`
`Third Edition
`
`Applied Pharmacokinetics
`Principles of Therapeutic Drug Monitoring
`
`Edited by
`
`William E. Evans, PharmD.
`First Tennessee Professor of
`
`, Clinical Pharmacy and Pediatrics
`University of Tennessee,
`Memphis, TN
`and
`3
`
`Chair, Pharmaceutical Division
`St. Jude Children’s Research Hospital
`
`k
`
`-
`
`.
`
`Jerome J. Schentag, PharmD.
`,. Professor of Pharmaceutics and Pharmacy
`State University of New York at Buffalo
`Buffalo, NY
`and
`
`Director, Clinical Pharmacokinetics Laboratory
`Millard Fillmore Hospital
`
`William J. Jusko, Ph.D.
`Professor of Pharmaceutics
`
`School of Pharmacy
`State University of New York at Buffalo
`Buffalo, NY
`
`Assistant Editor
`
`Mary V. Relling, Pharm.D.
`Assistant Member
`Pharmaceutical Division
`
`St. Jude Children's Research Hospital
`and
`
`Assistant Professor of Clinical Pharmacy
`University of Tennessee
`Memphis, TN
`
`Applied Therapeutics, Inc.
`Vancouver, WA
`
`J. Waack, RDR, ORR, COR
`
`EXHIBIT MOM
`(Z , 9J7 , :2
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`

`

`
`Printing and Binding: Edwards Brothers, Ann Arbor, MI
`Cover Design: Steven B. Naught
`
`Other Publications by Applied Therapeutics, Inc:
`Applied Therapeutics: The Clinical Use of Drugs, 5th edition
`Edited by Mary Anne Koda—Kirnble and Lloyd Y. Young
`ISBN 0—915486—14—8
`Basic Clinical Pharmacokinetics, 2nd edition
`by Michael E. Winter
`ISBN 0—915486—08—3
`Bedside Clinical Pharmacokinetics, revised edition
`by Carl C. Peck, Dale P. Conner, and M. Gail Murphy
`ISBN O~915486—10—5
`
`3 a /
`hflfli
`6 I
`I
`é, (2
`,/7)
`[9/
`/ [/0]
`
`Clinical Clerkship Manual
`Edited by Larry Boh
`ISBN 0—915486—17—2
`
`Drug Interactions & Updates
`by Philip D. Hansten and John R. Horn
`ISBN 0—8121—1381—0 ISSN 027143707
`Handbook of Applied Therapeutics, 2nd edition
`by Mary Anne Koda—Kimble, Lloyd Y. Young,
`Wayne A. Kradjan, and B. Joseph Guglielmo, Jr.
`ISBN 04915486464
`
`
`
`Applied Therapeutics, Inc.
`PO. Box 5077
`Vancouver, WA 986684077
`Phone: (206) 253—7123
`FAX:
`(206) 253—8475
`
`©
`Monitoring:
`Therapeutics, Inc,
`
`1-11—1
`
`

`

`
`
`Contents
`
`Acknowledgments ................................................................................................... iv
`
`Contributing Authors .................................................................................................v
`
`Editorial Review Board ........................................................................................... xv
`
`Notice to the Reader ............................................................................................. xxii
`
`Preface to Third Edition ...................................................................................... xxiii
`
`Applied Pharmacokinetics—A Prospectus .......................................................... P—l
`Gerhard Levy
`
`1. General Principles of Applied Pharmacokinetics ........................................... 1—1
`William E. Evans
`
`2. Guidelines for Collection and Analysis of Pharmacokinetic Data ................. 2—1
`William J. Jusko
`
`3. Analysis of Pharrnacokinetic Data for Individualizing
`Drug Dosage Regimens ................................................................................ 3—1
`Carl C. Peck, David Z. D ’Argenio, and John H. Rodman
`
`4. Pharmacodynamics .......................................................................................... 4—1
`Richard L. Lalonde
`
`5. Influence of Protein Binding and Use of
`Unbound (Free) Drug Concentrations .......................................................... 5—1
`Janis J. MacKichan
`
`6. Influence of Liver Function on Drug Disposition ........................................... 6-1
`Kim LR. Brouwer, George E. Dukes, and J. Robert Powell
`
`7. Genetic Polymorphisms of Drug Metabolism ................................................ 7—1
`Mary V. Relling and William E. Evans
`
`8. Influence of Renal Function and Dialysis on Drug Disposition ..................... 8-1
`Gary R. Matzke and Stephen P. Millikin
`
`9. Special Pharmacokinetic Considerations in the Elderly .................................9-1
`Michael Mayersohn
`
`10. Special Pharmacokinetic Considerations in Children .................................. 10-1
`Rebecca L Milsap, Malcolm R. Hill, and StanleyJ. Szefler
`
`11. Special Pharmacokinetic Considerations in the Obese ................................ 11—1
`Robert/1. Blouin and Mary H.H. Chandler
`
`xix
`
`

`

`
`
`
`
`__
`
`-
`-
`-
`$12. Dietary Influences on Drug Dlsposmon ...................
`ff
`Mary H.H. Chandler and Robert A. Blown
`J“
`.
`...................................... 13—1
`51:"
`13. Theophyllme .......................................
`5:
`DavidJ. Edwards, Barbara J. Zarownz, and Richard L. Slaughter
`.
`-
`................................................. 14-1
`53;
`14. Am1noglycos1des .........................................
`.2:
`Darwin E. Zaske
`I.
`-
`{3"
`15. Vancomycm ..............................................
`1;
`Gary R. Matzke
`16. Chloramphenicol .......................................................................................... 16-1
`Milap C. Nahata
`
`................................... 12—1
`
`.................................................... 15—1
`
`4.
`5.:
`1:;
`5:5?
`5:
`-'i_l_.
`
`';5‘
`.1:
`
`
`
`'
`
`__:_._,
`
`.a
`.
`
`:j:
`,1:
`
`"‘
`
`35-
`
`5
`
`,5
`
`.4
`
`':
`
`17. Dual Individualization with Antibiotics: Integrated Antlblotlc
`Management Strategies for Use in Hospitals ............................................ 17—1
`Jerome J. Schentag, Charles H. Ballow, Joseph A. Paladino,
`and David E. Nix
`18. Commentary on Dual Individualization with Antibiotics ............................ 18—1
`Michael N. Dudley
`
`19. Zidovudine .................................................................................................... 19—1
`Gene D. Morse
`
`20. Digoxin ......................................................................................................... 20—1
`Richard H. Reuning, Douglas R. Geraets, Mario L. Rocci Jr.,
`and Peter H. Vlasses
`
`21. Lidocaine ......................................................................................................21—1
`
`John A. Pieper and Kenneth E. Johnson
`
`22. Procainamide ................................................................................................ 22—1
`James D. Coyle and John J. Lima
`
`23. Quinidine ...................................................................................................... 23—1
`Clarence T. Ueda
`
`24. Beta Blockers................................................................................................24—1
`David J- Kazierad, Karen D. Schlanz, and Michael B. Bonmfi
`
`25. Phenytoin .........................................................................25 ~1
`Thomas N. Tozer and Michael E. Winter
`
`25- Carbfimazepine, Valproic Acid, Phenobarbital, and Ethosuximide ............26—1
`Rene H. Levy, Alan J. Wilensky, and Gail D. Anderson
`
`27. Corticosteroids .............................................
`William J, Jusko and Elizabeth A. Ludwig
`28. Cyclosporine ..........................................
`Gary C. Yee and Daniel R. Salomon
`29. Methotrexate ................................
`William R Cram and William E_ EVan‘; ......................................................
`
`............................................
`
`...................................
`
`27-1
`
`28—1
`
`29 1
`
`xx
`
`€
`

`

`
`
`30. Heparin ......................................................................................................... 30—1
`Robert J. Cipolle and Keith A. Rodvold
`
`31. Warfarin ........................................................................................................ 31—1
`R. Stephen Porter and William T. Sawyer
`
`32. Salicylates ..................................................................................................... 32—1
`Sydney H. Dromgoole and Daniel E. Furst
`
`33. Cyclic Antidepressants ................................................................................. 33—1
`C. Lindsay De Vane and C. Rick Jarecke
`
`34. Lithium ......................................................................................................... 34—1
`
`Stanley W. Carson
`
`Index ...................................................................................................................... I-l
`
`xxi
`
`

`

`
`
`(cid:19)(cid:14)(cid:18)
`
`
`
`
`
`Chapter 2
`
`Guidelines for Collection
`
`and Analysis of
`Pharmacokinetic Data
`
`William]. Iusko
`
`Efforts in both theoretical and applied pharmacokinetics over the past decades
`have emphasized the utilization of the principles of physiological pharmaco-
`kinetics and the use of noncompartmental approaches to analysis of drug
`disposition data. Physiological pharmacokinetics involves the deployment of
`pharmacokinetic models and equations based on anatomical constructions and
`
`functions, such as tissue masses, blood flow, organ metabolism and clearance,
`
`specific drug input rates and sites, and processes of partitioning, binding, and
`transport.Whi1e the complete applications of physiologic systems analysis may
`require extensive models,I even the simplest ofpharmacokinetic treatments should
`have a physiologic basis for interpretation. Noncompartmental techniques in
`pharmacokinetics can serve in this regard. This term applies to curve analysis
`methods of data treatment which do not require a specific model and which yield
`the prime phannacokinetic parameters, such as systemic clearance (CL) and
`steady-state volume of distribution (VSS), which summarize the major elimination
`and distribution properties.
`This chapter is intended to provide an overview of major components of
`experimentally applied pharrnacokinetics. A summary is provided of the most
`relevant concepts, models, equations, and caveats which may be useful in the
`design, analysis, and interpretation of pharmacokinetic studies. References are
`provided for more complete details of the aSSumptions, derivations, and applica-
`tions of these guidelines and relationships. This material may be helpful as a
`checklist in designing animal and/or human experiments in phannacokinetics and
`in reviewing drug disposition reports; with greater elaboration, it has served as a
`basis for a graduate course in physiological pharmacokinetics.
`
`

`

`
`
`2-2
`
`Chapter 2: Guidelines for Collection and Analysis
`
`CONTEXT OF PHARMACOKINETICS
`
`okinetic analysis must be made in context of, be consistent with, and
`A harmac
`.
`‘
`d disposrtion character—
`P
`explain the array of basic data regarding the properties an
`.
`.
`istics of the drug.
`.
`.
`The tasks of model and equation selection and interpretation of data require a
`fundamental appreciation and integration of principles of physiology, pharmacol-
`ogy, biochemistry, physicochemistry, analytical methodology, mathematics, and
`statistics. Pharmacokinetics has derived from these disciphnes, and the relevant
`aspects of many of these areas must be considered in reaching any conclusions
`regarding a particular set of data. The physicochemical properties of a drug such
`as chemical form (salt, ester, complex), stability, partition coefficient, pKa, and
`molecular weight can affect drug absorption, distribution, and clearance. A drug
`disposition profile must be correlated with studies of structure—activity, disposition
`in alternative species, perfused organ experiments, tissue or microsomal metabo-
`lism, tissue drug residues, disease-state effects, and pharmacology and toxicology.
`For example, a much larger LD50 for oral doses of a drug compared with parenteral
`administration may be indicative of either poor gastrointestinal absorption (low
`aqueous solubility?) or a substantial first-pass effect. Drug metabolism pathways
`may differ between species, but the biotransforrnation rate (Vmax and Km) of
`microsomes, homogenates, or perfused organs can often be applied directly to
`whole-body disposition rates and often correlate between species.“3
`In general, the pharmacokinetic model and analysis should either conform to,
`or account for, the known properties and accumulated data related to the drug. One
`set of disposition data may misrepresent the characteristics of the drug because of
`any one or combination of reasons. Experienced judgment is usually required in
`the final interpretation of any experimental findings and analysis.
`
`ARRAY OF BASIC DATA
`
`Pharrnacokinetic studies often serve to answer specific questions about the
`properties of a drug. For example, a limited experimental protocol can easily
`resolve the question of how renal impairment affects the systemic clearance of an
`antibiotic. In the total design and implementation of pharmacokinetic studies, an
`ideal and complete array of experimental data should include a number of
`considerations:
`
`A. The dosage form should be pre~analyzed. All calculations stem from
`knowledge of the exact dose given [e.g., CL : dose / AUC (area under the plasma
`concentration-time curve)]. Most commercial dosage forms are inexact, and
`content uniformity should be examined. Vials or ampules of injectables typically
`contain some overage and require analysis or aliquoting for administration of a
`precise dose. Solid dosage forms are required to yield an average of the stated
`quantity of drug with limited variability, but both injectable and solid forms may
`be inaccurate for pharmacokinetic purposes. Manninen and Koriionen4 provide an
`excellent example of both the variability and lack of stated quantity of digoxin in
`many commercial tablets. One product contained a range of 39% to 189% of the
`
`
`
`
`
`

`

`
`
`Chapter 2: Guidelines for Collection and Analysis
`
`2-3
`
`stated 0.25 mg dose of digoxin, while the most uniform product, Lanoxin,
`exhibited a range of about 95% to 106% for one batch of drug. To evaluate the
`potential uncertainty of the dose of drug used in disposition studies, it may be
`necessary to collect and analyze replicate doses of the product used. Poorly soluble
`and highly potent drugs are of most concern regarding erratic formulation.
`
`B. Accuracy in administration of the dose should be confirmed. All doses
`
`should be timed exactly for starting time and duration of administration. For ease
`in subsequent calculations, pharmacokinetic equations can be used to correct data
`from short-term infusion studies to the intercepts expected after bolus injection.
`The particular materials used in drug administration may cause loss of drug. In
`one of the most dramatic examples, MacKichan et al.5 found immediate loss of
`about 50% of a dose of intravenous diazepam by adsorption during passage
`
`through the plastic tubing of an infusion set. Inline filtration can also significantly
`reduce the potency of drugs administered intravenously.6
`C. Attention to methods and sites of blood collection is needed. Ideally, blood
`
`samples should be collected by direct venipuncture in clean glass tubes without
`anticoagulant. Otherwise, the presence of possible artifacts should be tested. In
`the absence of any in vitro artifacts, serum and plasma concentrations are usually
`
`identical, and these terms are commonly used interchangeably. However, there
`are several reasons why they may not be identical. For example, the presence of
`heparin can result in increased free fatty acid concentrations, causing altered
`plasma-protein binding.7 Also, the type of blood collection tube or anticoagulant
`may be a factor.8 If protein binding is temperature dependent, it may be necessary
`to centrifuge the blood sample at 37 CC to avoid changes in red cell-plasma
`distribution of some compounds.9 These problems primarily pertain to weak
`bases, such as propranolol and imipramine, for which binding to 0Ll acid glyco—
`
`protein is appreciable and displacement alters plasma—red cell drug distribution.
`Plasma or serum protein binding and red cell partitioning should be measured
`at 37 0C over the expected range of plasma drug concentrations. Both rate and
`degree of binding and uptake are theoretically important. This information may
`be especially needed for interpretation or normalization of nonlinear disposition
`patterns.
`
`Sometimes the site of blood collection and the presence of a tourniquet can alter
`the composition of the blood sample: serum proteins, calcium, and magnesium
`concentrations rise by 5% to 13% during venous stasis.10
`One of the major assumptions employed in most pharmacokinetic studies is
`that venous blood collected from one site adequately reflects circulating arterial
`blood concentrations. For practical purposes, venous blood samples are usually
`collected. The pharmacokinetic analysis may need to be somewhat qualified,
`because arterial and capillary blood concentrations may differ markedly from
`venous blood concentrations of many drugs.“ The AUC of arterial versus venous
`blood is expected to be identical for a non-clearing organ, and thus the principal
`difference expected is in distribution volumes. Physiologically, organ uptake of
`drugs occurs from the arterial blood, and clearance organ models are based on
`arterial-venous extraction principles.
`
`

`

`F7 ‘-
`2-4
`Chapter 2: Guidelines for Collection and Analysis
`
`D. Serum (or blood) concentration datafollowing intra ven ous injection (bolus
`or infusion) provides partial characterization of drug disposition properties.
`Accurate assessment of volumes of distribution, distribution clearance (CLD), and
`systemic clearance (CL) can best be attained with intravenous washout data.
`E. Serum (or blood) concentration data following oral doses of the drug in
`solution and common dosageforms provides additional pharmacokinetic param-
`eters related to absorption and intrinsic clearance. The doses (or resultant serum
`or blood concentrations of drug) should be comparable to those from the intrave-
`nous dose. These data permit assessment of either oral clearance (CLW) or
`bioavailability (F), and 0f the mean absorption time (MAT). If relevant, other
`routes of administration should be studied. For these, the FDA guidelines for
`bioavailability studies should be consulted.12
`F. Three dosage levels (both oral and intravenous) should be administered to
`span the usual therapeutic range of the drug to permit assessment of possible
`dose-dependence (nonlinearity) in absorption, distribution, and elimination.
`G. Urinary excretion rates of drug (as a function of time, dose and route of
`administration) should be measured to accompany the above studies. Urinary
`excretion is often a major route of drug elimination, and analyses permit quanti—
`tation of renal clearance (CLR). Collection of other excreta or body fluids (feces,
`bile, milk, saliva) may pemiit determination of other relevant elimination or
`distributional pathways.
`
`
`
`
`
`SerumGentamicmConcentration,pg/ml
`
`
`
`
`|
`
`
`l
`
`
`
`
`1
`
`Dose
`Central
`Compartment (
`
`Tissue
`Compartment
`
`Uptake——'
`4—
`Release
`
`LRenal Clearance .4 O
`
`0.4
`
`0.2
`
` 16
` 1210 14
`
`
`
`Time. Days
`
`
`
`
`ofile for gentamicin disposition during multiple
`terminal phase caused by strong tissue binding. These
`data were characterized with a two-comp
`artment model (inset) which included prediction of
`drug remaining in the body at the time of
`death of the patients. Data from reference 15 .
`
`
`
`

`

`
`
`Chapter 2: Guidelines for Collection and Analysis
`
`2—5
`
`H. Many drug metabolites are either pharmacologically active or otherwise
`of pharmacokinetic interest. Phase I products such as hydroxylated or
`demethylated metabolites are most commonly either active or toxic.13 Their
`measurement will allow evaluation of AUC and mean residence time (MRT) and
`perhaps permit quantitation of metabolite formation and disposition clearances.
`I. Multiple-dose and steady-state experiments are necessary if therapeutic use
`of the drug relies on steady-state concentrations. The duration of multiple-dosing
`in relation to the terminal half-life is crucial for ascertaining applicability to
`steady-state conditions. Comparative single- and multiple—dose studies permit
`further assessment of linearity and/or allow determination of chronic or time—de—
`pendent drug effects, such as enzyme induction,‘4 unusual accumulation,” or
`drug-induced alterations in disposition. For example, aminoglycoside uptake into
`tissues is extremely slow and difficult to assess from single-dose studies. Multi—
`ple-dose washout measures (see Figure 2—1) led to observation of a slow disposi-
`tion phase for gentamicin which was the result of tissue accumulation and release.”
`1. Tissue analyses add reality and specificity to drug distribution characteris—
`
`tics. Comprehensive studies in animals permit detection of unusual tissue affinities
`while generating partition coefficients (Kpi) for individual tissues (Va). This can
`lead to complete physiologic models for the drug in each species studied."2
`Autopsy or biopsy studies in man may extend or complement pharmacokinetic
`
`
`
`Zi
`
`—2 g< DL
`
`u
`P—
`90
`LL]
`.
`
`ED
`
`200
`
`300
`
`MEASURED AMOUNT IN THE BODY, mg
`
`Figure 2-2. Correlation of gentamicin accumulation in the body determined by pharmacoki-
`netic analysis ofserum concentration data (see Figure 2 -1 ) and by direct analysis ofbody tissues
`obtained at autopsy from the same patients who were evaluated pharmacokinetically before
`death. Dotted line indicates correlation. Data from references 15 and 16.
`
`a
`
`200
`
`C)
`
`E a(
`
`I)
`UJ
`.—
`
`Ip
`
`

`

`
`
`2—6
`
`Chapter 2: Guidelines for Collection and Analysis
`
`
`
`found to be extremely helpful (see Figure 2-2)
`'
`~
`.
`.
`roach was
`ations. This a
`fgentamicin in man which was antiCipated
`PP
`CXPBCt
`16
`in confirming the strong tissue binding 0 ‘
`.
`on the basis of serum concentration profiles (see Figure 2—l).
`.
`K Suitable drug disposition studies in patients wztlz various diseases and ages
`or given sec0ndary drugsform the basis of clinical pharmacokinetics. .Pertu‘rba—
`tions in organ function, blood flow, or response willoften alter drug disposnion
`in a way that may warrant quantitative characterisation. General prinCiples may
`not always apply, and each drug needs indiVidualiped study. For example, while
`hepatic dysfunction may diminish the rate of ox1dat10n of many drugs, some
`compounds, such as oxazepam and lorazepam, are predominantly metabolized by
`glucuronide conjugation, a process largely unaffected by liver diseases such as
`cirrhosis.i7 Each disease state may require evaluation of direct effects on pharma—
`cokinetic processes such as changes in renal clearance caused by kidney disease.
`However, indirect changes also require attention, such as the effects on both
`distribution and clearance caused by altered plasma protein binding.18 Finally,
`commonly encountered patient factors such as smoking habit‘9 and obesity may
`cause unusual changes in drug disposition and require Specific study and notation
`
`in patient surveys.
`L. Many questions ofdrug disposition can be resolvedfrom selected, carefully
`designed studies, and alternative types of information may be sufiicient to validate
`various assumptions and reduce experimental procedures. The investigator’s
`obligation is to adequately assess the literature, to avoid unwarranted assumptions,
`and to seek experimental strategies that would resolve a proposed hypothesis.
`A comprehensive overview ofpharmacokinetic needs in drug development has
`been constructed by Balant et a1.20
`
`DRUG ASSAYS
`
`Cenainty of specificity, sensitivity, and accuracy in measurement of drugs and
`their metabolites is a sine qua non in pharmacokinetics and deserves considerable
`attention. Guidelines for quality assurance in laboratory analyses have been
`concisely summarized by the American Chemical Society.“ It is now common-
`place to report the linearity, the coefficient of variation of the assay at low and
`high drug concentrations, the minimum level of detection, and the procedures used
`to assure specificity and stability, especially in the presence of metabolites,
`secondary drugs, and in specimens from diseased patients. Microbiological assays
`are notoriously unreliable with problems due to other antibiotics and active
`metabolites. An extreme case of metabolite inclusion is in the use of radioisotopic
`tracers; total radioisotope counts generally yield total drug and metabolite activity
`and possibly the products of radiolysis. Separation of parent drug and individual
`metabolites is required for specificity. Microbiologic, enzymatic, and radioimmu—
`noassays are often of uncertain specificity, and matrix effects may require prepa—
`ration of standards in each patient’s pretreatment plasma. Most drug companies
`provide analytical-grade samples of their drugs (and sometimes metabolites) to
`qualified investigators upon written request.
`
`
`
`

`

`
`
`Chapter 2: Guidelines for Collection and Analysis
`
`2-7
`
`Sample Handling
`
`Coupled with assay reliability is concern for the stability of drug in biological
`specimens, even in the frozen state. Ampicillin is unusual in that it is less stable
`frozen than when refrigerated.22 Some drug esters, such as hetacillin (a prodrug of
`ampicillin), continue hydrolyzing in blood and during the bioassay. Penicillamine
`is unstable in the presence of plasma proteins, and immediate deproteination after
`blood collection avoids loss ofreduced penicillamine before analysis.23 Cyclospor—
`ine is best assayed in EDTA rather than heparinized blood as the latter yields red
`cell aggregates that increase assay variability.94 Measurement of drug stability in
`blood will reveal whether hydrolysis can occur in blood or whether exposure to
`other body organs is required. Additional concerns in handling samples from a
`pharmacokinetic study include labeling and record—keeping procedures and doc—
`umentation of storage conditions.
`
`Sample Timing
`
`Appropriate pharmacokinetic evaluation requires properly timed specimens.
`The simplest and least ambiguous experiment is the determination of systemic
`plasma clearance during continuous infusion at steady state:
`
`k
`CL = *3
`CSS
`
`(Eq. 2—1)
`
`where k0 is the infusion rate and C55 is the steady—state plasma or serum concen-
`tration. For this equation to apply, the infusion period must be sufficiently long
`(about five terminal disposition half—lives) to allow steady state to be attained.
`Alternatively, a loading dose or short—term infusion may be administered to more
`rapidly achieve equilibrium.24
`Practical and cost—effective methods are available for designing optimal sam-
`pling strategies for kinetic experiments where the number of specimens is lim-
`ited,25 such as in the clinic. Optimal designs largely depend on the likely “true”
`model parameter values, the structure of the model, and the measurement error. A
`sequential approach has been advocated with pilot studies and a sampling schedule
`which distributes time points over the major phases of drug disposition as the first
`step. Subsequent experiments can then resolve a Specific hypothesis.
`A common and severe problem in applied pharmacokinetics is the inadequate
`or incomplete measurement of drug washout from the system, either because of
`premature termination of sample collection or because of analytical limitations.
`The “true” terminal disposition phase must be examined in order for most aspects
`of data treatment and interpretation to be accurate. For example, the early distrib-
`utive phase of aminoglycoside disposition measured by bioassay had long been
`accepted as the only phase, yet more sensitive radioimmunoassays, lengthier
`sample collection, and evaluation of multiple-dose washout revealed the slower
`phase of prolonged drug release from tissues (see Figure 2—1).
`The two summary physiologic parameters in pharmacokinetics, namely sys-
`temic clearance and steady—state volume of distribution, can be most easily
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2—8
`
`Chapter 2: Guidelines for Collection and Analysis
`
`calculated by use of the area under the plasma concentration—time curve (AUC)
`and the area under the moment curve (AUMC). Both area values require extrap-
`olation of plasma concentrations to time infinity, and the AUMC is, in particular,
`prone to exaggerated error from an inaccurate terminal slope.“ If analytical or
`ethical constraints limit blood sample availability, extended saliva or urine collec-
`tion may aid in defining the terminal disposition slope while adding one or two
`other pharrnacokinetic parameters to the analysis. Urine may be particularly useful
`in this regard (if renal clearance is linear), as the sample volume is large and urine
`concentrations often exceed plasma values by one or more orders of magnitude.
`The “midpoint” (Cay) is generally the most desirable time to collect blood
`samples to match an excretion interval in order to assess a time-dependent clearance
`process:
`
`
`Excretion Rate
`Amount Excreted
`Clearance —
`—-
`
`Cav
`
`AUC
`
`(Eq. 2-2)
`
`The arithmetic mean time is acceptable for slow processes, but errors will be
`incurred if the kinetic process produces rapid changes in plasma concentrations.”
`It IS common to miss an early exponential phase of drug disposition because of
`infrequent blood sampling. For a polyexponential curve with intercepts Ci and
`slopes 11 the total AUC is:
`
`
`
`

`

`Chapter 2: Guidelines for Collection and Analysis
`
`2-9
`
`lfthe initial distributive phase is missing (area = C1 / M), then the error incurred
`in calculation of a clearance parameter (CL 2 dose / AUC) is
`
`% of CL error =
`
`100 9
`
`7»,
`
`AUC
`
`(Eq.24)
`
`BASIC PHYSIOLOGIC PARANETERS
`
`The evolution of complete physiologic models1 and clearance concepts applied
`to perfused organ systems,“29 with the restrictions incurred by the limited in vivo
`visibility offered by most blood or plasma drug disposition profiles, has led to the
`employment of partial physiologic models for description of pharmacokinetic
`data. One such model is shown in Figure 2—3. Its construction and use should be
`viewed with some conceptual flexibility, and this material will apply to linear
`processes unless stated otherwise.
`
`Volumes
`
`The drug in blood or plasma (Cp) is considered to be part of the central
`compartment (VG) . The minimum value of VC is plasma volume (VP) , but, either
`because drug diffuses rapidly out of plasma or the number of early time data are
`limited, the Vc value often exceeds VP.
`Drug which is located outside of VP or Vcis, of course, present in tissues. The
`apparent volume of the tissue compartment (VT) has two basic determinants:
`physiologic weight or volume of each tissue (Vfi) and partition or distribution
`factors (Kpi). In analysis of plasma concentration-time profiles, [issues must
`commonly be clustered together (including the clearing organs) thus:
`
`This equation leads to definition of one of the primary pharmacokinetic
`parameters with a physiologic basis, volume of distribution at steady state (VSJI
`
`%=%+Vr
`
`@qzm
`
`Table 2-1. Physiological Determinants ofDrug Partition or
`Distribution Ratios between Tissues and Plasma
`
`
`Active transport
`Donnon ion effect
`
`Plasma protein binding
`Tissue binding
`
`Lipid partitioning
`pH differences
`
`
`

`

`r
`
`_
`
`'
`
`' '
`
`'
`
`-
`
`-
`
`..
`
`....—
`--—=._.—..'.......
`
`.-. ..-.-|-.
`
` ’J‘fll
`
`2 10
`
`Chapter 2: Guidelines for Collection and Analysis
`
`If plasma and tissue binding are the sole determinants of nonhomogeneous
`distribution of drug in the body, then one definition of V55 13
`
`f
`V”: VP + H ' VT
`
`(Eq. 2-7)
`.
`.
`0
`where f and fuI are the fractions of drug unbound in plasma and tissue.3 Other
`factors may also contribute to the apparent partition coefficient of drugs between
`tissues and plasma (see Table 2‘ 1). Since, by definition, VP and 2V... comprise total
`body weight (TBW),
`
`TBW = VP + Evil
`
`(Eq. 2-8)
`
`then the quotient of
`
`
`Vss
`KB : TBw
`
`(Eq. 2.9)
`
`defines the distribution coefficient (K13), a physicochemical and physiological
`measure of the average tissuezplasma ratio of the drug throughout the body.
`Approximate values of KD and the primary rationalization of the size of KD are
`
`Table 2-2. Distribution Coefficients (K0) for Various Drugs and
`Probable Physiologic (Physicochemical) Cause
`
`V
`55
`Drug
`KD _ TBW
`Explanation/indication
`
`
`g
`
`Indocyanine Green
`
`lnulin
`
`Ampicillin
`
`Theophylline
`
`Antipyrine
`
`Gentamicin
`
`Tetracycline
`Diazepam
`Digoxin
`
`Imipramine
`
`0.06
`
`0.25
`
`0.25
`
`0.5
`
`0.6
`
`1.1
`
`1.6
`1.7
`8.0
`
`10.0
`
`Strong binding to plasma proteins and
`limited extravascular permeability.
`
`Distribution limited to plasma and
`interstitial fluid owing to large molecular
`weight (5500) and lipid insolubility.
`
`Limited intracellular distribution owing to
`poor lipid solubility (common to
`penicillins).
`
`Moderate plasma binding and distribution
`primarily into total body water.
`Slight plasma binding and fairly uniform
`distribution into total body wa