GOODMAN and GILMANE
`
`The
`
`PharmacolagicaI
`Basis of
`
`Therapeutigs
`
`SEVENTH EDITION
`
`;
`13
`3
`i
`3
`
`!
`
`MACMILLAN PUBLISHING COMPANY
`New York
`
`COLLIER MACMILLAN CANADA,
`
`INC.
`Toronto
`COLLIER MACMILLAN PUBLISHERS
`London
`
`' Amnea|1025
`
`Amneal v. Supernus
`
`25
`
`
`
`

`

`
`
`COPYRIGHT © 1985. MACMILLAN PUBLISHING COMPANY.
`A DIVISION OF MACMILLAN, INC.
`
`PRINTED lN THE UNITED STATES OF AMERICA
`
`All rights reserved. No part of this book may be reproduced or
`transmitted in any form or by any means, electronic or mechanical,
`including photocopying, recording, or any information storage and
`retrieval system. without permission in writing from the Publisher.
`
`Earlier editions entitled The Pharmacological Basis of Therapeutics
`copyright l94l and 1955, © copYright 1965, copyright © 1970,. and
`copyright © 1975 by Macmillan Publishing Company. Earlier edition
`entitled Goodman and Gilman 's The Pharmacological Basis of
`Therapeutics copyright © 1980 by Macmillan Publishing Company.
`
`MACMlLLAN PUBLISHING COMPANY
`866 Third Avenue 0 New York, N .Y. 10022
`
`COLLIER MACMILLAN CANADA, INC
`
`COLLIER MACMILLAN PUBLISHERS - London
`
`Library of Congress catalog card number 85—15356
`
`Printing: 2345678
`
`Year: 67890l
`
`In this textbook, reference to proprietary names of drugs is ordinar-
`ily made only in chapter sections dealing with preparations. Such
`names are given in SMALL—CAP TYPE? usually immediately following
`the official or nonproprietary titles. Proprietary names of drugs also
`appear in the Index.
`
`PREFAI
`
`T H E first edit
`pharmacology
`appearance of
`menting on the
`sance or perhz
`ogy. The secoz
`post—World W
`ten as multiau‘:
`and function 0
`clinical science
`herein, becaus:
`all subsequent
`successful use
`students and 1:
`States and aim
`Those famili
`organization 01
`Nevertheless, t
`dozens of new-I
`5 years but alsc
`that knowledge
`a complete bio
`molecular gene
`impact in pharn
`ucts permit larg
`even greater Sig
`romoiecules ha.
`choline and ins1
`protein, and ma
`few years will
`predict the terti
`functions select
`impressive strid
`ing events, reg:-
`topics appears I
`practical applic:
`of this growth is
`presented in An
`the seventh edit
`Most of the c
`current undertag
`standing new au
`volume, Theod(
`In addition to
`and help receive
`special note is n
`tions of the tcx
`
`26
`
`

`

`1211 and
`iarma~
`
`|. This
`'harac-
`ied by
`e ade—
`5 limit
`1 their
`arma—
`
`rns for
`
`n and
`func-
`ieally,
`:ful in
`iatho-
`
`ice its
`clini—
`of its
`at the
`luno~
`coki—
`nd/or
`
`verse
`nany
`.toxi—
`perly
`icals
`) the
`isom-
`
`CHAPTER
`
`1
`
`PHARMACOKINETICS: THE DYNAMIQS OF
`
`DRUG ABSORPTION, DISTRIBUTION,
`
`AND ELIi‘i/iiNATiON
`
`Leslie Z. Benet and Lewis B. Sheiner
`
`To produce its characteristic effects, a
`drug must be present in appropriate con—
`centrations at its sites of action. Although
`obviously a function of the amount of drug
`administered,
`the concentrations attained
`also depend upon the extent and rate of its
`absorption, distribution, binding or locali—
`zation in tissues, biotransforaiation, and
`excretion. These factors are depicted in
`Figure 1—1.
`
`PHYSICOCHEMICAL FACTORS
`IN TRANSFER OF DRUGS
`ACROSS MEMBRANES
`
`The absorption, distribution, biotransfor-
`mation, and excretion of a drug all involve
`its passage across cell membranes. It is es—
`sential, therefore, to consider the mecha-
`
`nisrns by which drugs cross membranes and
`the physicoche‘micai properties of mole-
`cules and membranes that influence this
`transfer. Important characteristics of a drug
`are its molecular size and shape, solubility
`at the site of its absorption, degree of ioni-
`zation, and relative lipid solubility of its
`ionized and nonionized forms.
`When a drug permeates a cell, it must
`obviously traverse the cellular plasma
`membrane. Other barriers to drug move-
`ment may be a single layer of cells (intesti~
`rial epithelium) or several layers of cells
`(skin). Despite these structural differences,
`the diffusion and transport of drugs across
`these various boundaries have many com-
`mon characteristics, since drugs in general
`pass through cells rather than between
`them. The plasma membrane thus repre-
`sents the common barrier.
`
` LOCUS OF
`I
`
`
`ACTION
`; RESERVOIRS
`"RECEPTORS"
`
`
`i5
`
`Free ___,,‘ Sound
`Bound *1 Free
`
`
`
`
`TISSUE
`
`
`
`
`SYSTEMIC
`
`
`ClRCULATiON
`
`
`ABSORPTION
`
`Bound Drug
`
`
`Free Drug
` EXCRETiON IW
`
`/
` Metabolétes
`
`1’
`
`
`
`
`
`
`
` I
`
`1
`B IOTRANSFORMATION
`Figure 1—1. Schematic representation ofthc interrelationship of the absorption, distribution,
`binding, biotransformazion, and excretion of a drug and its concentration at its locus of
`action.
`
`Possible distribution and binding of metabolites are not depicted.
`
`
`
`

`

`
`
`
`(Chap. 1}
`Steady-state dosing is illustrated in Figure
`1~6.
`
`When drugs are administered by a route
`that is subject to first~pass loss, the equa-
`tions presented previously that contain the
`terms dose or dosing rate (equations 1, 4,
`10. and 11) must also include the bioavaila—
`bility term, F, such that the available dose
`or dosing rate is
`"
`
`ure 1—5, B). If the same drug is absorbed
`
`“-ig
`I’ll
`
`int:
`mat
`the
`trat
`one
`
`min
`
`C53
`
`whe
`
`of ir_
`tram
`
`NONLINEA
`Nonline:
`
`in such par
`botion. am
`centration
`protein biz
`renal trans
`
`Satin-able
`tration of
`must event
`become sat
`drug conce
`tens to hun.
`drug that i:
`ratio of eX'
`binding will
`as drug C0“
`remain cons
`C”. will not
`administrati
`cleared with
`
`

`

`
`
`3;
`
`iz
`
`,
`
`
`
`«wwwyow-<
`
`_W(yummy
`
`.;Wows”“worsens““a:
`
`
`
`(Chap. ll
`
`ted in Figure
`
`“ABILITY
`
`:ant to distin—
`xtent of drug
`at ultimately
`.tion, as dis—
`the drug that
`ttion can be
`the dose, F,
`lability. Rea-
`)n have been
`noted previ-
`:d in the liver
`.e active drug
`.inal tract will
`)efore it can
`nd be distrib—
`
`:d by a route
`55, the equa—
`tt contain the
`(nations 1, 4,
`‘he bioavaila—
`vailable dose
`ior example,
`
`(14)
`
`gh the rate of
`:eneral, influ-
`e concentra—
`
`lay still influ-
`is absorbed
`n as an intra—
`1 central vol-
`g will be high
`e drug is dis—
`Jme (see Fig-
`; is absorbed
`usion), it W31
`1g given, and
`twer and will
`y act to pro-
`irable effects
`(1 the rates of
`:ites may not
`ntensities of
`11g may thus
`if administra—
`
`o‘
`
`x
`
`5
`3,
`3
`a
`TIME (multiples of elimination half-time)
`
`Figure 1—6. Fundamental pharmacokinetic
`drugs.
`
`relationships for repeated administration of
`
`Light line is the pattern of drug accumulati
`on during repeated administration of a drug at
`intervals equal to its elimination halfitime, when drug absorption is ten times as rapid as elimi-
`nation. As the relative rate of absorption increases, the concentration maximal approach 2 and
`the minima approach 1 during the steady state. Heavy line depicts the pattern during adminis-
`tration of equivalent dosage by continuous intravenous infusion. Curves are based upon the
`one-compartment model. _
`Average concentration (Cm) when the stead
`ministration:
`
`y state is attained during intermittent drug ad-
`
`
`_ _ F -dose
`CS" CL . r
`
`where F- : fractional bioavailability of the dose
`and T = dosage interval (time). By substitution
`of infusion rate for F - dose/T, the formula is ca
`uivalent to equation 1 and provides the concen-
`tration maintained at steady state during continuous intravenous infusion.
`
`NONLINEAR PHARMACOKINBTICS
`
`Nonlinearity in pharmacokinetics (i.e., changes
`in such parameters as clearance, volume of distri—
`bution, and half-life as a function of dose or con—
`centration of drug) is usually due to saturation of
`protein binding, hepatic metabolism, or active
`renal transport of the drug.
`
`Saturable Protein Binding. As the molar concen—
`tration of drug increases,
`the unbound. fraction
`must eventually also increase (as all binding sites
`become saturated). This usually occurs only when
`drug concentrations in plasma are in the range of
`tens to hundreds of micrograms per milliliter. For a
`drug that is metabolized‘by the liver with a levy
`ratio of extraction, saturation of plasma protein
`binding will cause both V and clearance to increase
`as drug concentrations increase; half—life may thus
`remain constant (see equation 13). For such a drug,
`CU will not increase linearly as the rate of chug
`administration is increased. For drugs that are
`cleared with high extraction ratios, C” can remain
`
`linearly proportional to the rate of drug administra-
`tion. In this case, hepatic clearance would not
`change. and the increase in V would increase the
`half—time of disappearance by reducing the fraction
`of the total drug in the body that is delivered to the
`liver per unit time. Most drugs fall between these
`two extremes, and the effects of nonlinear protein
`binding may be difficult to predict.
`
`In this situation, the Mi~
`Saturable Metabolism.
`chaelis—Menten equation (equation 6') usually de—
`scribes the nonlinearity. All active processes are
`undoubtedly saturable, but they will appear to be
`linear if values of drug concentrations encountered
`in practice are much less than Km. When they ex-
`ceed Km. nonlinear kinetics is observed. The major
`consequences of saturation of metabolism are the
`opposite of those for saturation of protein binding.
`When both conditions are present simultaneously,
`they may virtually cancel each others’ effects, and
`surprisingly linear kinetics may result; this occurs
`over a certain range of concentrations for salicylic
`acid.
`
`
`
`CLINICAL PHARMACOKINETICS
`STEADY STATE
`. attained after approximately four half-times
`.tirne to
`steady state independent of dosage
`
`29
`
`FLUCTUATlONS
`spropartionat to dosage interval/half~iime
`ablunted by slow absorption
`
`STEADY—STATE CONCENTRATIONS
`a proportional to dose/dosage interval
`aproporiional to CL/F
`
` ~
`
`
`
`

`

`
`
`of drug
`a ministration The latter can be seen most easily
`y su stituting equation 61nto equation I and solv—
`mg or the steady-state concentration.
`C fi Dosmg rate~Km
`15)
`.
`s ~x
`Vm « Dosing rate
`‘
`
`(
`
`18 given for prophylaxxs)
`toxicrty and lack
`0
`e zcacy are bOth 90‘6“?“ dangers
`and/0T the the?$3811th index 18 narrow In
`t ese circumstances a target—level strategy
`S n
`' A
`S
`d ( 1360 St
`is tea 0 able.
`de ire
`ta
`ead
`
`approaches Vm, thedenominator
`0‘ equation l5 approaches zero and C” increases
`isproportionately Fortunately s
`'
`
`n and a dosage is com
`puted that IS expected to achieve this value
`DrugCOncentTatl
`
`n (see Appendlx II)
`K," 18 typically near the lower end ofthe therapeu-
`no 131186 (K — 5 to 10 mg/ht
`uals,
`
`the lower limit ofthe ther-
`apeutic range appears to be approxrmately
`equal to the dr
`'
`
`he upper limit of the
`.
`therapeutic range is fixed by toxicity, not
`It can be essentially un-
`by efficacy.
`bounded for a very nontoxic drug. In gen-
`erai, however, the upper limit of the thera—
`that no more than 5 to
`
`it
`., blood pressure)
`.
`can be used to guide dosage, and a trial—
`and—error approach to optimal dosage IS
`both practical and sens
`
`ations, drugs are administered in a senes of
`repetitive. doses oras a continuous infusmn
`m order to maintain a
`
`In most clinical Situ-
`
`.
`
`
`
`
`equations
`terms of ti
`
`Dosing rate ;
`
`If the CH
`centration (
`clearance a
`particular I)
`dosing intei
`
`Example.
`of theophyllin
`acute bronchi
`patient does 1
`except for the
`mean clearani
`0.65 ml ~ min~
`given as an in:
`
`Since almost al
`Phylline are av
`(aminophyfline)
`the infusion rate
`[(40 mg/hr)/(0.8:
`
`Dosing [in
`age.
`In gen
`drug concenti
`beneficial. If
`were instant;
`concentration:
`governed entii
`half-fife. If the
`sen to be equa}
`fluctuation we
`a tolerable var
`Pharmacody
`ify this, If a .
`such that con:
`necessary for'l
`ated. doses car
`terval can be m
`tion half-life (f0
`of peniciilin G '
`often given in v:
`hours.
`
`For some drugs ‘
`it may be impona:
`minimal concentral
`u-lar dosing interva
`corresponds to a in
`drug disposition (F.
`
`

`

`[Chap 1]
`
`some drugs. the ef-
`aeasure (or the drug
`s), toxicity and lack
`potential dangers,
`index is narrow. In
`target—level strategy
`ed (target) steady—
`:he drug (usually in
`l a dosage is com-
`) achieve this value.
`subsequently meas—
`sted if necessary to
`more closely.
`the
`level strategy,
`Just be defined in
`:e for the C“, often
`nge. For drugs for
`such as theophyl—
`er limit of the ther-
`> be approximately
`:n'tration that pro—
`greatest possible
`upper limit of the
`d by toxicity. not
`a essentially un—
`oxic drug. In gen—
`limit of the thera—
`no more than 5 to
`:n‘ence a toxic ef—
`is may mean that
`to is no more than
`course, these tig~
`do and some pa-
`V from drug con~
`the therapeutic
`suffer significant
`values. Barring
`n. however,
`the
`the center of the
`
`
`
`ivMfr.a...(--..-wc.xstz.
`
`
`
`most clinical situ-
`rred in a series of
`itinuous infusion
`dy—state concen-
`within a given
`alculation of. the
`losage is a pri—
`: chosen steady—
`ion, the rate of
`usted such that
`ate ofloss. This
`previously in
`
`new
`
`
`
`CLINICAL PHARMACOKINETICS
`equations 1 and 14 and is expressed here in
`terms of the desired target concentration:
`
`steady-state concentration, C,,,,,,;,,, may be reason-
`ably determined by the use of equation 17.
`
`31
`
`Dosing rate = Target - CL/F
`
`(16)
`
`If the clinician chooses the desired cork
`centration of drug in plasma and knows the
`Clearance and availability for that drug in a
`particular patient, the appropriate dose and
`dosing interval can be calculated.
`'
`
`Example. A steady-state plasma concentration
`of theophylline of 15 mg/liter is desired to relieve
`acute bronchial asthma in a 68-kg patient. If the
`except for the asthmatic condition, one can use the
`mean clearance given in Appendix II,
`that
`is,
`0.65 ml ~ min" ' kg". Because the drug is to be
`given as an intravenous infusion, F = l.
`
`Dosing rate = Target ' CL/F
`= 15 ug/ml ' 0.65 ml - min‘l . kg“
`= 9.75 ug ~ min” - kg”
`= 40 mg/hr for a 68-kg patient
`
`Since almost all intravenous preparations of theo—
`phylline are available as the ethylenediamine salt
`(aminophylline), which contains 85% theophylline,
`the infusion rate will be 47 mg/hr of aminophylline
`[(40 mg/hr)/(0.85)l.
`
`Dosing Interval for Intermittent Dos-
`age.
`In general, marked fluctuations in
`drug concentrations between doses are not
`beneficial. If absorption and distribution
`Were instantaneous,
`fluctuation of drug
`concentrations between doses would be
`governed entirely by the drug’s elimination
`half-life. If the dosing interval (T) was cho-
`Sen to be equal to the half~life, then the total
`fluctuation would be twofold; this is usually
`a tolerable variation.
`Pharmacodynamic considerations mod—
`ify this. If a drug is relatively nontoxic,
`such that concentrations many times that
`necessary for therapy can easily be toler‘
`ated. doses can be large and the dosing in-
`terval can be much longer than the elimina—
`tiOn half—life (for convenience). The half—life
`of penicillin G is less than 1 hour, but it is
`often given in very large doses every 6 or 12
`hours.
`
`For some drugs with a narrow therapeutic range,
`it may be important to estimate the maximal and
`minimal concentrations that will occur for a partic—
`ular dosing interval. if the closing interval chosen
`corresponds to a time during the log-linear phase of
`drug disposition (Figure 1—5, B), then the minimal
`
`__
`. _ F-dose/Vm .
`Cmen—W ch( AT)
`
`(17)
`
`where k is the terminal rate constant for elimination
`(see Figure 1—5, B) and Tis the dosing interval. The
`term e.rp(—kT) is, in fact, the fraction of the last
`dose (corrected for bioavailability) that remains in
`the body at the end of a dosing interval.
`For drugs that follow multiexponential kinetics
`and that are administered orally, the estimation of
`the maximal steady-state concentration, C,,,,,,,,,,
`involves a complicated set of exponential constants
`for distribution and absorption. If these terms are
`ignored for multiple oral dosing, one may easily
`predict a maximal steady-state concentration by
`omitting the exp(~kT} term in the numerator of
`equation 17 (see equation 18, below). Because of
`the approximation, the predicted maximal concen-
`tration from equation 18 will be greater than that
`actually observed.
`Example. When the acute asthmatic attack in
`the patient discussed above is relieved, the clini—
`cian might want to maintain the plasma concentra-
`tion of theophylline at 15 tug/liter, with oral dosage
`at intervals of 6, 8, or 12 hours. The correct rate of
`drug administration, independent of consideration
`of the dosing interval, is 40 mg/hr for this patient.
`as calculated above, since the availability of theo—
`phylline from an oral dose is 100%. Thus, the ap—
`propriate intermittent doses would be 240 mg every
`6 hours. 320 mg every 8 hours, or 480 mg every 12
`hours. All of these regimens would yield the same
`average concentration,
`l5 mg/liter, but different
`maximal and minimal concentrations would per—
`tain. F:3r a lZ—hour dosing interval, the following
`maximal and minimal concentrations would be pre-
`dicted:
`
`Crcmax "
`
`
`F - dose/VS,
`1 ~ exp(~kT)
`,
`.
`_ 430 tug/34 liters ‘ 7
`‘ W“— " 21.. “lg/liter
`
`18)
`
`l
`
`Quentin = C:.r,lmz,r ' €Xp("kT)
`= (21.7 mg/liter) ' (0.35) = 7.6 mg/liter
`
`(.19)
`
`The calculations in equations 18 and 19 were per~
`formed assuming oral doses of 480 mg every 12
`hours of a drug with a half-life of 8 hours (k =
`(1693/8 hr = 0.0866 hr”). a volume of distribution
`of 0.5 liter/kg (V3, = 34 liters for a (all—kg patient),
`and an oral availability of 1. Since the predicted
`minimal concentration, 7.6 nag/liter, falls below the
`suggested effective concentration and the predicted
`maximal concentration is above that suggested to
`avoid toxicity (see Appendix ll), the choice of a
`Izohour dosing interval is probably inappropriate.
`A more appropriate choice would be 320 mg every
`8 hours or 240 mg every 6 hours; for T: 6 hr,
`Gym” = 17 rug/liter; Cmmm = 10 rug/liter. The cli-
`nicaan must of course balance the problem of com-
`
`
`
`

`

`
`
`32
`
`PHARMAcoxiNarrcs
`pliance with regimens that involve frequent dosage
`against the problem of periods when the patient
`may be subjected to concentrations of the drug that
`could be too high or too low.
`
`[Chap 1]
`is, however, unpredictable variation be~
`tween normal individuals; for many drugs,
`one standard deviation in the values ob-
`served for F, CL, and V3, is about 20%,
`50%, and 30%, respectively. This means
`that 95% of the time the C3,. that is achieved
`will be between 35% and 270% of the tar-
`get; this is an unacceptably wide range for a
`drug with a low therapeutic index. If values
`of C,, are measured, one can estimate val~
`ues of F, CL, and V“ directly, and this per-
`mits more precise adjustment of a dosage
`regimen. Such measurement and adjust—
`ment are appropriate for many drugs with
`low therapeutic indices (e.g., cardiac glyco~
`sides, an'tiarrhythmic agents, anticonvul-
`sants, theophylline, and others)
`
`Loading Dose. The “loading dose” is
`one or a series of doses that may be given at
`the onset of therapy with the aim of achiev-
`ing the target concentration rapidly. The
`appropriate magnitude for the loading dose
`18.
`
`Loading close = Target Cp - Vm/F
`
`(20)
`
`A loading dose may be desirable if the
`time required to attain steady state by the
`administration of drug' at a constant rate
`(four elimination half-lives) is long relative
`to the temporal demands of the condition
`being treated. For example, the half-life of
`lidocaine is usually more than 1 hour. Ar—
`rhythmias encountered after myocardial
`infarction may obviously be life threaten—
`ing, and one cannot wait for 4 to 6 hours to
`achieve a therapeutic concentration of lido—
`caine by infusion of. the drug at the ratere~
`quired to maintain this concentration.
`Hence, use of a loading dose of lidocaine in
`the coronary care unit is standard.
`The use of a loading dose also has signifi—
`cant disadvantages. First, the particularly
`sensitive individual may be exposed ab-
`ruptly to a toxic concentration of a drug.
`Moreover, if the drug involved has a long
`half-life, it will take a long-time for the con-
`centration to fall if the level achieved was
`excessive. Loading doses tend to be large,
`and they are often given parenterally and
`rapidly; this can be particularly dangerous
`if toxic effects occur as a result of actions of
`the drug at sites that are in rapid equilib—
`rium with plasma.
`
`Individualizing Dosage. To design a ra-
`tional dosage regimen,
`the clinician must
`know F, CL, VB, and rm, and have some
`knowledge about rates of absorption and
`distribution of the drug. Moreover, one
`
`THERAPEUTIC DRUG MONITORING
`The major use of measured concentra—
`tions of drugs (at steady state) is to refine
`the estimate of CL/F for the patient being
`treated (using equation 14 as rearranged
`below):
`
`CLJF (patient) 2 Dosing rate/CS, (measured)
`
`(21)
`
`The new estimate of CL/F can be used in
`equation 16 to adjust the maintenance dose
`to achieve the desired target concentration.
`Certain practical details and pitfalls related to
`therapeutic drug monitoring should be kept
`in
`mind. The first of these concerns the time of sam-
`pling for measurement of the drug concentration. If
`intermittent dosing is utilized, When, during a dos-
`ing interval, should samples be taken? It is neces
`sary to distinguish between two possible uses of
`measured drug concentrations in order to under.
`drug measured in a sample taken at virtually any
`time during the dosing interval will provide infor-
`mation that may aid in the assessment of drug tox»
`icity. This is one type of therapeutic drug monitor~
`ing. it should be stressed. however, that such use
`of a measured concentration of drug is fraught with
`difficulties caused by interindividual variability in
`sensitivity to the drug. When there is a question of
`toxicity,
`the drug concentration can be no more
`than just one of many items that serve to inform the
`clinician.
`
`rameters and appropriate adjustments that
`may be necessitated by disease or other
`factors are presented in Appendix II. There
`
`relative to changes in plasma concentration be-
`cause of a slow rate of distribution or pharmacody-
`namic factors. Concentrations of digoxin, for ex—
`ample, regularly exceed 2 rig/ml (a potentially toxic
`value) shortly after an oral dose. yet these peak
`concentrations do not cause toxicity; indeed, they
`
`
`
`occur well beft
`dons of drugs
`administration c
`leading.
`When concen
`poses of adjust
`tained shortly 2
`almost invariab.
`pling during sug
`one’s estimate 1
`dosage. Early .'
`not reflect clear;
`by the rate of at
`the steady—state
`rate of distribut:
`netic features 0
`term, steady-stat
`urement is adjust
`be taken well aft
`thumb just befor
`concentration is ;
`tion to this appn
`pletely eliminate
`ing the initial por
`such drugs, it is
`concentrations a:
`shortly after a dc
`concern is that 1:
`may cause accu.
`measured just be:
`accumulation ant
`this purpose than
`centration. For 5
`maximal and mini
`mended.
`A second impo
`pling is its relation
`tenance dosage r;
`given, steady stat
`lives have passed
`after dosage is be
`clearance. Yet, ft
`steady state is ass
`done. Some sim
`When it is import
`concentrations, or
`two half—lives (as
`patient), assuming
`If the concentrat‘
`eventual expecte
`tion,
`the dosage
`sample obtained
`lives, and. the do:
`exceeds the target
`too high, one pro<
`age; even if the e
`pected, one can
`steady state in anc
`then proceed to at
`If dosage is inter
`with the time at t
`determination of d:
`has been obtained
`recommended, on
`value, not the meal
`the estimated met
`
`

`

`[Chi—1p. ll
`
`ble variation be-
`; for many drugs,
`n the values ob—
`755 is about 20%,
`rely. This means
`S, that is achieved
`270% of the tar~
`5/ wide range for a
`%c index. If values
`can estimate val-
`ctly, and this per-
`nent of a dosage
`sent and adjust—
`many drugs with
`g., cardiac glyco-
`ants, anticonvul—
`lthers).
`
`'ITORING
`
`sored concentra-
`itate) is to refine
`the patient being
`4 as rearranged
`
`
`
`
`
`(oz-5315.13»..'W,~z~c’:«7?-.~
`
`'3 (measured)
`
`(21)
`
`and;u
`
`7 can be used in
`raintenance dose
`at concentration.
`
`l pitfalls related to
`should be kept
`in
`us the time of sam—
`ug concentration. If
`vhen. during a dos-
`talren? It is neces-
`Io possible uses of
`in order to under~
`l concentration of
`en at virtually any
`will provide infor-
`ssment of drug tox-
`eutic drug monitor-
`:ver, that such use
`irug is fraught with
`idual variability in
`ere is a question of
`n can be no more
`serve to inform the
`
`gs may be delayed
`concentration be-
`an or pharmacody—
`)f digoxin. for ex—
`(a potentially toxic
`re, yet these peak
`icity; indeed, they
`
`
`
`iv
`
`33
`CLINICAL PHARMACOKINETiCS
`occur well before peak effects. Thus, concentra~
`lated by using equation 17 if the dosing interval
`trons of drugs in samples obtained shortly after
`chosen corresponds to a time during the log-linear
`administration can be uninformative or even mis-
`phase of drug disposition (La,
`the rates of drug
`absorption and distribution are fast relative to the
`rate of drug elimination). Since C,,_,,,,~,, is directly
`related to dose, the ratio between the measured and
`desired concentrations can be used to adjust the
`dose.
`
`When concentrations of drugs are used for our
`poses of adjusting dosage regimens, samples ob-
`tained shortly after administration of a dose are
`almost invariably misleading. The point ofsarn—
`pling during supposed steady state is to modify
`one's estimate of CL/F and thus one‘s choice of
`dosage. Early postabso‘rptive concentrations do
`not reflect clearance; they are determined primarily
`by the rate of absorption, the central (rather than
`the steady—state) volume of distribution, and the
`rate of distribution, all of which are pharmacolri—
`netic features of virtually no relevance to long-
`term, steady-state dosage. When the goal of meas-
`urement is adjustment of dosage, the sample should
`be taken well after the previous dose~as a rule of
`thumb just before the next planned dose, when the
`concentration is at its minimum. There is an excep—
`tion to this approach. Some drugs are nearly com—
`pletely eliminated between doses and act only dun
`ing the initial portion of each dosing interval. If, for
`such drugs, it is questionable whether efficacious
`concentrations are being achieved, a sample taken
`shortly after a dose may be helpful. Yet, if another
`concern is that low clearance (as in renal failure)
`may cause accumulation of drug, concentrations
`measured just before the next dose will reveal such
`accumulation and are considerably more useful for
`this purpose than is knowledge of the maximal con~
`centration. For such drugs, determination of both
`maximal and minimal concentrations is thus recom—
`mended.
`
`was =W (22)
`C,,,,,,,«,,(desired)
`Dose(new)
`
`When absorption is known to be slow or when
`the interval between doses is less than 50% of the
`half—life, then the criteria for calculation of C,,),,,,~,,
`with equation 17 are not met. Under these condi—
`tions, the concentration measured at the end of a
`dosing interval may be assumed to approximate the
`mean or steady—state concentration and equation 14
`can be used to adjust dosage.
`Other difficulties of interpretation of drug con~
`centrations arise from problems with specificity of
`
`tionship of concentration to effect may appear to
`change over time (e.g., as metabolites that are de—
`void of pharmacological activity accumulate).
`This may be especially noticeable in patients with
`renal failure. The opposite results from accumula—
`tion of active metabolites that are not measured by
`a specific assay. As specific and sensitive assays
`for drugs and metabolites are developed, such
`problems should decrease.
`
`A second important aspect of the timing of sam-
`pling is its relationship to the beginning of the main-
`tenance dosage regimen. When constant dosage is
`given, steady state is reached only after four half-
`lives have passed. If a sample is obtained too soon
`after dosage is begun, it will not accurately reflect
`clearance. Yet, for toxic drugs, if one waits until
`steady state is assured, the damage may have been
`done. Some simple guidelines can be offered.
`When it is important to maintain careful control of
`concentrations, one may take the first sample after
`two half-lives (as calculated and expected for the
`patient), assuming no loading dose has been given.
`if the concentration already exceeds 90% of the
`eventual expected mean steady-state concentra-
`tion,
`the dosage rate should be halved, another
`sample obtained in another two (supposed) half-
`liv'es, and the dosage halved again if this sample
`exceeds the target. If the first concentration is not
`too high, one proceeds with the initial rate of dos-
`age; even if the concentration is lower than ex-
`pected, one can usually await the attainment of
`steady state in another two estimated half-lives and
`then proceed to adjust dosage as described above.
`If dosage is intermittent, there is a third concern
`with the time at which samples are obtained for
`determination of drug concentrations. If the sample
`has been obtained just prior to the next dose, as
`recommended, concentration will be a minimal
`value, not the mean. However, as discussed above,
`the estimated mean concentration may be calcu-
`
`General References
`Goidstein, A; Aronow, L.; and Kalman, S. M. Princi-
`ples of Drug Action: The Basis of Pharmacology, 2nd
`ed. John Wiley & Sons, lnc., New York, 1974.
`Levine, R. R. Pharmacology: Drug Actions and Reac-
`tions. 3rd ed. Little, Brown & Co., Boston. 1983.
`Meltnon, K. L, and Morrelli. H. F. (eds). Clinical Phar-
`macology: Basic Principles in Therapeutics, 2nd ed.
`Macmillan Publishing Co., New York, 1978.
`Historical Background
`Holmstedt, 33., and Lifiestrand, G. (eds). Readings in
`Pharmacology. Pergamon Press, Ltd. Oxford. 1963.
`Shuster, L. (ed). Readings in Pharmacology. Little.
`Brown & Co., Boston, 1962.
`
`Absorption, Distribution,
`Bz‘otransformation. and Excretion
`American Pharmaceutical Association. The Bioavailabil~
`try ofDrug Products, cumulative ed. The Association,
`Washington, D. C., 1978.
`Berliner, R. W.; Clubb. L. E: Doluisio, J. T.; Melmon,
`K. L.; Nados. A. 8.; Dates, 1. A.: Rcigclmen, S.;
`Shideman, F. E; Zelin, M.; and Robbins, F. C. Drug
`Bioeqm’yalcnce. Office of Technological Assessment,
`US. Government Printing Office, Washington, D. C.,
`1974.
`Brodie. B. B. Physicochemical factors in drug absorp-
`tion. in, Absorption and Distribution ofDrugs. (Binns.
`T. 8., ed.) The Williams & Wilkins Co., Baltimore,
`1964, pp. 16—48.
`Green, T. R; O‘Dea, R. F.: and Mirkin, B. L. Determi-
`nants of drug disposition and effect in the fetus. Arum.
`Rey. Pharmacol. Toxicol., 1979, 19, 285—322.
`
`
`
`

`

`n\v\v
`
`CLINICAL PHARMACOKINETICS
`of drugs in biological fluids. The impor—
`tance of pharmacokinetics in patient care
`rests on the improvement in efficacy that
`can be attained by attention to its principles
`when dosage regimens are chosen and mod—
`ified.
`
`23
`
`order kinetics~a constant fraction of drug
`is eliminated per unit time. If mechanisms
`for elimination of a given drug become satu-
`rated, the kinetics become zero order—~a
`constant amount of drug is eliminated per
`unit
`time. Under such a circumstance,
`clearance becomes variable. Principles of
`drug clearance are similar to those of renal
`physiology, Where, for example, creatinine
`clearance is defined as the rate of elimina—
`tion of creatinine in the urine relative to its
`concentration in plasma. At the simplest
`level, clearance of a drug is the rate of elim~
`ination by all routes normalized to the con-
`centration of drug, C,
`in some biological
`fluid:
`
`The various physiological and patho-
`physiological variables that dictate adjust-
`ment of dosage in individual patients often
`do so as a result of modification of pharma-
`cokinetic parameters. The three most im-
`portant parameters are bioavailabz‘lity, the
`fraction of drug absorbed as such into the
`systemic circulation; clearance, a measure
`of the body’s ability to eliminate drug; and
`volume of distribution, a measure of the
`apparent space in the body available to con-
`tain the drug. Of lesser importance are the
`rates of availability and distribution of the
`agent.
`
`CLEARANCE
`
`Clearance is the most important concept
`to be considered when a rational regimen
`for drug administration is to be designed.
`The clinician usually wants to maintain
`steady-state concentrations of a drug within
`a known therapeutic range (see Appendix
`H). Assuming complete bioavailability, the
`steady state will be achieved when the rate
`of drug elimination equals the rate of drug
`administration:
`
`Dosing rate .= CL - C”
`
`(l)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CL = Rate of elimination/C
`
`(2)
`
`It is important to note that clearance does
`not indicate how much drug is being re-
`moved but, rather, the volume of biological
`fluid such as blood or plasma that would
`have to be completely freed of drug to ac-
`count for the elimination. Clearance is ex»
`pressed as a volume per unit of time. Clear-
`. ance is usually further defined as blood
`clearance (CLb), plasma clearance (CL,,),
`or clearance based on the concentration of
`unbound or free drug (CLR), depending on
`the concentration measured (Cb, CD, or C“).
`(For additional discussion of clearance con~
`cepts, see Benet et (21., 1984.)
`Clearance by means of various organs of
`elimination is additive. Elimination of drug
`may occur as a result of processes that
`occu