`
`SECOND EDITION EDITION
`
`Edited by
`M. E. Aulton
`
`Ad/j) CHURCHILL
`LIVINGSTONE
`
`angoor (cid:9)m
`
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`CHURCHILL LIVINGSTONE
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`First published 1988
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`l
`l r
`
`19
`19
`Dosage regimens
`Dosage regimens
`
`Stuart Proudfoot (updated by John Collett)
`Stuart Proudfoot (updated by John Collett)
`
`CHAPTER CONTENTS
`CHAPTER CONTENTS
`
`Dosage regimens: their influence on the
`Dosage regimens: their influence on the
`concentration—time profile of a drug in the
`concentration-time profile of a drug in the
`body 275
`body 275
`
`One-compartment open model of drug disposition
`One-compartment open model of drug disposition
`in the body 276
`"
`in the body 276
`
`Rate of drug input versus rate of drug output 276 Rate of drug input versus rate of drug output 276
`Elimination rate constant and biological half-life of a
`Elimination rate constant and biological half-life of a
`drug 277
`drug 277
`Concentration—time curve of a drug in the body
`Concentration-time curve of a drug in the body
`following the peroral administration of equal
`following the peroral administration of equal
`doses of a drug at fixed intervals of time 278
`doses of a drug at fixed intervals of time 278
`
`Important factors influencing steady-state plasma
`Important factors influencing steady-state plasma
`drug concentrations 281
`drug concentrations 281
`Dose size and frequency of administration 281
`Dose size and frequency of administration 281
`Size of dose 281
`Size of dose 281
`interval between successive equal doses 281
`Interval between successive equal doses 281
`
`Summary of the effects of dose size and Summary of the effects of dose size and
`frequency of administration 282
`frequency of administration 282
`The concept of 'loading doses' 284
`The concept of 'loading doses' 284
`Influence of changes in the apparent elimination
`Influence of changes in the apparent elimination
`rate constant of a drug: the problem of patients
`rate constant of a drug: the problem of patients
`with renal impairment 285
`with renal impairment 285
`Influence of the 'overnight no-dose period' 286
`Influence of the 'overnight no-dose period' 286
`Concluding comments 287
`Concluding comments 287
`
`Bibliography 288
`Bibliography 288
`
`DOSAGE REGIMENS: THEIR INFLUENCE
`DOSAGE REGIMENS: THEIR INFLUENCE
`ON THE CONCENTRATION-TIME
`ON THE CONCENTRATION-TIME
`PROFILE OF A DRUG IN THE BODY
`PROFILE OF A DRUG IN THE BODY
`
`The subject of dosage regimens is concerned with
`The subject of dosage regimens is concerned with
`the dose, time of administration and drug plasma
`the dose, time of administration and drug plasma
`levels factors associated with multiple dosing of a
`levels factors associated with multiple dosing of a
`drug. The influence that physiological factors, the
`drug. The influence that physiological factors, the
`physicochemical properties of a drug and dosage
`physicochemical properties of a drug and dosage
`form factors can have in determining whether a
`form factors can have in determining whether a
`therapeutically effective concentration of a drug is
`therapeutically effective concentration of a drug is
`achieved in the plasma following peroral adminis-
`achieved in the plas_ma following peroral adminis(cid:173)
`tration of a single dose of drug has been discussed
`tration of a single dose of drug has been discussed
`previously in Chapters 16, 17 and 18.
`previously in Chapters 16, 17 and 18.
`Some drugs, such as hypnotics, analgesics and
`Some drugs, such· as hypnotics, analgesics and
`antiemetics, may provide effective treatment follow-
`antiemetics, may provide effective treatment follow(cid:173)
`ing the administration of a single dose. However,
`ing the administration of a single dose. However,
`the duration of most illnesses is longer than the
`the duration of most illnesses is longer than the
`therapeutic effect produced by the administration
`therapeutic effect produced by the administration
`of a single dose of a drug in a conventional dosage
`of a single dose of a drug in a conventional dosage
`form, i.e. a dosage form which is formulated to give
`form, i.e. a dosage form which i~ formulated to give
`rapid and complete drug release. In such cases
`rapid and complete drug release. In such cases
`doses are usually administered on a repetitive basis
`doses are usually administered on a repetitive basis
`over a period of time determined by the nature of
`over a period of time determined by the nature of
`the illness. For instance, one 250 mg ampicillin
`the illness. For instance, one 250 mg ampicillin
`capsule may be administered every 6 hours for a
`capsule may be administered every 6 hours for a
`period of 5 days to treat a bacterial infection. Such
`period of 5 days to treat a bacterial infection. Such
`a regimen, in which the total dose of drug (i.e. in
`a regimen, in which the total dose of drug (i.e. in
`this example 5 g) administered over 5 days is given
`this example 5 g) administered over 5 days is given
`in the form of multiple doses (i.e. each of 250 mg)
`in the form of multiple doses (i.e. each of 250 mg)
`at given intervals of time (i.e. every 6 hours) is
`at given intervals of time (i.e. every 6 hours) is
`known as a multiple-dosage regimen.
`known as a nutlti'ple-dosage 1·egimen.
`The proper selection of both the dose size and the
`The proper selection of both the dose size and the
`frequency of administration is an important factor
`frequency of administration is an important factor
`that influences whether a satisfactory therapeutic
`that influences whether a satisfactory therapeutic
`plasma concentration is achieved and maintained
`plasma concentration is achieved and maintained
`over the prescribed course of treatment. Thus the
`over the prescribed course of treatment. Thus the
`design of a multiple-dosage regimen/ is crucial to
`design of a multiple-dosage regimen' is crucial to
`successful drug therapy.
`successful drug therapy.
`
`Supplied by The British Library - "The world's knowledge"
`Supplied by The British Library- "The world's knowledge"
`
`275
`275
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1011 p. 003
`
`

`

`BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY
`
`ONE-COMPARTMENT OPEN MODEL OF
`DRUG DISPOSITION IN THE BODY
`
`In order to understand how the design of a dosage
`regimen can influence the time course of a drug in
`the body, as measured by its plasma concentration-
`time curve, consider that the complex kinetic
`processes of drug input, output and distribution in
`the body may be represented by the pharmacokinetic
`model of drug disposition, the one-compartment
`open model, shown in Figure 19.1. In this case the
`drug is considered to be distributed instantly
`throughout the whole body following its release
`and absorption from the dosage form. Thus the
`body behaves as a single compartment in
`which absorbed drug is distributed so rapidly that
`a concentration equilibrium exists at any given
`time between the plasma, other body fluids,
`and the tissues into which the drug has become
`distributed.
`To assume that the body behaves as one-
`compartment open model does not necessarily
`mean that the drug concentrations in all
`body tissues at any given time are equal. The model
`does assume, however, that any changes that
`occur in the plasma reflect quantitatively changes
`occurring in the concentration of drug at the site(s)
`of action.
`
`Rate of drug input versus rate of drug
`output
`In a one-compartment open model, the overall
`kinetic processes of drug input and drug output are
`described by first-order kinetics. In the case of a
`perorally administered dosage form, the process of
`drug input into the body compartment involves drug
`release from the dosage form and passage of the
`drug across the cellular membranes constituting the
`gastrointestinal barrier. The rate of input of absorp-
`tion represents the net result of all these processes.
`The rate of input (absorption) at any given time is
`proportional to the concentration of drug, which
`is assumed to be in an absorbable form, in solution
`
`in the gastrointestinal fluids at the site(s) of absorp-
`tion, i.e. the effective concentration, Co of drug at
`time t. Hence:
`rate of drug input at time t a Ce (cid:9)
`
`(19.1)
`
`and
`
`rate of drug input at time t = -ka Ce (19.2)
`where ka is the apparent absorption rate constant.
`The negative sign in Eqn 19.2 indicates that the
`effective concentration of drug at the absorption
`site(s) decreases with time. The apparent absorption
`rate constant gives the proportion (or fraction) of
`drug that enters the body compartment per unit
`time. Its units are time-', e.g. h-1.
`Unlike the rate of drug input into the body com-
`partment, the apparent absorption rate constant, ka,
`is independent of the effective concentration of drug
`at the absorption site(s). Because the rate of drug
`input is proportional to the effective drug concentra-
`tion, it will be maximal following the administration
`of a dose contained in a peroral dosage form which
`gives rapid and complete drug release. The rate of
`drug input will decrease gradually with time as a
`consequence of the effective drug concentration at
`the absorption site(s) decreasing progressively with
`time, chiefly as a result of absorption into the body
`compartment. Other processes, such as chemical
`degradation and movement of drug away from the
`absorption site(s), will also contribute to the gradual
`decrease in the effective drug concentration with
`time.
`In the case of a one-compartment open model, the
`rate of drug output or elimination is a first-order
`process. Consequently, the magnitude of this para-
`meter at any given time is dependent on the concen-
`tration of drug in the body compartment at that
`time. Immediately following administration of the
`first dose of a peroral dosage form, the rate of drug
`output from the body will be low as little of the drug
`will have been absorbed into the body compartment.
`However, as absorption proceeds - initially at a
`higher rate than the rate of drug output - the net
`concentration of drug in the body will increase with
`time. Likewise, the rate of drug output from the
`
`Drug
`in
`dosage
`form
`
`Drug in
`solution in
`gastrointestinal
`fluids
`
`INPUT
`
`Drug in
`body
`compartment
`
`OUTPUT
`
`Drug
`in
`urine
`
`Fig. 19.1 One-compartment open model of drug disposition for a perorally administered drug.
`
`276
`
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`
`

`

`DOSAGE REGIMENS
`
`body compartment will also increase with time. As
`the rate of drug output is increasing with time while
`the rate of input into the body compartment is
`decreasing with time, the situation is eventually
`reached when the rate of drug output just exceeds
`that of drug input. Consequently, the net concentra-
`tion of drug in the body compartment will reach a
`peak value and then begin to fall with time. The
`ensuing decreases in the net concentration of drug in
`the body will also cause the rate of drug output to
`decrease with time.
`These changes in the rates of drug input and
`output relative to each other with time are responsi-
`ble for the characteristic shape of the concentra-
`tion—time course of a drug in the body shown in
`Figure 19.2 following peroral administration of a
`single dose of drug.
`It is evident from the above discussion and
`Figure 19.2, that the greater the rate of drug input
`relative to that of drug output from the body com-
`partment over the net absorption phase, the higher
`will be the peak concentration achieved in the
`body or plasma following peroral administration of
`
`a single dose of drug. This interplay explains why
`increases in dose size and formulation changes in
`dosage forms which produce increases in the effec-
`tive concentration of drug at the absorption site(s),
`result in higher peak plasma and body concentra-
`tions being obtained for a given drug. It should
`also be noted that any unexpected decrease in the
`rate of drug output relative to that of drug input,
`which may occur as the result of renal impairment,
`is also likely to result in higher plasma and body
`concentrations of drug than expected, and the pos-
`sibility of the patient exhibiting undesirable side-
`effects. The adjustment of dosage regimens in
`cases of patients having severe renal impairment is
`considered later in this chapter.
`
`Elimination rate constant and biological
`half-life of a drug
`In the case of a one-compartment open model the
`rate of elimination or output of a drug from the body
`compartment follows first-order kinetics (Chapter 7)
`and is related to the concentration of drug, G„
`
`Absorption
`phase
`
`Elimination
`phase
`
`Rate of drug input = rate of drug output
`
`b
`
`2E
`
`0 Z.
`C 3—
`co 0
`
`1.1 0
`C.0
`N
`c.) C .0
`O
`C.) •c
`
`Time following administration
`of a single dose
`
`a— b rate of drug absorption > rate of drug elimination
`c—d rate of drug elimination > rate of drug absorption
`
`Fig. 19.2 Concentration—time course of a drug in the body following peroral administration of a single dose of drug which confers
`one-compartment open model characteristics on the body.
`
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`
`277
`
`

`

`BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY
`
`remaining in the body compartment at time r, by the
`following equation:
`rate of elimination at time t = (cid:9)
`(19.3)
`where ke is the apparent elimination rate constant.
`The negative sign in Eqn 19.3 indicates that elimi-
`nation is removing drug from the body compart-
`ment.
`The apparent elimination rate constant of a drug
`gives the proportion or fraction of that drug which is
`eliminated from the body per unit time. Its units are
`in terms of time-1. The apparent elimination con-
`stant of a given drug therefore provides a quantita-
`tive index of the persistence of that drug in the body.
`An alternative parameter used is the biological or
`elimination half-life of the drug, t112. This is the time
`required for the body to eliminate 50% of the drug
`that it contained. Thus, the larger the biological half-
`life exhibited by a drug, the slower will be its elimi-
`nation from the body or plasma.
`For a drug whose elimination follows first-order
`kinetics, the value of its biological half-life is inde-
`pendent of the concentration of drug remaining in
`the body or plasma. Hence, if a single dose of a drug
`having a biological half-life of 4 hours was adminis-
`tered perorally, then after the peak plasma concen-
`tration had been reached the plasma concentration
`of drug would fall by 50% every 4 hours until all the
`drug had been eliminated or a further dose was
`administered. The relationship between the numbers
`of half-lives elapsed and the percentage of drug elim-
`inated from the body following administration of a
`single dose is given in Table 19.1.
`An appreciation of the relationship between the
`percentage of drug eliminated from the body and the
`number of biological half-lives elapsed is useful
`when considering how much drug is eliminated from
`
`Table 19.1 Relationship between the amount of drug
`eliminated and the number of half-lives elapsed.
`
`Number of half-lives
`elapsed
`
`Percentage of drug
`eliminated
`
`0.5
`1.0
`2.0
`3.0
`3.3
`4.0
`4.3
`5.0
`6.0
`6.6
`7.0
`
`278
`
`29.3
`50.0
`75.0
`87.5
`90.0
`94.0
`95.0
`97.0
`98.4
`99.0
`99.2
`
`Table 19.2 (cid:9) The biological half-life ranges for
`phenobarbitone, digoxin and theophylline
`
`Drug
`
`Phenobarbitone
`
`Digoxin
`
`Theophylline
`
`Biological half-life (h)
`
`50-120
`
`36-51
`
`3-8
`
`the body over the time interval between successive
`doses in a multiple-dosage regimen. Biological half-
`life varies from drug to drug and, even for a given
`drug, from patient to patient. Some biological half-
`lives for various drugs are given in Table 19.2.
`For a drug whose elimination follows first-order
`kinetics, the biological half-life, t112, is related to the
`apparent elimination rate constant, k„ of that drug
`according to the following equation:
`
`=
`
`0.693
`ke
`
`(19.4)
`
`Thus the biological half-life of a drug will be
`influenced by any factor that influences the appar-
`ent elimination rate constant of that drug. This
`explains why factors such as genetic differences
`between individuals, age and disease can affect
`the biological half-life exhibited by a given drug.
`Biological half-life is an important factor that
`influences the plasma concentration-time curve
`obtained following peroral administration of a
`multiple-dosage regimen.
`
`Concentration-time curve of a drug in
`the body following the peroral
`administration of equal doses of a drug
`at fixed intervals of time
`
`In discussing how the design of multiple peroral
`dosage regimen can influence the concentration-
`time course of a drug in the body, the following
`assumptions have been made:
`
`1. The drug confers upon the body the
`characteristics of a one-compartment open
`model.
`2. The values of the apparent absorption rate and
`apparent elimination rate constants for a given
`drug do not change during the period for which
`the dosage regimen is administered to a patient.
`3. The fraction of each administered dose which is
`absorbed by the body compartment remains
`constant for a given drug.
`
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`
`

`

`DOSAGE REGIMENS
`
`4. The aim of drug therapy is to achieve promptly
`and maintain a concentration of drug at the
`appropriate site(s) of action which is both
`clinically efficacious and safe for the desired
`duration of treatment. This aim is assumed to be
`achieved by the prompt attainment and
`maintenance of plasma concentrations of drug
`which lie within the therapeutic range of that
`drug.
`
`If the interval between each perorally administered
`dose is longer than the time required for complete
`elimination of the previous dose, then the plasma
`concentration—time profile of a drug will exhibit a
`series of isolated single-dose profiles, as shown in
`Figure 19.3.
`Consideration of the plasma concentration—time
`profile shown in Figure 19.3 in relation to the
`minimum effective and maximum safe plasma con-
`centrations (MEC and MSC, respectively) for the
`drug reveals that the design of this particular dosage
`regimen is unsatisfactory. The plasma concentration
`only lies within the therapeutic concentration range
`of the drug for a relatively short period following the
`administration of each dose, and the patient remains
`undermedicated for relatively long periods. If the
`dosing time interval is reduced so that it is now
`shorter than the time required for complete elimina-
`
`tion of the previous dose, then the resulting plasma
`concentration—time curve exhibits the characteristic
`profile shown in Figure 19.4.
`Figure 19.4 shows that at the start of this multiple-
`dosage regimen the maximum and minimum plasma
`concentrations of drug observed during each
`dosing time interval tend to increase with succes-
`sive doses. This increase is because the time inter-
`val between successive doses is less than that
`required for complete elimination of the previous
`absorbed dose. Consequently, the total amount of
`the drug remaining in the body compartment at
`any time after a dose is equal to the sum of that
`remaining from all the previous doses. The accumu-
`lation of drug in the body and plasma with succes-
`sively administered doses does not continue
`indefinitely. Provided drug elimination follows first-
`order kinetics, the rate of elimination will increase as
`the average concentration of drug in the body (and
`plasma) rises. If the amount of drug supplied to the
`body compartment per unit dosing time interval
`remains constant, then a situation is eventually
`reached when the overall rate of elimination from
`the body over the dosing time interval becomes
`equal to the overall rate at which drug is being
`supplied to the body compartment over that inter-
`val, i.e. the overall rate of elimination has effectively
`caught up with the overall rate of supply. This effect
`
`Dose
`
`Dose (cid:9)
`
`Dose
`
`Time (h)
`
`Fig. 19.3 Plasma concentration—time curve following peroral administration of equal doses of a drug at time intervals that allow
`complete elimination of the previous dose. (MSC, maximum safe plasma concentration of the drug; MEC, minimum effective plasma
`concentration of the durg.)
`
`Supplied by The British Library - "The world's knowledge"
`
`279
`
`(cid:9)
`

`

`BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY
`
`D
`
`D
`
`D
`
`D
`
`D
`
`Time (hours)
`
`Fig. 19.4 Plasma concentration—time curve following peroral administration of equal doses, D, of a drug every 4 hours. (MSC,
`maximum safe plasma concentration of the drug; MEC, minimum effective plasma concentration of the drug.)
`
`is due to the elimination rate increasing as the
`residual concentration of drug in the plasma rises
`(as elimination is first order here).
`When the overall rate of drug supply equals
`the overall rate of drug output from the body
`compartment, a steady state is reached with respect
`to the average concentration of drug remaining in
`the body over each dosing time interval. At steady
`state, the amount of drug eliminated from the body
`over each dosing time interval is equal to the amount
`that was absorbed into the body compartment fol-
`lowing administration of the previous dose.
`Figure 19.5 shows that the amount of drug in the
`body, as measured by the plasma concentration,
`fluctuates between maximum and minimum values
`which remain more or less constant from dose to
`dose. At steady state the average concentration of
`drug in the plasma, Cs? ;erago over successive dosing
`time intervals remains constant.
`For a drug administered repetitively in equal doses
`and at equal time intervals, the time required for the
`average plasma concentration to attain the corre-
`sponding steady-state value is a function only of the
`biological half-life of the drug, and is independent of
`both the size of the dose administered and the length
`of the dosing time interval. The time required for the
`average plasma concentration to reach 95% of the
`
`steady-state value corresponding to the particular
`multiple dosage regimen is 4.3 times the biological
`half-life of the drug. The corresponding figure for
`99% is 6.6 times. Therefore, depending on the mag-
`nitude of the biological half-life of the drug being
`administered, the time taken to attain the average
`steady-state plasma concentration may range from a
`few hours to several days.
`From a clinical viewpoint the time required to
`reach steady state is important, because for a prop-
`erly designed multiple-dosage regimen the attain-
`ment of steady state corresponds to the achievement
`and maintenance of maximal clinical effectiveness of
`the drug in the patient.
`It should be noted that for a drug such as pheny-
`toin, whose elimination is not described by first-
`order kinetics, the peroral administration of equal
`doses at fixed intervals may not result in the attain-
`ment of steady-state plasma levels. If the concentra-
`tion of such drug in the body rises sufficiently
`following repetitive administration, the pathway
`responsible for its elimination may become satu-
`rated. If this occurred the rate of elimination would
`become maximal and could not increase to cope
`with any further rises in the average concentration of
`drug in the body. Hence the overall rate of elimina-
`tion would not become equal to the overall rate of
`
`280
`
`Supplied by The British Library - "The world's knowledge"
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`DOSAGE REGIMENS
`
`cgax
`
`•
`
`C:?verage.
`
`- - - - Cnr,
`
`co
`Q.
`C
`
`Concentration of drug
`
`Fig. 19.5 Fluctuation of concentration of drug in the plasma at steady state resulting from repetitive peroral administration of equal
`doses, D, of drug at a fixed interval of time, T. Cg„, CMin and Crw„ge represent the maximum, minimum and average plasma
`concentrations of drug, respectively, achieved at steady state.
`
`Time
`
`..
`
`11•111111.•1••
`
`••01111.
`
`supply over each dosing time interval, and the con-
`dition necessary for the attainment of steady state
`would not be achieved. If repetitive administration
`continued at the same rate, the average concentra-
`tion of drug in the body and plasma would tend to
`continue to accumulate, rather than to reach a
`plateau.
`
`IMPORTANT FACTORS INFLUENCING
`STEADY-STATE PLASMA DRUG
`CONCENTRATIONS
`
`Dose size and frequency of
`administration
`In designing a multiple-dosage regimen that bal-
`ances patient convenience with the achievement and
`maintenance of maximal clinical effectiveness, only
`two parameters can be adjusted for a given drug: the
`size of dose and the frequency of administration.
`Consider how the maximum, minimum and average
`steady-state plasma concentrations of drug are
`influenced by these parameters.
`
`Size of dose
`Figure 19.6 illustrates the effects of changing the
`dose size on the concentration of drug in the
`plasma following repetitive administration of
`peroral doses at equal intervals of time. As the size
`
`of the administered dose is increased, the higher
`are the corresponding maximum, minimum and
`average plasma drug levels, Cgax, Cgin and Cg.erag„
`respectively, achieved at steady state. What may not
`be so well appreciated is that the larger the dose the
`larger is the fluctuation between Cgax and cnr,
`during each dosing time interval. Large fluctua-
`tions between Q,;,„ and cni, can be hazardous,
`particularly with a drug such as digoxin, which has
`a narrow therapeutic range. In such cases, it is
`possible that Cg,x could exceed the maximum safe
`plasma concentration. Figure 19.6 also illustrates
`that the time required to attain steady-state plasma
`concentrations is independent of the size of the
`administered dose.
`
`Inteival between successive equal doses
`Figure 19.7 illustrates the effects of constant doses
`administered at various dosing intervals, which are
`multiples of the biological half-life of the drug t112.
`The uppermost plasma concentration-time curve in
`Figure 19.7 shows that the repetitive administration
`of doses at a time interval which is less than the bio-
`logical half-life of the drug results in higher steady-
`state plasma drug concentrations being obtained.
`This is a consequence of the extent of elimination of
`the drug from the body over a dosing time interval
`equal to 0.5 t112 being smaller than that which is
`eliminated when the dosing time interval is equal to
`t112 (see Table 19.1).
`
`281
`
`Supplied by The British Library - "The world's knowledge"
`
`

`

`A
`
`- -- --------- -
`
`
`
` MSC
`
`B
`
`MM. • WM. (cid:9)
`
`MEC
`
`C
`
`BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY
`
`••••
`
`Concentration of drug in plasma
`
`. 0 6 12 18 24 30 36 42 48 54 60 66 72
`
`Time (h)
`
`Fig. 19.6 Diagrammatic representation of the effect of dose size on the plasma concentration—time curve obtained following peroral
`administration of equal doses of a given fixed drug at fixed intervals of time equal to the biological half-life of the drug. Curve A, dose =
`250 mg. Curve B, dose = 100 mg. Curve C, dose = 40 mg.
`
`Figure 19.7 also shows that repetitive administra-
`tion of doses at intervals greater than the biological
`half-life of the drug results in the lower steady-state
`plasma drug concentrations being obtained. This is a
`consequence of a greater proportion of the drug
`being eliminated over a dosing time interval equal to
`2r1,2, compared to that which is eliminated when the
`dosing time interval is equal to t112.
`
`Summary of the effects of dose size and
`frequency of administration
`
`Consideration of the effects of dose size and the
`dosage interval on the amount of a given drug
`achieved in the body, as measured by the plasma
`
`concentration, following repetitive peroral adminis-
`tration of equal doses, have revealed the following
`relationships:
`
`1. The magnitude of the fluctuations between the
`maximum and minimum steady-state amounts
`of drug in the body is determined by the size of
`dose administered or, more accurately, by the
`amount of drug absorbed following each dose
`administered.
`2. The magnitude of the fluctuations between the
`maximum and minimum steady-state plasma
`concentrations are an important consideration
`for any drug that has a narrow therapeutic
`range, e.g. digoxin. The more freqUent
`administration of smaller doses is a means of
`
`282
`
`Supplied by The British Library - "The world's knowledge"
`
`(cid:9)
`

`

`DOSAGE REGIMENS
`
`A
`
`B
`
`MSC
`
`— — MEC
`
`C
`
`Concentration of drug in plasma
`
`0
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`Time (h)
`
`Fig. 19.7 Diagrammatic representation of the effect of changing the dosing time interval, r, on the plasma concentration—time curve
`obtained following repetitive peroral administration of equal size doses of a given drug. Curve A, dosing time interval = 3 hours (0.5t, ).
`Curve B, dosing time interval = 6 hours (ti_). Curve C, dosing time = 12 hours (2t).
`
`reducing the steady-state fluctuations without
`altering the average steady-state plasma
`concentration. For example, a 500 mg dose
`given every 6 hours will provide the same Cs.! .verage
`value as a 250 mg dose of the same drug given
`every 3 hours, whereas the Gina:, and Cmin
`fluctuation for the latter dose will be liecreased
`by half.
`3. The average maximum and minimum amounts
`of drug achieved in the body at steady state are
`influenced by either the dose size, the dosage
`time interval in relation to the biological half-life
`of the drug, or both. The greater the dose size
`and the smaller the dosage time interval relative
`to the biological half-life of the drug, the greater
`are the average, maximum and minimum steady-
`state amounts of drug in the body.
`4. For a given drug, the time taken to achieve
`steady state is independent of dose size and
`dosage time interval.
`
`5. If the maximum safe and minimum effective
`plasma drug concentrations are represented by
`the dashed lines shown in Figures 19.6 and
`19.7, respectively, then it is evident that the
`proper selection of dose size and dosage time
`• interval are important with respect to achieving
`and maintaining steady-state plasma
`concentrations that lie within the therapeutic
`range of the particular drug being administered.
`
`It is evident from the preceding discussion that the
`proper selection of the dose size and the dosage time
`interval is crucial in ensuring that a multiple-dosage
`regimen provides steady-state concentrations of
`drug in the body which are both clinically efficacious
`and safe.
`Mathematical relationships that predict the values
`of the various steady-state parameters achieved in
`the body fol