Clinical Plturmucokinetics
`Concepts and Applications
`
`third edition
`
`MALCOLM ROWLAND
`
`THOMAS N. TOZER
`
`CFAD Ex. 1026 (1 of 4)
`
`

`
`Clinical Pharmacokinetics
`
`Concepts and Applications
`
`third edition
`
`MALCOLM ROWLAND, Ph.D.
`Department of Pharmacy
`
`University of M anchester
`
`Manchester, England
`
`THOMAS N. TOZER, Ph .D.
`School of Pharmacy
`
`University of California
`
`San Francisco, California
`
`A Lea & Febiger Book
`
`Williams & Wilkins
`
`BA l TIMORE • PHI LADELPH IA • HONG KONG
`LO NDON • MUN ICH • SYDNEY • TO KYO
`
`A WAVER LY COMPANY
`1995
`
`

`
`CHAPTER 5
`
`THERAPEUTIC RESPONSE AND TOXICITY
`
`57
`
`Therapeutic Window
`
`Let us expand philosophically on this concept of weighting developed for procainamide
`using the information in Fig. 5-3, adding hypersensitivity and assigning values to the re(cid:173)
`sponses according to our best judgment. Figure 5-4 shows the probabilities of the re(cid:173)
`sponses, plus that of hypersensitivity, each weighted by a judgmental factor versus the
`logarithm of the plasma concentration. The factor is negative for undesirable effects and
`positive for desirable effects. On algebraically adding the weighted probabilities, a utility
`curve is obtained that simply shows the chance of therapeutic success as a function of the
`plasma concentration. Both low and high concentrations have a negative utility; i.e., at
`these concentrations, the drug is potentially more harmful than helpful. There is an optimal
`concentration (8 mg/L) at which therapeutic success is most likely, and there is a range of
`concentrations (about 4 to 10 mg/L) within which the chances of successful therapy are
`high. This is the therapeutic window or therapeutic concentration range. Precise limits, of
`course, are not definable, particularly considering the subjective nature of the utility curve.
`Each drug produces its oWn peculiar responses, and the weighting assigned to these re(cid:173)
`sponses differ, but both the incidence of the drug effects and the relative importance of
`each effect must be evaluated to determine the therapeutic concentration range.
`There are problems associated with the acquisition of the incidence of the various re(cid:173)
`sponses. For example, the procainamide data were obtained in patients who were some(cid:173)
`times titrated with the drug. That is, the dosage was adjusted when the patient had not
`adequately responded or when toxicity was present. However, patients even on the usual
`
`~
`<?~
`<?<0·
`~
`~
`~ (f)
`
`100
`
`80
`
`..-..
`+-' c:::
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`~
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`c:::
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`"C
`·c:;
`c:::
`
`20
`
`0
`
`0
`
`4
`8
`Plasma Procainamide Concentration (mg/L)
`
`10
`
`Fig. 5-3. Schematic representation of the frequency of ineffective therapy, effective therapy, minor side effects,
`serious toxicity, and "therapeutic effectiveness" with plasma concentration of procainamide in patients receiving
`this drug for the treatment of arrhythmias. Therapeutic effectiveness is defined arbitrarily as the difference in the
`frequency between effective therapy and toxic effects; the therapeutic effectiveness (colored line) of procainamide
`reaches a peak of 8 mg/L (1 mg/L = 4.3 11M). (Adapted from the data of Koch-Weser, J.: In Pharmacology and
`the Future: Problems in Therapy. Edited by G.T. Okita and G.H . Archeson. Karger, Basel, 1973, Vol. 3, pp.
`69-85.)
`
`

`
`98
`
`MULTIPLE-DOSE REGIMENS
`
`CHAPTER 7
`
`Consequently, either the dosing interval necessary to achieve a desired average steady-state
`concentration or the average concentration resulting from administering the dose every
`dosing interval can be calculated.
`By definition of Css,w the value of -r · Css,av is the AUG within a dosing interval at steady
`state. Thus, this area is equal to that following a single dose. This principle is shown in Fig.
`7-9, and a practical illustration is shown in Fig. 7- 10.
`Given the plasma concentrations with time after a single oral dose, the concentration at
`any time during repeated administration of the same dose can be readily calculated by
`adding the concentrations remaining from each of the previous doses. For example, if doses
`are given at 0, 12, and 24 hr, then the concentration at 30 hr is equal to the sum of the
`values at 30, 18, and 6 hr after a single dose.
`
`<=
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`
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`
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`ro
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`
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`
`0
`
`0
`
`12
`
`24
`Hours
`
`36
`
`48
`
`0
`
`0
`
`12
`
`24
`Hours
`
`36
`
`48
`
`Fig. 7-9. Plasma concentrations of a drug given intravenously (left) and orally (right) on a fixed dose of 50 mg
`and fixed dosing interval of 6 hr. The half-life is 12 hr. Note that the AUG dming a dosing interval at steady state
`is equal to the total area under the curve following a single dose. The fluctuation of the concentration is diminished
`when given orally (absorption half-life is 1.4 hr), but the average steady-state concentration is the same as that
`after i.v. administration, when, as in this example, F = 1. The equations used for the simulations are given in
`Appendix 1-D.
`
`Fig. 7-10. Twenty-four subjects each re(cid:173)
`ceived a single 20-mg oral dose of the benzo(cid:173)
`diazepine, clobazam, followed 1 month later by
`an oral regimen of 10 mg of clobazam daily for
`22 consecutive days. The observed average pla(cid:173)
`teau clobazam concentration was well predicted
`by the value calculated from the single dose
`data, obtained by dividing the AUG by the dos(cid:173)
`ing interval and correcting for dose. The solid
`line is the perfect prediction (1 mg!L = 33 1-!M)
`(Redrawn from Greenblatt, D.J., Divali, M.,
`Puri, S.K., Ho, 1., Zinny, M.A., and Shader, R.I.:
`Reduced single-dose clearance of clobazam in
`elderly men predicts increased multiple-dose
`accumulation. Glin. Pharmacokinet., 8:83- 94,
`1983. Reproduced with permission of ADIS
`Press Australasia Pty Limited.)
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0
`
`. . . . . . . .
`
`0.1
`0.5
`0.4
`0.3
`0.2
`0
`Predicted Average Clobazam Plateau
`Concentration (mg/L)
`
`- - - -
`
`-
`
`-
`
`-- -
`
`- - - --
`
`-
`
`- -- -- -
`
`- -- - --
`- - - -- -.
`
`,-r-1·