SIXTH EDITION
`
`' ••■;;--0i5'''--:rg-^&k.
`- ■:<
`
`CONCEPTS IN CLINICAL
`PHARMACOKINETICS
`
`\i 'P-
`
`•'**''
`
`William J. Spruil
`William E. Wade
`Joseph T. DiPiro
`Robert A. Blouin
`Jane M. Prueme
`
`asimnubpublkatfons
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`

`

`Concepts in Clinical
`Pharmacokinetics
`
`SIXTH EDITION
`
`William J. Spruill, PharmD, FASHP, FCCP
`Associate Professor
`Department of Clinical and Administrative Sciences
`University of Georgia, College of Pharmacy
`Athens, Georgia
`
`William E. Wade, PharmD, FASHP, FCCP
`Professor
`Department of Clinical and Administrative Sciences
`University of Georgia, College of Pharmacy
`Athens, Georgia
`
`Joseph T. DiPiro, PharmD
`Executive Dean
`South Carolina College of Pharmacy
`Charleston , South Carolina
`
`Robert A. Blouin, PharmD
`Professor and Dean
`UNC Eshelman School of Pharmacy
`The University of North Carolina at Chapel Hill
`Chapel Hill, North Carolina
`
`Jane M. Pruemer, PharmD, BCOP, FASHP
`Professor of Clinical Pharmacy Practice
`James L. Winkle College of Pharmacy
`University of Cincinnati
`Cincinnati, Ohio
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
`
`

`

`Any correspondence regarding this publication should be sent to the publisher, American Society of Health-System
`Pharmacists, 4500 East West Highway, Suite 900, Bethesda, MD 20814, attention: Special Publishing.
`
`The information presented herein reflects the opinions of the contributors and advisors. It should not be interpreted as an
`official policy of ASHP or as an endorsement of any product.
`
`Because of ongoing research and improvements in technology, the information and its applications contained in this text
`are constantly evolving and are subject to the professional judgment and interpretation of the practitioner due to the
`uniqueness of a clinical situation. The editors and ASHP have made reasonable efforts to ensure the accuracy and
`appropriateness of the information presented in this document. However, any user of this information is advised that the
`editors and ASHP are not responsible for the continued currency of the information, for any errors or omissions, and/or
`for any consequences arising from the use of the information in the document in any and all practice settings. Any reader
`of this document is cautioned that ASHP makes no representation, guarantee, or warranty, express or implied, as to the
`accuracy and appropriateness of the information contained in this document and specifically disclaims any liability to any
`party for the accuracy and/or completeness of the material or for any damages arising out of the use or non-use of any of
`the information contained in this document.
`
`Director, Special Publishing: jack Bruggeman
`Acquisitions Editor: Robin Coleman
`Editorial Project Manager: Ruth Bloom
`Produc.tion Manager: johnna Hershey
`Cover & Page Design: David Wade
`
`Library of Congress Cataloging - in - Publication Data
`Spruill, William j., author.
`Concepts in clinical pharmacokinetics j authors, William j. Spruill, William E. Wade, joseph T. DiPiro.-- Sixth edition.
`p. ; em.
`Preceded by Concepts in clinical pharmacokinetics j joseph T. DiPiro ... [et al.] . Includes bibliographical references and
`index.
`ISBN 978 - 1 - 58528 - 387 - 3
`I. Wade, William E., author. II. DiPiro, joseph T., author. Ill. American Society of Health-System Pharmacists. IV. Title.
`[DNLM: 1. Pharmacokinetics-- Programmed Instruction. 2. Pharmaceutical Preparations-- administration & dosage
`--Programmed Instruction. QV 18.2]
`RM301.5
`615 '.7-- dc23
`
`2013041917
`
`© 2014, American Society of Health-System Pharmacists, Inc. All rights reserved.
`
`No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
`including photocopying, microfilming, and recording, or by any information storage and retrieval system, without written
`permission from the American Society of Health-System Pharmacists.
`
`ASHP is a service mark of the American Society of Health-System Pharmacists, Inc.; registered in the U.S. Patent and
`Trademark Office.
`
`ISBN : 978-1-58528-387-3
`
`Corrections were incorporated, effective with this second printing, October 2017.
`
`10 9 8 7 6 54 3 2
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
`

`

`' i ,
`
`Table of Contents
`
`Preface................................................................................................................................................. v
`Acknowledgments ............................................................................................................................ vii
`A Note from the Authors on Using This Edition.................................................................... vii
`Abbreviations....................................................................................................................................
`ix
`
`Lessons and Practice Sets
`
`Lesson 1.
`Introduction to Pharmacokinetics and Pharmacodynamics................ 1
`Lesson 2. Basic Pharmacokinetics ..................................................................................... 21
`Lesson 3. Half-Life, Elimination Rate, and AUC ............................................................. 31
`Practice Set 1 ................................................................................................................................. 45
`Lesson 4.
`Intravenous Bolus Administration, Multiple Drug
`Administration, and Steady-State Average Concentrations .................. 49
`Lesson 5. Relationships of Pharmacokinetic Parameters and
`Intravenous Intermittent and Continuous Infusions............................... 65
`Lesson 6. Two-Compartment Models................................................................................ 81
`Practice Set 2 ................................................................................................................................. 93
`Lesson 7. Biopharmaceutics: Absorption ....................................................................... 99
`Lesson 8. Drug Distribution and Protein Binding ........................................................ 115
`Lesson 9. Drug Elimination Processes .............................................................................. 127
`Lesson 10. Nonlinear Processes ............................................................................................. 149
`Lesson 11. Pharmacokinetic Variation and Model-Independent
`Relationships ........................................................................................................... 159
`Practice Set 3 .................................................................................................................................. 17 5
`Lesson 12. Aminoglycosides ................................................................................................... 179
`Lesson 13. Vancomycin .............................................................................................................. 203
`Lesson 14. Theophylline ............................................................................................................ 221
`Lesson 15. Phenytoin and Digoxin ........................................................................................ 231
`Appendix A. Basic and Drug-Specific Pharmacokinetic Equations ............................ 249
`Appendix B. Supplemental Problems ..................................................................................... 259
`Appendix C. Glossary ................................................................................................................... 267
`Index ................................................................................................................................................... 271
`
`..
`
`iii
`
`,,
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
`
`

`

`Preface
`
`For students just entering the world of pharmacy or seasoned practitioners, the
`study of pharmacokinetics and the mathematical equations required for drug
`dosing can be quite intimidating. Combined with the terminology of the science,
`this may make a course in pharmacokinetics a considerable challenge. In this sixth
`edition of Concepts in Clinical Pharmacokinetics, we continue to focus on the funda(cid:173)
`mental pharmacokinetic concepts. These concepts, along with the mathematical
`equations, are broken down to their simplest forms, and a step-by-step approach is
`adopted to explain the "how to" of the discipline. We believe that such an approach
`allows the student to gain greater comprehension of the subject matter, which
`allows adaptation of concepts to specific clinical drug dosing situations.
`Pharmacokinetic concepts are further illustrated by application to clinical
`dosing cases, including aminoglycosides, vancomycin, theophylline, digoxin, and
`phenytoin. These cases are designed to show the easily understandable, step(cid:173)
`by-step approach for performing appropriate clinical dosing consults. All cases
`provide the complete mathematical solutions for each calculation, allowing
`readers to "check their math." Equations are explained in detail, and all similar
`equations used throughout the text are cross-referenced to the basic concept. In
`addition there is a valuable appendix containing basic and drug-specific pharma(cid:173)
`cokinetic equations.
`This edition expands on several concepts including proper estimation of renal
`function, extended-interval aminoglycoside dosing, pharmacogenomic effects on
`drug metabolism, a phenytoin "cheat sheet" to help you through the calculations
`maze, and new vancomycin cases based on higher desired vancomycin levels and
`trough-only dose estimations. As with past editions the reader will find numerous
`clinical correlates throughout the text to further highlight specific clinical or math(cid:173)
`ematical explanations.
`The goal for this edition, as with the previous five editions, remains the same(cid:173)
`to provide the student or practitioner with the concepts and clinical applications
`needed for a better understanding of this complicated, yet vital, subject.
`
`William j. Spruill
`William E. Wade
`joseph T. DiPiro
`Robert A. Blouin
`jane M. Pruemer
`
`February 2014
`
`..
`
`v
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
`
`

`

`Acknowledgments
`
`We are indebted to our wives Paula Spruill, Theresa Wade, and Cecily DiPiro for
`their love and patience during the preparation of this sixth edition.
`
`A Note from the Authors on Using This Edition
`
`This book teaches the basic biopharmaceutic concepts, mathematical models, and
`clinical applications needed to determine such values as dose, interval, steady(cid:173)
`state concentration, etc. Specific conceptual and mathematical formulas are
`combined to solve more complex dosing situations. Eleven chapters contain a
`practice quiz to chart your progress, and there are three practice sets of questions
`with answers. The last four chapters are completely devoted to clinical cases that
`fully explain, step-by-step, how to dose several drugs that generally require serum
`drug concentrations. We strongly encourage you to attempt to solve these cases
`without looking at the step-by-step answers, and then when finished, check to see
`if you got them right.
`
`-WS,WW,JD
`
`A complete online course based on this book with four enrollment options is
`available through the University of Georgia Center for Continuing Education.
`To learn more go to:
`http:/ jwww.georgiacenter.uga.edujcoursesjhealthcare-pharmacy
`
`..
`
`vii
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 6
`
`

`

`Abbreviations
`
`a : distribution rate constant for two-compartment model
`AUC : area under plasma drug concentration versus time curve
`AUMC : area under the (drug concentration x time) versus time (moment) curve
`JJ : terminal elimination rate constant
`C : concentration
`average steady-state concentration
`
`C0, Cv C2
`
`initial Uust after infusion), first, second concentrations
`
`cin
`
`clast
`
`concentration in blood on entering organ
`
`last measured concentration
`
`maximum concentration
`
`cmax
`CmaxV CmaxZ first, SeCOnd maximum COncentratiOnS
`
`cmax(steadystate) steady-state maximum concentration
`
`cmin(steadystate) steady-state minimum concentration
`minimum concentration
`
`cmin
`
`cout
`
`cpeak
`
`css
`
`ct
`
`ctrough
`
`Cl : clearance
`Clb
`Clh
`Cl;
`Clm
`
`concentration in blood on leaving organ
`
`peak concentration
`
`steady-state concentration
`concentration at time t
`trough concentration
`
`biliary clearance
`
`hepatic (liver) clearance
`
`intrinsic clearance
`
`clearance by metabolism (mainly liver)
`
`Clother organs clearance by other organs
`Clp....,mx
`formation clearance for a given metabolite X
`Clp__,m 1
`fractional clearance of parent drug (P) to form metabolite 1 (m 7)
`Clr
`renal clearance
`Cit
`total body clearance
`cone : concentration
`Ll : change in
`E : extraction ratio
`
`continued on next page
`
`ix
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 7
`
`

`

`i
`
`Abbreviations
`
`X
`
`e : base of natural logarithm
`F : fraction of drug absorbed that reaches systemic
`circulation (bioavailability)
`fraction of m1 formed from a single dose of the
`parent drug
`
`Fm1
`
`fraction of unbound drug in plasma
`
`fraction of unbound drug in tissue
`
`FP
`Ft
`GFR : glomerular filtration rate
`GI : gastrointestinal
`K : elimination rate constant
`rate of drug infusion
`Ko
`K12
`
`rate constant for transfer of drug from
`compartment 1 to compartment 2
`
`KZ1
`
`rate constant for transfer of drug from
`compartment 2 to compartment 1
`
`absorption rate constant
`
`Ka
`Km
`
`Michaelis-Menten constant (drug concentration
`at which elimination rate = :0 Vmax)
`A. : terminal elimination rate constant
`mv mz, m3 : metabolites 1, 2, and 3
`m 1, Ul m 2, u• m 3, u : amount of m,, m2, or m3 excreted in the
`urine
`MRT: mean residence time
`n : number of doses
`Q : bloodflow
`Qh
`hepatic bloodflow
`
`S : salt form of drug
`SST : serum separator tube
`T : dosing interval
`t : time (after dose)
`time after end of infusion (t' = • - t for trough
`t'
`concentration)
`
`t"
`to
`TY.z
`
`t90%
`
`time (duration) of loading infusion
`
`time zero
`
`half-life
`
`time required to reach 90% of steady-state
`concentration
`
`V : volume; volume of distribution
`varea volume of distribution by area
`volume of central compartment
`vc
`vextrap extrapolated volume of distribution
`vp
`plasma volume
`vss
`tissue volume
`vt
`vmax maximum rate of the elimination process
`
`steady-state volume of distribution
`
`X : amount of drug
`Xo
`dose (or initial dose) of drug
`Xv X2 amount of drug at different times
`amount of drug in central compartment
`XC
`xd
`xp
`
`daily dose of drug
`
`amount of drug in peripheral compartment
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 8
`
`

`

`LESSON 1
`Introduction to
`Pharmacokinetics
`and Pharmacodynamics
`
`OBJECTIVES
`
`After completing Lesson 1, you should be able to:
`
`1. Define and differentiate between pharmacokinetics and clinical pharmacokinetics.
`
`2. Define pharmacodynamics and relate it to pharmacokinetics.
`
`3. Describe the concept of the therapeutic concentration range.
`
`4.
`
`Identify factors that cause interpatient variability in drug disposition and drug
`response.
`
`5. Describe situations in which routine clinical pharmacokinetic monitoring would be
`advantageous.
`
`6. List the assumptions made about drug distribution patterns in both one- and
`two-compartment models.
`
`7. Represent graphically the typical natural log of plasma drug concentration versus time
`curve for a one-compartment model after an intravenous dose.
`
`Pharmacokinetics is currently defined as the study of the time course of drug
`absorption, distribution, metabolism, and excretion. Clinical pharmacokinetics is
`the application ofpharmacokinetic principles to the safe and effective therapeutic
`management of drugs in an individual patient.
`Primary goals of clinical pharmacokinetics include enhancing efficacy and
`decreasing toxicity of a patient's drug therapy. The development of strong corre(cid:173)
`lations between drug concentrations and their pharmacologic responses has
`enabled clinicians to apply pharmacokinetic principles to actual patient situations.
`A drug's effect is often related to its concentration at the site of action, so it
`would be useful to monitor this concentration. Receptor sites of drugs are gener(cid:173)
`ally inaccessible to our observations or are widely distributed in the body, and
`therefore direct measurement of drug concentrations at these sites is not practical.
`For example, the receptor sites for digoxin are thought to be within the myocar(cid:173)
`dium. Obviously we cannot directly sample drug concentration in this tissue.
`However, we can measure drug concentration in the blood or plasma, urine, saliva,
`and other easily sampled fluids (Figure 1-1). Kinetic homogeneity describes the
`predictable relationship between plasma drug concentration and concentration at
`the receptor site where a given drug produces its therapeutic effect (Figure 1-2).
`Changes in the plasma drug concentration reflect changes in drug concentrations
`
`1
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 9
`
`

`

`r.
`
`Concepts in Clinical Pharmacokinetics
`
`2
`
`I
`Drug in , . Drug in
`Blood
`Tissue
`
`1111 I
`I
`
`~ ~
`
`Sample Removed for Drug Concentration
`Determination
`
`FIGURE 1-1.
`Blood is the fluid most often sampled for drug concentration
`determination.
`
`at the receptor site, as well as in other tissues. As
`the concentration of drug in plasma increases, the
`concentration of drug in most tissues will increase
`proportionally.
`Similarly, if the plasma concentration of a drug
`is decreasing, the concentration in tissues will also
`decrease. Figure 1-3 is a simplified plot of the drug
`concentration versus time profile after an intrave(cid:173)
`nous drug dose and illustrates this concept.
`The property of kinetic homogeneity is important
`for the assumptions made in clinical pharmaco(cid:173)
`kinetics. It is the foundation on which all therapeutic
`and toxic plasma drug concentrations are established.
`That is, when studying concentrations of a drug in
`plasma, we assume that these plasma concentrations
`directly relate to concentrations in tissues where the
`disease process is to be modified by the drug (e.g.,
`
`c::
`cno
`:::J ·.;::
`c ....
`....
`Ill
`mE E Cll
`Ill 0
`Ill c::
`
`- 0 Q.(.)
`
`Concentration of Drug in
`Tissues
`
`FIGURE 1-2.
`Relationship of plasma to tissue drug concentrations.
`
`High
`
`r:::
`0
`;;
`Clf!
`::::1-
`... r:::
`CCII
`0 r:::
`0
`()
`
`Kidney
`Plasma
`Low ...._ _____ -_-:_-:._-_- Receptor
`
`FIGURE 1-3.
`Drug concentration versus time.
`
`the central nervous system in Parkinson's disease or
`bone in osteomyelitis). This assumption, however,
`may not be true for all drugs.
`
`Clinical Correlate
`
`Drugs concentrate in some tissues because of
`physical or chemical properties. Examples include
`digoxin, which concentrates in the myocardium,
`and lipid-soluble drugs, such as benzodiazepines,
`which concentrate in fat.
`
`Basic Pharmacodynamic Concepts
`
`relationship
`the
`to
`refers
`Pharmacodynamics
`between drug concentration at the site of action
`and the resulting effect, including the time course
`and intensity of therapeutic and adverse effects.
`The effect of a drug present at the site of action is
`determined by that drug's binding with a receptor.
`Receptors may be present on neurons in the central
`nervous system (i.e., opiate receptors) to depress
`pain sensation, on cardiac muscle to affect the
`intensity of contraction, or even within bacteria to
`disrupt maintenance of the bacterial cell wall.
`For most drugs, th~ concentration at the site of
`the receptor determines the intensity of a drug's
`effect (Figure 1-4). However, other factors affect
`drug response as well. Density of receptors on the
`cell surface, the mechanism by which a signal is
`transmitted into the cell by second messengers
`(substances within the cell), or regulatory factors
`that control gene translation and protein produc-
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 10
`
`

`

`Lesson 1 1
`
`Introduction to Pharmacokinetics and Pharmacodynamics
`
`3
`
`0
`
`)
`/ Maximum Effect (E
`I('
`max
`
`100
`
`.. .............. -~-·;.;·..;..· .... - - -
`
`Cell Signal
`(2nd Messenger)
`
`Altered
`Receptor
`Expressron
`
`l "-:,. Cellular
`
`Event
`
`""- Gene Regulatron
`
`~
`Regulation of Protein Production
`I CELLI
`
`Drug
`
`Receptor
`
`FIGURE 1-4.
`Relationship of drug concentration to drug effect at the
`receptor site.
`
`tion may influence drug effect. This multilevel
`regulation results in variation of sensitivity to drug
`effect from one individual to another and also deter(cid:173)
`mines enhancement of, or tolerance to, drug effects.
`In the simplest examples of drug effect, there is
`a relationship between the concentration of drug
`at the receptor site and the pharmacologic effect. If
`enough concentrations are tested, a maximum effect
`(Emax) can be determined (Figure 1-5). When the
`logarithm of concentration is plotted versus effect
`(Figure 1-5), one can see that there is a concentration
`below which no effect is observed and a concentra(cid:173)
`tion above which no greater effect is achieved.
`One way of comparing drug potency is by the
`concentration at which SO% of the maximum effect
`is achieved. This is referred to as the 50% effective
`concentration or EC50• When two drugs are tested
`in the same individual, the drug with a lower EC 50
`would be considered more potent. This means that
`a lesser amount of a more potent drug is needed to
`achieve the same effect as a less potent drug.
`The EC 50 does not, however, indicate other impor(cid:173)
`tant determinants of drug response, such as the
`duration of effect. Duration of effect is determined
`by a complex set of factors, including the time that
`a drug is engaged on the receptor as well as intra(cid:173)
`cellular signaling and gene regulation.
`
`5
`
`10
`
`20
`
`Plasma Drug Concentration (mg/L)
`
`;;g
`e....
`ti
`Q) 50
`~ w
`
`100
`
`;;g
`e....
`ti 50
`£ w
`
`10
`
`100
`
`Plasma Drug Concentration (mg/L)
`(log scale)
`
`FIGURE 1-5.
`Relationship of drug concentration at the receptor site to effect
`(as a percentage of maximal effect).
`
`For some drugs, the effectiveness can decrease
`with continued use. This is referred to as toler(cid:173)
`ance. Tolerance may be caused by pharmacokinetic
`factors, such as increased drug metabolism, that
`decrease the concentrations achieved with a given
`dose. There can also be pharmacodynamic toler(cid:173)
`ance, which occurs when the same concentration
`at the receptor site results in a reduced effect with
`repeated exposure. An example of drug tolerance
`is the use of opiates in the management of chronic
`pain. It is not uncommon to find these patients
`requiring increased doses of the opiate over time.
`Tolerance can be described in terms of the dose(cid:173)
`response curve, as shown in Figure 1-6.
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 11
`
`

`

`Concepts in Clinical Pharmacokinetics
`
`4
`
`Later Doses
`
`100
`
`.......
`
`~ -(J 50
`~ w
`
`Plasma Drug Concentration (log scale)
`
`FIGURE 1-6.
`Demonstration of tolerance to drug effect with repeated dosing.
`
`To assess the effect that a drug regimen is likely
`to have, the clinician should consider pharmaco(cid:173)
`kinetic and pharmacodynamic factors. Both are
`important in determining a drug's effect.
`
`Clinical Correlate
`
`Tolerance can occur with many commonly
`used drugs. One example is the hemodynamic
`tolerance that occurs with continued use of
`organic nitrates, such as nitroglycerin. For this
`drug, tolerance can be reversed by interspersing
`drug-free intervals with chronic drug use.
`
`Clinical Correlate
`
`One way to compare potency between two drugs
`that are in the same pharmacologic class is to
`compare EC50 • The drug with a lower EC50 is
`considered more potent.
`
`and application of the resulting concentration
`data to develop safe and effective drug regimens.
`If performed properly, this process allows for the
`achievement of therapeutic concentrations of a
`drug more rapidly and safely than can be attained
`with empiric dose changes. Together with observa(cid:173)
`tions of the drug's clinical effects, it should provide
`the safest approach to optimal drug therapy.
`The usefulness of plasma drug concentration
`data is based on the concept that pharmacologic
`response is closely related to drug concentration
`at the site of action. For certain drugs, studies in
`patients have provided information on the plasma
`concentration range that is safe and effective in
`treating specific diseases-the therapeutic range
`(Figure 1-7). Within this therapeutic range, the
`desired effects of the drug are observed. Below it,
`there is greater probability that the therapeutic
`benefits are not realized; above it, toxic effects may
`occur.
`No absolute boundaries divide subtherapeutic,
`therapeutic, and toxic drug concentrations. A gray
`area usually exists for most drugs in which these
`concentrations overlap due to variability in indi(cid:173)
`vidual patient response.
`
`......
`~
`
`:0
`
`> = 50
`~ e a.
`
`Response
`
`Toxicity
`
`/,.,-·
`
`/
`
`/
`
`/
`
`/
`
`/
`
`/
`
`/
`
`/
`
`I
`
`/
`
`---
`
`20
`Drug Concentration (mg/L)
`
`30
`
`Therapeutic Drug Monitoring
`
`Therapeutic drug monitoring is defined as the
`use of assay procedures for determination of drug
`concentrations in plasma, and the interpretation
`
`FIGURE 1-7.
`Relationship between drug concentration and drug effects for a
`hypothetical drug.
`Source: Adapted with permission from Evans WE, editor.
`General principles of applied pharmacokinetics. In:
`Applied Pharmacokinetics, 3rd ed. Vancouver, WA: Applied
`Therapeutics; 1992. pp.1-3.
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 12
`
`

`

`Lesson 1 I Introduction to Pharmacokinetics and Pharmacodynamics
`
`5
`
`C) 30-
`::s
`.....
`25-
`Clc:::
`a::s.Q
`Eca
`20-
`CJ)
`.....
`a::s"E 15-
`-Q)
`a..(.)
`-
`c::: 10-
`C/)0
`~(.)
`5-
`C)
`:C
`
`• • -t Mean
`
`•
`1~0
`Dose (mg)
`
`(..)
`
`Q) en
`c:
`0
`0.. en
`Q) a:
`·a,
`0
`~
`E ....
`<13
`..c:
`0..
`
`Plasma Drug Concentration
`
`FIGURE 1-8.
`Example of variability in plasma drug concentration among
`subjects given the same drug dose.
`
`FIGURE 1-9.
`When pharmacologic effects relate to plasma drug
`concentrations, the latter can be used to predict the former.
`
`characteristics
`Numerous pharmacokinetic
`of a drug may result in variability in the plasma
`concentration achieved with a given dose when
`administered to various patients (Figure 1-8). This
`interpatient variability is primarily attributed to
`one or more of the following:
`• Variations in drug absorption
`• Variations in drug distribution
`• Differences in an individual's ability to metab(cid:173)
`olize and eliminate the drug (e.g., genetics)
`• Disease states (renal or hepatic insuffi(cid:173)
`ciency) or physiologic states (e.g., extremes
`of age, obesity) that alter drug absorption,
`distribution, or elimination
`• Drug interactions
`Therapeutic monitoring using drug concentration
`data is valuable when:
`• A good correlation exists between the
`pharmacologic response and plasma concen(cid:173)
`tration. Over at least a limited concentration
`range, the intensity of pharmacologic effects
`should increase with plasma concentration.
`This relationship allows us to predict phar(cid:173)
`macologic effects with changing plasma
`drug concentrations (Figure 1-9).
`• Wide intersubject variation in plasma drug
`concentrations results from a given dose.
`• The drug has a narrow therapeutic index
`(i.e., the therapeutic concentration is close
`to the toxic concentration).
`
`• The drug's desired pharmacologic effects
`cannot be assessed readily by other simple
`means (e.g., blood pressure measurement
`for antihypertensives).
`The value of therapeutic drug monitoring is
`limited in situations in which:
`• There is no well-defined therapeutic plasma
`concentration range.
`• The formation of pharmacologically active
`metabolites of a drug complicates the appli(cid:173)
`cation of plasma drug concentration data to
`clinical effect unless metabolite concentra(cid:173)
`tions are also considered.
`• Toxic effects may occur at unexpectedly
`low drug concentrations as well as at high
`concentrations.
`• There are no significant consequences asso(cid:173)
`ciated with too high or too low levels.
`Theophylline is an excellent example of a drug in
`which significant interpatient variability in pharma(cid:173)
`cokinetic properties exists. This is important from a
`clinical standpoint as subtle changes in serum concen(cid:173)
`trations may result in marked changes in drug response.
`Figure 1-10 shows the relationship between theoph(cid:173)
`ylline concentration (x-axis, on a logarithmic scale)
`and its pharmacologic effect (changes in pulmonary
`function [y-axis]). This figure illustrates that as the
`concentration of theophylline increases, so does the
`intensity of the response for some patients. Wide
`interpatient variability is also shown.
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 13
`
`

`

`•.
`
`Concepts in Clinical Pharmacokinetics
`
`6
`
`60
`
`.tl. F EV1
`
`>
`~ 40
`.!: c: Q)
`Q) e a.
`
`E
`
`§
`-g 20
`.!::!
`iii
`E
`0 z
`
`'E
`Q)
`E
`Ui>
`"' ~
`·-"'
`'CIIl
`.. Ill
`Q)
`Q)"
`ClQ)
`.. c
`Ill
`0
`'C
`
`A diagnosis is made
`
`A drug is selected
`
`t
`t
`
`Dosage schedule is
`.....---~~ designed to reach a
`target plasma
`concentration
`
`Drug is administered
`
`Patient assessments
`are performed
`
`Drug concentrations
`are determined
`
`t
`/ ~
`~ /
`
`L------ model is applied and
`
`A pharmacokinetic
`
`0
`
`20
`10
`5
`Theophylline Concentration (mg/L)
`
`30
`
`FIGURE 1-10.
`Relationship between plasma theophylline concentration and
`change in forced expiratory volume (FEV) in asthmatic patients.
`Source: Reproduced with permission from Mitenko PA, Ogilvie
`Rl. Rational intravenous doses of theophylline. N Eng/ J Med
`1973;289:600-3. Copyright 1973, Massachusetts Medical Society.
`
`Figure 1-11 outlines the process clinicians may
`choose to follow in making drug dosing decisions
`by using therapeutic drug monitoring. Figure 1-12
`shows the relationship of pharmacokinetic and
`pharmacodynamic factors.
`Examples of therapeutic ranges for commonly
`used drugs are shown in Table 1-1.
`As can be seen in this table, most drug concen(cid:173)
`trations are expressed as a unit of mass per volume.
`
`Clinical Correlate
`
`A drug's effect may also be determined by
`the amount of time that the drug is present
`at the site of action. An example is with beta(cid:173)
`lactam antimicrobials. The rate of bacterial
`killing by beta-lactams (the bacterial cell would
`be considered the site of action) is usually
`determined by the length of time that the drug
`concentration remains above the minimal
`concentration that inhibits bacterial growth.
`
`clinical judgment is
`used
`
`FIGURE 1-11.
`Process for reaching dosage decisions with therapeutic drug
`monitoring.
`
`TABLE 1-1. Therapeutic Ranges for Commonly
`Used Drugs
`
`Drug
`Digoxin
`Lidocaine
`Lithium
`Phenobarbital
`Phenytoin
`Quinidine
`Cyclosporine
`Valproic acid
`Carbamazepine
`Ethosuximide
`Primidone
`
`Range
`0.5-2.0 ng/ml
`1.5-5.0 mg/L
`0.6-1.4 mEq/L
`15-40 mg/L
`10-20 mg/L
`2-5 mg/L
`150-400 ng/ml
`50-100 mg/L
`4-12 mcg/L
`40-100 mg/L
`5-12 mg/L
`
`Source: Adapted with permission from Bauer LA. Clinical
`pharmacokinetics and pharmacodynamics. In: DiPiro JT, Talbert RL,
`Vee GC, et al., editors. Pharmacotherapy: a Pathophysiologic Approach,
`8th ed. New York: McGraw-Hill; http://Accesspharmacy.com
`
`Pharmacokinetic Models
`
`The handling of a drug by the body can be very
`complex, as several processes (such as absorption,
`distribution, metabolism, and elimination) work
`to alter drug concentrations in tissues and fluids.
`Simplifications of body processes are necessary to
`
`Opiant Exhibit 2059
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 14
`
`

`

`Lesson 1 I Introduction to Pharmacokinetics and Pharmacodynamics
`
`1
`
`Pharmacokinetics
`