{LEON SHARGEL / ANDREW B.C. YU} Hopewell EX1076 (Part 1 of 2)
`
`HSCODENUNIEELOCCTEATON
`Pharmacokinetics
`
`0.6.0.1
`
`Hopewell v. Merck
`IPR2023-00480
`
`Hopewell EX1076 (Part 1 of 2)
`Hopewell v. Merck
`IPR2023-00480
`
`1
`
`

`

`|
`APPLIED
`Biopharmaceutics
`e7Pharmacokinetics
`
`fourth edition
`
`Leon Shargel, PhD
`Vice President and Technical Director
`National Association of Pharmaceutical Manufacturers
`Garden City, New York
`
`Adjunct Associate Professor
`School of Pharmacy
`University of Maryland
`Baltimore, Maryland
`
`Andrew Yu, PhD
`Associate Professor of Pharmaceutics
`Albany College of Pharmacy
`Albany, NewYork*
`
`*Present affiliation
`HFD-520 CDER, FDA, Rockville, MD.
`(The contents of this book reflect the personal views of the authors and not that of the FDA.)
`
`
`
`APPLETON & LANGE
`
`Stamford, Connecticut
`
`2
`
`

`

`=
`
`‘
`
`Notice: The authors and the publisher of this volume have taken care to makecertain
`that the doses of drugs and schedules of treatment are correct and compatible with the
`standards generally accepted at the time of publication. Nevertheless, as new information
`becomes available, changes in treatment and in the use of drugs become necessary. The
`readeris advised to carefully consult the instruction and information material included in
`the package insert of each drug of therapeutic agent before administration. This advice is
`especially important when using, administering, or recommending new or infrequently
`used drugs. The authors and publisher disclaim all responsibility for any liability, loss, in-
`jury, or damage incurred as a consequence,directly or indirectly, of the use and applica-
`tion of any ofthe contents of this volume.
`
`
`
`Copyright © 1999 by Appleton & Lange
`A Simon & Schuster Company
`Copyright © 1993 by Appleton & Lange
`Copyright © 1985, 1980 by Appleton-Century-Crofts
`
`All rights reserved. This book, or any parts thereof, may not be used or reproducedin
`any manner without written permission. For information, address Appleton & Lange,
`Four Stamford Plaza, PO Box 120041, Stamford, Connecticut 06912-0041.
`
`www.appletonlange.com
`
`99 00010203 /10987654321
`
`Prentice Hall International (UK) Limited, London
`Prentice Hall of Australia Pty. Limited, Sydney
`Prentice Hall Canada, Inc., Toronto
`Prentice Hall Hispanoamericana, S.A., Mexico
`Prentice Hall of India Private Limited, New Delhi
`Prentice Hall ofJapan, Inc., Tokyo
`Simon & Schuster Asia Pte. Ltd., Singapore
`Editora Prentice Hall do Brasil Ltda., Ro de Janeiro
`Prentice Hall, Upper Saddle River, New Jersey
`
`Library of Congress Cataloging-in-Publication Data
`
`Shargel, Leon, 1941-
`Applied biopharmaceutics and pharmacokinetics / Leon Shargel,
`Andrew Yu. —4thed.
`Pp.
`cm.
`Includes bibliographical references and index.
`ISBN 0-8385-0278-4 (case : alk. paper)
`1. Biopharmaceutics.
`2. Pharmacokinetics.
`1945-
`.
`II. Title
`{[DNLM:
`1. Biopharmaceutics.
`1999]
`RM301.4.852
`615',7—dc21
`DNLM/DLC
`for Library of Congress
`
`I. Yu, Andrew B. C.,
`
`2. Pharmacokinetics. QV 38 S53la
`
`1999
`
`98-49079
`
`Editor-in-Chief: Cheryl L. Mehalik
`Production Service: York Production Services
`Art Coordinator: Eve Siegel
`Cover Design: Aimee Nordin
`Illustrator; Wendy Beth Jackelow
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`ISBN
`0-4385-0e78-4
`90000
`MMwi
`
`our
`
`80838
`
`502785
`
`ia
`
`3
`
`

`

`
`
`ANLEEho
`
`Preface / XIII
`
`1. REVIEW OF MATHEMATICAL FUNDAMENTALS/ 1
`
`Estimation and the Use of Calculators and Computers / 1
`Calculus / 6
`Graphs / 9
`Units in Pharmacokinetics / 16
`Measurement andthe Use of Significant Figures / 17
`Units for Expressing Blood Concentrations / 18
`Statistics / 18
`
`Rates and Orders of Reactions / 21
`Frequently Asked Questions / 26
`Learning Questions / 26
`References / 28
`
`Bibliography / 28
`
`}
`
`INTRODUCTION TO BIOPHARMACEUTICS AND
`PHARMACOKINETICS / 29
`
`Biopharmaceutics / 29
`Pharmacokinetics / 30
`
`Clinical Pharmacokinetics / 30
`
`Pharmacodynamics / 31
`’Toxicokinetics and Clinical Toxicology / 31
`Measurementof Drug Concentrations / 32
`Basic Pharmacokinetics and Pharmacokinetic Models / 36
`Frequently Asked Questions / 43
`Learning Questions / 43
`References / 44
`
`Bibliography / 45
`
`ONE-COMPARTMENT OPEN MODEL / 47
`
`Intravenous Route of Administration of Drug / 47
`Elimination Rate Constant / 48
`
`4
`
`

`

`
`
` VI CONTENTS
`
`Apparent VolumeofDistribution / 49
`Clearance / 52
`
`Calculation of k from Urinary Excretion Data / 58
`Clinical Application / 62
`Frequently Asked Questions / 63
`Learning Questions / 64
`Bibliography / 66
`
`4. MULTICOMPARTMENTAL MODELS / 67
`Two-Compartment Open Model / 69
`Three-Compartment Open Model / 85
`Determination of Compartment Models / 88
`Frequently Asked Questions / 95
`Learning Questions / 95
`References / 98
`Bibliography / 98
`
`5. PHYSIOLOGIC FACTORS RELATED TO
`DRUG ABSORPTION / 99
`Nature of the Cell Membrane / 99
`Passage of Drugs Across Cell Membranes / 101
`Route of Drug Administration / 108
`Frequently Asked Questions / 125
`Learning Questions / 126
`References / 127
`Bibliography / 128
`
`6. BIOPHARMACEUTIC CONSIDERATIONS IN DRUG
`PRODUCT DESIGN / 129
`Rate-Limiting Steps in Drug Absorption / 130
`Pharmaceutic Factors Affecting Drug Bioavailability / 131
`Physicochemical Nature of the Drug / 133
`Formulation Factors Affecting Drug Dissolution / 135
`In Vitro Dissolution Testing / 138
`Compendial Methodsof Dissolution / 140
`Methodsfor Testing Enteric-Coated Products / 143
`Meeting Dissolution Requirements / 143
`Unofficial Methods of Dissolution Testing / 144
`Problems of Variable Control in Dissolution Testing / 145
`
`5
`
`

`

`
`
` CONTENTS VII
`
`In Vitro—In Vivo Correlation of Dissolution / 146
`
`Failure of Correlation of Jn Vitro Dissolution to Jn Vive Absorption / 150
`Biopharmaceutic Considerations / 151
`Pharmacodynamic Considerations / 152
`Drug Considerations / 152
`Drug Product Considerations / 152
`Patient Considerations / 154
`
`Route of Drug Administration / 154
`Clinical Example / 160
`Frequently Asked Questions / 164
`Learning Questions / 164
`References / 165
`
`Bibliography / 165
`
`MODIFIED-RELEASE DRUG PRODUCTS/ 169
`
`Modified-Release Drug Products / 169
`Biopharmaceutic Factors / 172
`Dosage Form Selection / 174
`Drug Release from Matrix / 174
`Advantages and Disadvantages of Extended-Release Products / 175
`Kinetics of Controlled-Release Dosage Forms / 176
`Pharmacokinetic Simulation of Extended-Release Products / 178
`Types of Extended-Release Products / 180
`Considerations in the Evaluation of Modified-Release Products / 193
`
`Regulatory Studies for the Evaluation of Modified-Release Products / 195
`Evaluation of Jn Vivo Bioavailability Data / 198
`Frequently Asked Questions / 200
`Learning Questions / 200
`References / 201
`
`Bibliography / 202
`
`TARGETED DRUG DELIVERY SYSTEMS AND
`BIOTECHNOLOGICAL PRODUCTS / 205
`
`Targeted Drug Delivery / 205
`Biotechnology / 207
`Bioequivalence of Biotechnology Products / 219
`Frequently Asked Questions / 220
`Learning Questions / 220
`References / 220
`Bibliography / 221
`
`
`
`6
`
`

`

`VIII=CONTENTS
`
`9. PHARMACOKINETIC MODEL OF ORAL ABSORPTION / 223
`Pharmacokinetics of Drug Absorption / 223
`Zero-Order Absorption Model / 224
`First-Order Absorption Model / 225
`Significance of Absorption Rate Constants / 242
`Frequently Asked Questions / 242
`Learning Questions / 243
`References / 244
`Bibliography / 245
`
`10. BIOAVAILABILITY AND BIOEQUIVALENCE / 247
`Definitions / 247
`Purpose of Bioavailability Studies / 249
`Relative and Absolute Availability / 250
`Methodsfor Assessing Bioavailability / 252
`Bioequivalence Studies / 256
`Design and Evaluation of Bioequivalence Studies / 259
`Bioequivalence Example / 265
`Generic Substitution / 271
`Frequently Asked Questions / 272
`Learning Questions / 273
`References / 278
`Bibliography / 279
`
`ll. PHYSIOLOGIC DRUG DISTRIBUTION AND PROTEIN
`BINDING / 281
`
`Physiologic Factors / 281
`Calculation of Apparent VolumeofDistribution / 299
`Protein Binding of Drugs / 303
`Kinetics of Protein Binding / 306
`Determination of Binding Constants and BindingSites
`by Graphic Methods / 309
`Clinical Significance of Drug—Protein Binding / 313
`Frequently Asked Questions / 320
`Learning Questions / 320
`References / 322
`Bibliography / 323
`
`12. DRUG ELIMINATION AND CLEARANCE CONCEPTS/ 325
`Drug Elimination / 325
`The Kidney / 326
`Drug Clearance / 333
`
`
`
`ssnaandonemsenseeAil
`
`7
`
`

`

`
`
`CONTENTS IX
`
`Physiologic Approach to Clearance / 335
`Renal Clearance / 336
`
`Renal Drug Excretion / 337
`Drug Clearance / 340
`Determination of Renal Clearance / 34]
`Relationship of Clearance Elimination Half-Life and
`Volume of Distribution / 347
`
`Frequently Asked Questions / 349
`Learning Questions / 350
`References / 351
`Bibliography / 351
`
`13.
`
`HEPATIC ELIMINATION OF DRUGS / 353
`
`Fraction of Drug Excreted Unchanged (/.) and Fraction of Drug
`Metabolized (1 — /.) / 354
`Clinical Focus / 355
`
`Pharmacokinetics of Drugs and Metabolites / 355
`Anatomy and Physiology of the Liver / 362
`Hepatic Enzymes Involved in the Biotransformation of Drugs / 365
`Drug Biotransformation Reactions / 366
`Route of Drug Administration and Extrahepatic Drug Metabolism / 376
`First-Pass Effects / 377
`Hepatic Clearance / 383"
`Significance of Drug Metabolism / 389
`Biliary Excretion of Drugs / 390
`Frequently Asked Questions / 393
`Learning Questions / 393
`References / 396
`Bibliography / 397
`
`14.
`
`‘INTRAVENOUS INFUSION / 399
`One-Compartment Model Drugs / 399
`Infusion Methodfor Calculating Patient Elimination Half-Life / 404
`Loading Dose Plus IV Infusion / 406
`Estimation of Drug Clearance and Vp fromInfusion Data / 412
`Estimation of k and Vj of Aminoglycosides in Clinical Situations / 412
`Intravenous Infusion of Two-Compartment Model Drugs / 413
`Frequently Asked Questions / 414
`Learning Questions / 415
`References / 417
`Bibliography / 417
`
`8
`
`

`

`X
`
`CONTENTS
`
`15. MULTIPLE-DOSAGE REGIMENS / 419
`
`Drug Accumulation / 419
`Repetitive Intravenous Injections / 424
`Intermittent Intravenous Infusion / 430
`
`Multiple Oral Dose Regimen / 433
`Loading Dose / 436
`Determinationof Bioavailability and Bioequivalence in a
`Multiple-Dose Regimen / 437
`Bioequivalence Studies / 438
`Dosage Regimen Schedules / 441
`Frequently Asked Questions / 445
`Learning Questions / 445
`References / 446
`Bibliography / 447
`
`16. NONLINEAR PHARMACOKINETICS / 449
`
`Saturable Enzymatic Elimination Processes / 451
`Drug Elimination by Capacity-Limited Pharmacokinetics:
`One-Compartment Model, IV Bolus Injection / 454
`Equations for Drugs Distributed as One-Compartment Model and
`Eliminated by Nonlinear Pharmacokinetics / 467
`Time-Dependent Pharmacokinetics / 468
`Bioavailability of Drugs That Follow Nonlinear Pharmacokinetics / 469
`Nonlinear Pharmacokinetics Due to Drug-Protein Binding / 469
`Frequently Asked Questions / 472
`Learning Questions / 472
`References / 473
`Bibliography / 474
`
`17, APPLICATION OF PHARMACOKINETICS IN CLINICAL
`SITUATIONS / 475
`
`Individualization of Drug Dosage Regimen / 475
`Therapeutic Drug Monitoring / 476
`Design of Dosage Regimens / 484
`Conversion From Intravenous Infusion to Oral Dosing / 485
`Determination of Dose / 487
`Effect of Changing Dose and Dosing Interval on Cyax®, Gnin®,
`and C,,* / 489
`Determination of Frequency of Drug Administration / 490
`Determination of Both Dose and Dosage Interval / 491
`Nomograms and Tabulations in Designing Dosage Regimens / 492
`
`sie
`
`9
`
`

`

`
`
`CONTENTS XI
`
`Determination of Route of Administration / 493
`
`Dosing of Drugs in Infants and Children / 494
`Dosing of Drugs in the Elderly / 496
`Dosing of Drugs in the Obese Patient / 500
`Pharmacokinetics of Drug Interactions / 501
`Inhibition of Drug Metabolism / 504
`Inhibition of Biliary Excretion / 506
`Induction of Drug Metabolism / 506
`Altered Renal Reabsorption Due to Changing Urinary pH / 506
`Inhibition of Drug Absorption / 507
`Effect of Food on Drug Disposition / 507
`Adverse Viral Drug Interactions / 508
`Population Pharmacokinetics / 508
`Frequently Asked Questions / 522
`Learning Questions / 523
`References / 526
`Bibliography / 528
`
`18.
`
`DOSAGE ADJUSTMENT IN RENAL AND
`HEPATIC DISEASE / 531
`
`Pharmacokinetic Considerations / 531
`General Approaches for Dose Adjustment in Renal Disease / 532
`Dose Adjustment Based on Drug Clearance / 533
`Method Based on Changes in the Elimination Rate Constant / 534
`Measurement of GlomerularFiltration Rate / 535
`
`Serum Creatinine Concentration and Creatinine Clearance / 536
`
`Dosage Adjustment for Uremic Patients / 54]
`Extracorporeal Removal of Drugs / 554
`Dialysis / 555
`Hemoperfusion / 561
`‘Hemofiltration / 561
`Effect of Hepatic Disease on Pharmacokinetics / 562
`Frequently Asked Questions / 567
`Learning Questions / 568
`References / 569
`Bibliography / 570
`
`RELATIONSHIP BETWEEN PHARMACOKINETIC AND
`PHARMACODYNAMICS / 573
`
`Pharmacodynamics and Pharmacokinetics / 573
`Relation of Dose to Pharmacologic Effect / 575
`
`10
`
`10
`
`

`

`XII
`
`CONTENTS
`
`
`
`Relationship Between Dose and Duration ofActivity (fem),
`Single IV Bolus Injection / 577
`Effect of Both Dose and Elimination Half-Life on the
`Duration of Activity / 579
`Effect of Elimination Half-Life on Duration of Activity / 580
`Rate of Drug Absorption and Pharmacodynamic Response / 584
`Drug Tolerance and Physical Dependency / 585
`Hypersensitivity and Adverse Response / 586
`Drug Distribution and Pharmacologic Response / 587
`Pharmacodynamic Models / 590
`Frequently Asked Questions / 603
`Learning Questions / 603
`References / 604
`
`Bibliography / 605
`
`20.
`
`PHYSIOLOGIC PHARMACOKINETIC MODELS, MEAN
`RESIDENCE TIME, AND STATISTICAL MOMENT THEORY/ 607
`Physiologic Pharmacokinetic Models / 608
`Mean Residence Time (MRT) / 619
`Statistical Moment Theory / 624
`Mean Absorption Time (MAT) and MeanDissolution Time (MDT) / 635
`Selection of Pharmacokinetic Models / 637
`
`Frequently Asked Questions / 639
`Learning Questions / 639
`References / 640
`
`Bibliography/ 641
`
`Appendix A Statistics / 643
`
`Appendix B Application of Computers in Pharmacokinetics / 653
`
`Appendix C Solutions to Frequently Asked Questions (FAQ) and Learning Questions / 667
`
`Appendix D Guiding Principles for Human and Animal Research / 727
`
`Appendix E
`
`Popular Drugs and Pharmacokinetic Parameters / 731
`
`Appendix P Glossary / 737
`
`Index / 739
`
`11
`
`

`

`INTRODUCTION TO
`BIOPHARMACEUTICS
`AND
`PHARMACOKINETICS
`
`BIOPHARMACEUTICS
`
`Biopharmaceutics considers the interrelationship of the physicochemical properties
`of the drug, the dosage form in which the drug is given, and the route of admin-
`istration on the rate and extent of systemic drug absorption. Thus, biopharma-
`ceutics involves factors that influence the (1) protection of the activity of the drug
`within the drug product, (2) the release of the drug from a drug product, (3) the
`rate of dissolution of the drug at the absorption site, and (4) the systemic absorp-
`tion of the drug.Figure 2-1 is a general schemedescribing this dynamic relation-
`ship.
`The study of biopharmaceutics is based on fundamental scientific principles and
`experimental methodology. These methods must be able to assess the impact of
`the physical and chemical properties of the drug, drugstability and large scale pro-
`duction of the drug and drug product onthe biological performance of the drug.
`Moreover, biopharmaceutics considers the requirements of the drug and dosage
`form in a physiological environment and the drug’s intended therapeutic use and
`route of administration.
`Studies in biopharmaceutics use both in-vitro and in-vivo methods. In-vitro meth-
`ods are procedures employing test apparatus and equipment withoutinvolving lab-
`oratory animals or humans. /n-vivo methods are more complex studies involving
`human subjects or laboratory animals. Some of these methodswill be discussed in
`Chapter 5. Historically, pharmacologists evaluated the relative systemic drug avail-
`ability im vivo after giving a drug product to an animal or human and then com-
`paring specific pharmacologic, clinical, or possible toxic responses. For example,
`a drug such as isoproterenol causes an increase in heart rate when given intra-
`venously but has no observable effect on the heart when given orally at the same
`dose level. Therefore, systemic drug availability may differ according to the route
`
`29
`
`12
`
`12
`
`

`

`30
`
`CHAPTER 2.
`
`
`INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS
`
`Drug release and
`dissolution
`
`|
`|
`
`Drugin systemic
`circulation
`
`Drug in
`tissues
`
` Elimination
`
`
`Excretion and
`metabolism
`
`Pharmacologic or
`clinical effect
`
`Figure 2-1. Scheme demonstrating the dynamic relationship between the drug, the drug product,
`and the pharmacologic effect.
`
`of administration. In addition, the bioavailability (a measure of systemic availabil-
`ity of a drug) may differ from one drug product to another containing the same
`drug. This difference in drug bioavailability may be manifested by observing the
`difference in the therapeutic effectiveness of the drug products.
`
`PHARMACOKINETICS
`
`Pharmacokinetics involves the kinetics of drug absorption, distribution, andelimi-
`nation (ie, excretion and metabolism). The description of drug distribution and
`eliminationis often termed drug disposition. The study of pharmacokinetics involves
`both experimental and theoretical approaches. The experimental aspect of phar-
`macokinetics involves the development ofbiological sampling techniques, analyti-
`cal methods for the measurement of drugs and metabolites, and procedures that
`facilitate data collection and manipulation. The theoretical aspect of pharmacoki-
`netics involves the development of pharmacokinetic models that predict drug dis-
`position after drug administration. The application ofstatistics is an integral part
`of pharmacokinetic studies. Statistical methods are used for pharmacokinetic pa-
`rameterestimation and data interpretation. Statistical methods are applied to phar-
`macokinetic models to determine data error and structural model deviations.
`Mathematics and computer techniques form the theoretical basis of manyphar-
`macokinetic methods. Classical pharmacokinetics is a study of theoretical models
`focusing mostly on model development and parameterization.
`
`CLINICAL PHARMACOKINETICS
`
`Clinical pharmacokinetics is the application of pharmacokinetic methodsin drug ther-
`apy. Clinical pharmacokinetics involves a multidisciplinary approach to individu-
`ally optimized dosing strategies based on the patient’s disease state and
`patient-specific considerations. The study of clinical pharmacokinetics of drugs in
`disease states requires input from medical and pharmaceutical research. Table 2.1
`is a list of 10 age-adjusted rates of death from 10 leading causes of death in the
`USA, 1993. The influence of many diseases on drug disposition is not adequately
`studied. Age, gender, genetic, and ethnic differences can also result in pharmaco-
`kinetic differences that may affect the outcome ofdrug therapy. The study of phar-
`macokinetic differences of drugs in various population groupsis termed population
`
`.
`
`nntl
`
`13
`
`

`

`INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS CHAPTER 2.
`
`ot
`
`Ratio of Age-Adjusted Death Rates, by Male/Female Ratio from the 10
`TABLE 2.1
`Leading Causes of Death in the USA, 1993
`DISEASE
`
`RANK
`
`MALE:FEMALE
`
`Disease of heart
`Malignant neoplasms
`Cerebrovascular diseases
`
`Chronic obstructive pulmonary diseases
`Accidents and others*
`Pneumonia and influenza
`Diabetes mellitus
`HIV infections
`Suicide
`Homicide and legal intervention
`
`|
`2
`3
`
`4
`5
`6
`7
`8
`9
`10
`
`“Death due to adverse effects suffered as defined by CDC.
`
`Source: CDCMMWR (Morbidity and Mortality Weekly Report), March |, 45:8, 1996
`
`1g
`1.5
`led
`
`1.6
`2.6
`1.6
`1.2
`6.3
`44
`3.8
`
`pharmacokinetics (Sheiner and Ludden, 1992), Another important aspect of phar-
`macokinetics is therapeutic drug monitoring (TDM). When drugs with narrow thera-
`peutic indices are used in patients,
`it
`is necessary to monitor plasma drug
`concentrationsclosely by taking periodic blood samples. The pharmacokinetic and
`drug analysis services necessary for safe drug monitoring are generally provided by
`the clinical pharmacokinetic service (CPKS). Some drugs frequently monitored are the
`aminoglycosides and anticonvulsants. Other drugs closely monitored are those used
`in cancer chemotherapy in order to minimize adverse side effects (Rodman and
`Evans, 1991).
`
`PHARMACODYNAMICS
`
`Pharmacodynamics refers to the relationship between the drug concentration at the
`site of action (receptor) and pharmacologic response, including biochemical and
`physiologic effects that influence the interaction of drug with the receptor. Thein-
`teraction of a drug molecule with a receptor causes the initiation of a sequence of
`molecular events resulting in a pharmacologic or toxic response. Pharmacokinetic-
`pharmacodynamic models are constructed to relate plasma drug level to drug con-
`centration in the site of action and establish the intensity and time course of the
`drug: Pharmacodynamics and pharmacokinetic-pharmacodynamic models are dis-
`cussed more fully in Chapter 19,
`
`TOXICOKINETICS AND CLINICAL TOXICOLOGY
`
`Toxicokinetics is the application of pharmacokinetic principles to the design, con-
`duct and interpretation of drug safety evaluation studies (Leal et al, 1993) and used
`in validating dose related exposure in animals. Toxicokinetic data aids in the in-
`terpretation of toxicologic findings in animals and extrapolation of the resulting
`data to humans. Toxicokinetic studies are performed in animals during preclini-
`cal drug development and may continue after the drug has beentested in clinical
`trials.
`
`14
`
`
`
`14
`
`

`

`32
`
`
`
`CHAPTER 2. INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS
`
`Clinical toxicology is the study of adverse effects of drugs and toxic substances
`(poisons) in the body. The pharmacokinetics of a drug in an over-medicated (in-
`toxicated) patient may be very different from the pharmacokinetics of the same
`drug given in therapeutic doses. At very high doses, the drug concentration in the
`body may saturate enzymes involved in the absorption, biotransformation, or ac-
`tive renal secretion mechanisms thereby changing the pharmacokinetics from {in-
`ear to nonlinear pharmacokinetics. Nonlinear pharmacokinetics is discussed in
`Chapter 16. Drugs frequently involved in toxicity cases include acetaminophen, sal-
`icylates, morphine andthetricylic antidepressants (TCA). Manyof these drugs can
`be assayed conveniently by fluorescence immunoassay (FIA)kits.
`
`MEASUREMENT OF DRUG CONCENTRATIONS
`
`Sensitive, accurate, and precise analytical methodsare available for the direct mea-
`surement of drugs in biologic samples, such as milk, saliva, plasma, and urine.
`Measurements of drug concentrationsin these biological samples are generallyval-
`idated so that accurate information is generated for pharmacokinetic and clinical
`monitoring. In general, chromatographic methods are more discriminating since
`chromatography separates the drug from other related materials that may cause
`assay interference.
`
`Sampling of Biologic Specimens
`
`Onlya few biologic specimens may be obtained safely from the patient to gain in-
`formation as to the drug concentration in the body. /nvasive methodsinclude sam-
`pling blood, spinal fluid, synovial fluid, tissue biopsy, or any biologic material that
`requires parenteral or surgical intervention in the patient. In contrast, noninvasive
`methods include sampling ofurine, saliva, feces, expired air, or any biologic ma-
`terial that can be obtained without parenteral or surgical intervention. The mea-
`surement of drug concentration in each ofthese biologic materials yields different
`information.
`
`Drug Concentrations in Blood, Plasma, or Serum
`
`Measurement ofdrug concentration (levels) in the blood, serum, or plasmais the
`most direct approach to assessing the pharmacokinetics of the drug in the body,
`Whole blood contains the cellular elements including red blood cells, white blood
`cells, platelets, and various other proteins, such as albumin and globulins. In gen-
`eral, serumor plasmais used for drug measurement. To obtain serum, whole blood
`is allowed to clot and the serum is collected from the supernatant after centrifu-
`gation. Plasma is obtained from the supernatant of centrifuged whole blood to
`which an anticoagulant, such as heparin, has been added. Therefore, the protein
`content of serum and plasmais not the same. Plasma perfusesall the tissues ofthe
`body including the cellular elements in the blood. Assuming that a drug in the
`plasma is in dynamic equilibrium with the tissues, then changes in the drug con-
`centration in plasma will reflect changes in tissue drug concentrations.
`
`Plasma Level-Time Curve
`The plasmalevel-time curve is generated by measuring the drug concentration in
`plasma samples taken at various time intervals after a drug product is administered.
`
`-
`
`15
`
`

`

`_—
`
`
`
`INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS CHAPTER 2. 33
`
`The concentration of drug in each plasma sample is plotted on rectangular coor-
`dinate graph paper against the corresponding time at which the plasma sample
`was removed. As the drug reaches the general (systemic) circulation, plasma drug
`concentrations will rise up to a maximum. Usually absorption of a drug is more
`rapid than elimination. As the drug is being absorbed into the systemic circulation,
`the drugis distributed to all the tissues in the bodyandis also simultaneously being
`eliminated. Elimination of a drug can proceed by excretion or biotransformation
`or a combination ofboth.
`Therelationship of the drug level—-time curve and various pharmacologic param-
`eters for the drug is shown in Figure 2-2. MEC and MTCrepresent the minimum
`effective concentration and minimum toxic concentration of drug, respectively, For some
`drugs, such as those acting on the autonomic nervoussystem,it is useful to know
`the concentration of drugthatwill just barely produce a pharmacologic effect (ie,
`MEC). Assuming the drug concentration in the plasmais in equilibrium with the
`tissues, the MEC reflects the minimum concentration of drug needed at the re-
`ceptors to producethe desired pharmacologic effect. Similarly, the MTC represents
`the drug concentration needed to just barely produce a toxic effect. The onset time
`correspondsto the time required for the drug to reach the MEC.The intensity of
`the pharmacologic effect is proportional to the numberof drug receptors occu-
`pied, which is reflected in the observation that higher plasma drug concentrations
`producea greater pharmacologic response, up toa maximum. The durationof drug
`action is the difference between the onset time and the time for the drug to de-
`cline back to the MEC.
`In contrast, the pharmacokineticist can also describe the plasma level-time curve
`in terms of such pharmacokinetic terms as peak plasmalevel, time for peak plasma
`level, and area under the curve, or AUC (Fig. 2-3). The time of peak plasma level
`is the time of maximum drug concentration in the plasma and is a rough marker
`of average rate of drug absorption. The peak plasmalevel or maximumdrug con-
`
` wana nanan nana s------- MTC
`
`Peak concentration
`
`&
`e
`a
`3
`
`3
`e
`a
`3
`
`Onset
`time
`
`Tena
`
`ime
`
`Time
`
`Figure 2-2. Generalized plasma level-time
`curve after oral administration of a drug.
`
`Plasma level-time curve showing
`Figure 2-3.
`peak time and concentration. The shaded por-
`tion represents the AUC (area underthe curve}.
`
`16
`
`16
`
`

`

`34
`
`
`
`CHAPTER 2. INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS
`
`centrationis related to the dose, the rate constant for absorption, and elimination
`constant of the drug. The AUCis related to the amount of drug absorbed system-
`ically. These and other pharmacokinetic parameters are discussed in succeeding
`chapters.
`
`Drug Concentrations in Tissues
`
`Tissue biopsies are occasionally removed for diagnostic purposes suchas the ver-
`ification of a malignancy. Usually, only a small sample oftissue is removed, mak-
`ing drug concentration measurement difficult. Drug concentrations in tissue
`biopsies may not reflect drug concentration in other tissues nor drug concen-
`tration in the tissue from which the biopsy material was removed. For example,
`if the tissue biopsy was for the diagnosis of a tumorwithin the tissue, the blood
`flow to the tumorcells may not be the same as the blood flowto other cells in
`this tissue. In fact, for manytissues, blood flow to one part of the tissues need
`not be the same as the blood flowto anotherpart of the same tissue. The mea-
`surement of the drug concentration in tissue biopsy material may be usedtoas-
`certain if the drug reached the tissues and obtained the proper concentration
`within the tissue.
`
`Drug Concentrations in Urine and Feces
`
`Measurement of drug in urine is an indirect method to ascertain the bioavailabil-
`ity of a drug. The rate and extent of drug excreted in the urine reflects the rate
`and extent of systemic drug absorption. The use of urinary drug excretion
`measurements to establish various pharmacokinetic parameters is discussed in
`Chapter 10.
`Measurementof drug in feces mayreflect drug that has not been absorbedafter
`an oral dose or mayreflect drug that has been expelled bybiliary secretion after
`systemic absorption. Fecal drug excretion is often performedin mass balance stud-
`ies in which the investigator attempts to account for the entire dose given to the
`patient. For a mass balance study, both urine andfeces are collected and their drug
`content measured. For certain solid oral dosage forms that do not dissolve in the
`gastrointestinal tract but slowly leach out drug, fecal collection is performed tore-
`cover the dosage form. The undissolved dosage formis then assayed for residual
`drug.
`
`Drug Concentrations in Saliva
`
`Saliva drug concentrations have been reviewed for manydrugs for therapeutic drug
`monitoring (Pippenger and Massoud, 1984). Because only free drug diffuses into
`the saliva, saliva drug levels tend to approximate free drug rather than total plasma
`drug concentration. Thesaliva/plasma drug concentrationratio is less than 1 for
`many drugs. The saliva/plasma drug concentration ratio is mostly influenced by
`the pKa of the drug and pH ofthe saliva. Weak acid drugs and weak base drugs
`with pKasignificantly different than pH 7.4 (plasma pH) generally have better cor-
`relation to plasma drug levels. The saliva drug concentrations taken after equilib-
`rium with the plasma drug concentration generally provide more stable indication
`of drug levels in the body. The use of salivary drug concentrations as a therapeu-
`tic indicator should be used with caution and preferably used as a secondaryindi-
`cator,
`
`17
`
`

`

`
`
`INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS CHAPTER 2. 35
`
`Forensic Drug Measurements
`
`Forensic science is the application ofscience to personal injury, murder, and other
`legal proceedings. Drug measurements in tissues obtained at autopsy or in other
`bodily fluids such as saliva, urine, and blood may beuseful if the person has taken
`an overdose of a legal medication, has been poisoned, or has been using drugs of
`abuse such as opiates (eg, heroin), cocaine or marijuana. The appearanceofso-
`cial drugs in blood, urine, and saliva drug analysis show short-term drug abuse.
`These drugs may be eliminated rapidly, making it more difficult to prove that the
`subject has been using drugs of abuse. The analysis for drugs of abusein hair sam-
`ples by verysensitive assay methods, such as gas chromatography coupled with mass
`spectrometry, provides information regarding past drug exposure. A recent study
`(Cone et al, 1993) showedthat the hair samples from subjects who were known
`drug abusers contained cocaine and 6-acetylmorphine, a metabolite of heroine(di-
`acetylmorphine).
`
`Significance of Measuring Plasma Drug Concentrations
`Theintensity of the pharmacologic or toxic effect of a drug is often related to the
`concentration of the drug at the receptorsite, usually located in the tissuecells.
`Because most ofthetissue cells are richly perfused with tissue fluids or plasma,
`checking the plasma drug level is a responsive method of monitoring the course
`of therapy.
`Clinically, individual variations in the pharmacokinetics of drugs are quite com-
`mon. Monitoring the concentration of drugs in the bloodor plasmaascertains that
`the calculated dose actually delivers the plasmalevel required for therapeutic ef-
`fect. With somedrugs, receptor sensitivity in individuals varies so that monitoring
`ofplasma levels is needed to distinguish the patient who is receiving too much of
`a drug from the patient who is supersensitive to the drug. Moreover, the patient’s
`physiologic functions may be affected by disease, nutrition, environment, concur-
`rent crug therapy, and otherfactors. Pharmacokinetic models allow more accurate
`interpretation of the relationship between plasma drug levels and pharmacologic
`response. In the absence of pharmacokinetic information, plasma drug levels are
`relatively useless in dosage adjustment. For example, suppose a single blood sam-
`ple from a patient was assayed and found to contain 10 wg/mL. According to the
`literature, the maximumsafe concentration of