`
`RB Ex. 2041
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`
`
`Ah7T
`'7
`
`Executive Editor: Donna Balado
`Developmental Editors; Frances Klass, Lisa Stead
`Production Manager: Laurie Forsyth
`Project Editor: Robert D. Magee
`
`Copyright © 1995
`Lippincott Williams BC Wilkins
`530 Walnut Street
`Philadelphia, Pennsylvania 19106-3621 USA
`
`All tights reserved. This book is protected by copyright. No part of this book may be reproduced in any
`form or by any means, including photocopying, or utilized by any information storage and retrieval system
`without written 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 bibliogiaphiml references and index.
`ISBN 978-0-683-07404-8
`ISBN 0-683-07404-0
`1. Phannacokinetics.
`II. Title.
`[DNIM: 1. Pharrnacokinetics.
`RM301.5.R68
`1994
`615.7—dC20
`DNIM/DLC
`for Library of Congress
`
`2. Chemotherapy.
`
`I. Tozer, Thomas N.
`
`2. Drug Therapy.
`
`QV 38 R883c 1994]
`
`The Publishers have made even; effort to trace the copyright holdersfor borrowed material. If they have in-
`advertently overlooked any, they will be pleased to make the necessary arrangements at tbefirst oppommity.
`
`12 1314 15 16 17 18 19 20
`
`94-26505CIP
`
`Page 2
`
`
`
`I g transport
`
`(apparent)
`ntration in
`
`WHY CL|N|CAL 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 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 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 oitro and in viva 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
`‘I
`
`Page 3
`
`
`
`WHY CL|NlCAL PHARMACOKINETICSZ
`
`CHAPTER 1
`
`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-
`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-
`tion, and elimination but also of the kinetics of these processes, that is, pharrrmcokinetics.
`The application of pharmacokinetic principles to the therapeutic management of patients
`is clmical phamwcokinetics.
`
`Table 1-1 . Empiricully Derived Usual Aclull Dosage Regimens of Some
`Represenialive Drugs Before Ihe Introduction of clinical Pharmucokineiicr
`DRUG
`INDICATED USE
`ROUTE
`DOSAGE REGIMEN
`
`Tetracycline
`Digoxin
`
`Oxytocin
`
`Treatment of Infections
`Amelioration of congestive
`cardiac failure
`
`Oral
`Oral
`
`lnduction and maintenance
`of labor
`
`250 mg every &8 hr
`l .5—2 mg initially over 24
`hr, thereafter O.25—O.5
`mg once a clay
`0.2-4 milliunits/min by
`infusion
`
`l0 mg when needed
`Not recommended because
`of reduced effectiveness
`
`Intravenous
`
`intramuscular
`Oral
`
`Morphine sulfate
`
`Relief of severe pain
`
`°Tal<en from American Medical Association: Drug Evaluations. 2nd Ed., Publishers Science Group, Acton, MA, 1973.
`
`Fig. 1-1. Plasma concentration of
`theophylline in a subject following a.n
`oral dose of a 600—mg controlled—re—
`lease formulation. Before the peak is
`reached, the rate of absorption ex-
`ceeds that of elimination. At the
`peak, the two rates are equal; there-
`after, the rate of elimination exceeds
`that of absorption. (Redrawn from
`Sauter, E., Steinijans, V.W,, Diletti,
`E., Btihrn, A., and Schulz, H.U.:
`Presentation of results in bioequival—
`ence studies. Int. Clin. Pharmacol.
`Ther. Toxicol, 30:87-30, 1992.)
`
`
`
`PlasmaTheophylline
`
`
`
`Concentration(mg/L)
`
`Page 4
`
`
`
`Ct AFTER 1
`
`CHAPTER I
`
`WHY CLINICAL PHARMACOKINLTICSE
`
`S01'Pti0I1, distribu-
`pharnuzcokinetics.
`
`mg iniliolly over 24
`hereafter O.25~O.5
`once a day
`milliunirs/min by
`ion
`
`: when needed
`
`The events following drug administration can be divided into two phases, a pharmaco-
`kinetic phase, in which the adjustable elements of dose, dosage form, frequency, and route
`of administration are related to drug level—time relationships in the body, and a pharma-
`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
`Regimen
`
`Plasma
`A» Concen—
`tration
`
`'
`
`Effects
`
`Fig. 1-2. An approach to the design of a dosage regimen. The pharmacokinetics and the pharmacodynamics of
`the drug are first defined. Then, either the plasma drug concentration—time data or the effects produced are used
`via pharmacokinetics as a feedback (dashed lines) to modify the dosage regimen to achieve optimal therapy.
`
`Page 5
`
`
`
`
`
`
`
`Page 6
`
`
`
`CHAMER 1
`
`WHY CLINICAL PHARNIACOKINETICS?
`
`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
`
`CLINICAL (HUMAN) TESTING
`Dose (Conc)
`Population PK/PD
`Response Trials
`Characteristics in
`Post"
`Large Efficacy Trials
`<.:: Ma"‘3“”9
`,:> Surveillance
`
`4:5 PK—guided 1;’.-7:7
`Efficacy I:>
`In vitro PK/PD
`Dose escalation
`Animalpx/PD
`a;j_~~.w\ Dosage
`PK/PD in Special
`Populations
`‘T Selection
`
`Animal Testing
`
`Phase I
`
`.>
`
`Patient Variables
`
`Ii)
`
`.
`
`Fig. 1-4. The development and subsequent marketing of a drug. The prehuman data helps to identify promising
`compounds and to suggest useful doses for testing in humans. Phases I, II, and III of human assessment generally
`correspond to the first administration to humans, early evaluation in selected patients, and the larger trials,
`respectively. _Pharmacol<inetic (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 of warfarin required to produce similar
`prothrombin times in 200 adult patients varies widely. (1 mg/L =
`3.3 uM). (Redrawn from Koch—Wwer, ].: The serum level ap-
`proach to individualization of drug dosage. Eur.
`Clin. Pharma-
`col. 91-3, 1975.)
`,
`
`25
`
`20
`
`15
`
`10
`
`PercentofObservations
`
`N‘-‘P.°?°‘.°?°’.°?°’.°>.°£°‘.
`\/C\J<‘O<I'LO<.Ol\OOC‘.o©©
`l
`I
`I
`I
`I
`I
`l
`lw—w—
`,\oz.«-
`(\JC‘0’<I'LOLOl\O0O'> I
`
`Daily Dose (mg)
`
`Page 7
`
`
`
`WHY CLINICAL PHARMACOKXNEIICSE
`
`CHAPTER 1
`
`agulant Warfarin needed to produce a similar prothrombin time (an index of blood coag-
`ulability). Sources of variability in drug response include the patients 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-
`sible during drug development by gathering, albeit limited, individual plasma concentration
`and response data in a large population of patients during Phase III clinical trials. Attempts
`are then made to account for this variability in terms of such patient characteristics as age
`and weight. These population pharmacokinetic/pharmacodynamic studies form a basis for
`dosage regimen recommendations in clinical practice.
`Coadministration of several drugs to a patient, prevalent in clinical practice, can pose
`problems. Although the response produced by each drug alone may be predictable, that
`produced by the combination may be less certain and occasionally unpredictable. Ketc-
`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 pharrnacokinetics. 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 uM.) (Re-
`drawn from Lund, L.: Effects of phenytoin in pa-
`tients with epilepsy in relation to its concentration
`in plasma. In Biological Effects of Drugs in Relation
`to Their Plasma Concentration. Edited by DS. Da-
`vies and B.N.C. Prichard, Macmillan, London and
`Basingstoke, 1973, pp. 227-238.)
`
`
`
`PlasmaPhenytoinConcentration(mg/L)
`
`
`
`
`
`50
`
`Daily Dose (mg/kg)
`
`Page 8
`
`
`
`CHAPTER I
`
`'ndex of blood coag-
`age, weight, degree
`netic makeup, other
`It is that a standard
`effective in otl1ers,
`g for an individual
`narrow therapeutic
`are critical to drug
`phenytoin, used to
`- 'rway resistance in
`nsplantat-ion. With
`ajor source of total
`
`Variability as pos-
`: ma concentration
`Cal trials. Attempts
`racteristics as age
`s form a basis for
`
`ractice, can pose
`' predictable, that
`redictable. Ketc-
`tes the effect of
`
`ance, as in many
`s stimulate drug-
`
`CHAPTER 1
`
`WHY CUNICAL PHARMACOKJNETICSE
`
`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 phamlacoldnetics of a drug varies continuously with the plasma concentration ofthe
`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 that may need to
`be coadministered.
`Figure 1-6 illustrates a situation in which monitoring of the drug concentration may be
`e antiepileptic drug phenytoin, the
`"thin 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-
`cokinetics is the major source of variability. A pragmatic approach to this problem would
`be to adjust the dosage until the desired objective is achieved. Control on a dosage basis
`alone, however, has proved difficult. Control is achieved more readily and accurately when
`plasma drug concentration data and the pharmacokinetics of the drug are known.
`Drug selection and therapy have traditionally been based solely on observations of the
`effects produced. In this chapter, the application ofpharrnacokinetic 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.
`
`Page 9