..Cl
`<l:
`Q.) ro
`
`80
`
`0 - 60
`
`40
`
`First Order
`
`Ol
`c
`c
`ro
`E
`
`Q.) a: - 20
`
`c
`Q.)
`u .....
`
`Q.)
`Q_
`
`0
`
`100
`50
`
`10
`
`5
`
`Zero Order
`
`First Order
`
`-0
`Q.)
`.....
`..Cl
`0 en
`..Cl
`<l:
`Q.) ro
`
`0 -Ol
`
`c
`c
`ro
`E
`
`Q.) a: -c
`
`Q.)
`
`u .....
`
`Q.)
`Q_
`
`Time
`
`Time
`
`Fig. 4- 1. A comparison of zero-order and first-order absorption processes. Depicted are: A , regular and B,
`semilogarithmic plots of the percent remaining to be absorbed against time.
`
`BODY LEVEL-TIME RELATIONSHIPS
`
`Comparison With an Intravenous Dose
`
`Absorption delays and reduces the magnitude of the peak compared to that seen following
`an equal i.v. bolus dose. These effects are portrayed for aspirin in Fig. 4- 2. The rise and
`fall of the drug concentration in plasma are best understood by remembe1ing (Chap. 2,
`Eq. 2, p. 16) that at any time
`
`dAa
`dt
`Rate of
`absorption
`
`k ·A
`
`Rate of
`eli mination
`
`dA
`dt
`Rate of
`change of
`drug in
`body
`
`DRL EXHIBIT 1022 PAGE 12
`
`

`

`36
`
`EXTRAVASCUlAR DOSE
`
`CHAPTER 4
`
`where Aa is the amount of drug at the absorption site remaining to be absorbed. When
`absorption occurs by a first-order process, the rate of absorption is given by ka ·Aa .
`Initially, with all drug at the absorption site and none in the body, rate of absorption is
`maximal and rate of elimination is zero. Thereafter, as drug is absorbed, its rate of absorp(cid:173)
`tion decreases, whereas its rate of elimination increases. Consequently, the difference be(cid:173)
`tween the two rates diminishes. However, as long as the rate of absorption exceeds that of
`elimination the plasma concentration continues to rise. Eventually, a time t,,,aX' is reached
`when the rate of elimination matches the rate of absorption; the concentration is then at
`a maximum, C,,,ac Subsequently, the rate of elimination exceeds the rate of absorption and
`the plasma concentration declines.
`The peak plasma concentration is always lower following extravascular administration
`than the initial value following an equal i.v. bolus dose. In the former case, at the peak
`time some drug remains at the absorption site and some has been eliminated, while the
`entire dose is in the body immediately following the i.v. dose. Beyond the peak time, the
`plasma concentration exceeds that following i.v. administration of the same dose because
`of the continual entry of drug into the body.
`Frequently, the rising portion of the plasma concentration-time curve is called the ab(cid:173)
`sorption phase and the declining portion, the elimination phase. As will be seen, this de(cid:173)
`scription may be misleading. Also, if bioavailability is low, the drug concentration may
`remain lower than that observed after i.v. administration at all times.
`Lag time, the delay between drug administration and the beginning of absorption, may
`be particularly important when a rapid onset of effect is desired. The lag time can be
`anywhere from a few minutes to many hours. Long lag times have been observed following
`ingestion of ente1ic-coated tablets. The coating is resistant to the gastric environment, thus
`protecting an acid-labile drug or preventing gastric irritation by a drug. Factors contributing
`to the lag time are the delay in emptying the product from the stomach and the time taken
`for the protective coating to dissolve or to swell and release the inner contents into the
`intestinal fluids. Once absorption begins, however, it may be as rapid as with uncoated
`tablets. Clearly, enteric-coated products should not be used when a prompt and predictable
`response is desired. A method for estimating lag time is discussed in Appendix I-C.
`Bioavailability and area are also important factors. As discussed more fully in Chaps. 7
`and 9, the completeness of absorption is of primary importance in therapeutic situations.
`
`c
`0
`·.;::::;
`ro ,_
`
`-c
`
`(/)
`<(
`ro
`E
`(/) ro
`0....
`
`CJ.)
`u
`c
`__J -- 6
`o -u
`c Ol
`·;::::: E
`·a.- 4
`
`10
`
`8
`
`2
`
`0
`
`0
`
`20
`
`40
`
`60
`Minutes
`
`80
`
`100
`
`120
`
`Fig. 4-2. Aspi1in (650 mg) was administered as an intravenous bolus (• ) and as an oral solution (o) on separate
`occasions to the same individual. Absorption causes