Biopharmaceutics and
`Clinical Pharmacokinetics
`
`MILO GIBALDI, PH.D.
`Dean, School of Pharmacy
`Associate Vice President,
`Health Sciences
`University of Washington
`Seattle, Washington
`
`E.S. FARLEY LIBRARY
`WILKES UNIVERSITY
`WILKES-BARRE, PA
`
`FOURTH EDITION
`
`LEA & FEBIGER
`
`• Philadelphia
`
`• London
`
`•
`
`1991
`
`Page 1
`
`SHIRE EX. 2048
`KVK v. SHIRE
`IPR2018-00290
`
`

`

`Lea & Febiger
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`
`Library of Congress Cataloging-in-Publication Data
`
`Gibaldi, Milo.
`Biopharmaceutics and clinical pharmacokinetics / Milo Gibaldi.-
`4th ed.
`P.
`cm.
`Includes bibliographical references.
`ISBN 0-8121-1346-2
`1. Biopharmaceutics. 2. Pharmacokinetics. I. Title
`[DNLM: 1. Biopharmaceutics. 2. Pharmacokinetics. QV 38 G4371)]
`RM301.4.G53 1990
`615' .7—dc20
`DNLM/DLC
`for Library of Congress
`
`90-5614
`CIP
`
`First Edition, 1971
`Reprinted 1973, 1974, 1975
`Second Edition, 1977
`Reprinted 1978, 1979, 1982
`Third Edition, 1984
`Reprinted 1988
`Fourth Edition, 1991
`First Spanish Edition, 1974
`First Japanese Edition, 1976
`Second Japanese Edition, 1981
`Second Turkish Edition, 1981
`
`The use of portions of the text of USP XX-NF XV is by permission of the USP Convention. The Convention
`is not responsible for any inaccuracy of quotation or for false or misleading implication that may arise
`from separation of excerpts from the original context or by obsolescence resulting from publication of a
`supplement.
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`Copyright © 1991 by Lea & Febiger. Copyright under the International Copyright Union. All Rights Reserved. This
`book is protected by copyright. No part of it may be reproduced in any manner or by any means without written permission
`from the publisher.
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`PRINTED IN THE UNITED STATES OF AMERICA
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`Print no.: 4 3 2 1
`
`Page 2
`
`

`

`7
`Prolonged-Release Medication
`
`PHARMACOKINETIC THEORY
`The duration of drug effect is a function of the
`pharmacokinetics of the drug molecule in an in-
`dividual patient. The clearance and apparent vol-
`ume of distribution of a drug determine the degree
`of persistence of the molecule in the body. This
`persistence is characterized in terms of half-life or
`mean residence time (MRT). Because the duration
`of drug action is related to the distribution and
`elimination kinetics of a drug, the frequency of
`dosing must also bear some relationship to the
`drug's half-life or MRT.
`We often find that the frequency of dosing
`needed to maximize the benefit-to-risk ratio of a
`drug is unreasonable. For example, in most pa-
`tients, procainamide must be given every 3 to 4 hr
`around the clock to assure continuous suppression
`of irregular cardiac rhythms. The same dosing re-
`quirements apply to the use of the bronchodilator
`theophylline in children. The optimum use of idox-
`uridine eye drops for herpetic keratitis calls for
`hourly administration.
`A particularly conscientious patient may be able
`to comply with these requirements during the wak-
`ing hours, but even he is confounded during the
`sleep period. Excessively frequent dosing require-
`ments do not encourage compliance to the pre-
`scribed drug regimen, particularly when the drug
`is used prophylactically or to treat a silent disease
`such as hypertension.
`The alternative solutions to this important ther-
`apeutic problem include giving the drug less fre-
`quently and accepting a less favorable therapeutic
`outcome, seeking new drugs with similar phar-
`macologic effects but more favorable pharmaco-
`kinetic characteristics, or developing a prolonged-
`release dosage form. In most cases, experience
`
`124
`
`dictates that the pharmaceutical solution be ex-
`amined first.
`
`Drug Absorption and Duration of Effect
`Prolonged-release medication is a dosage form
`containing more drug than a conventional dosage
`form but releasing the drug far more slowly, over
`a period of hours or even days rather than seconds
`or minutes. In essence, we seek a situation where
`the duration of drug action is substantially deter-
`mined by the duration of drug release from the
`dosage form rather than the drug molecule's phar-
`macokinetic properties.
`This idea can be expressed mathematically by
`considering the intravenous and oral administration
`of a drug that distributes rapidly from the blood-
`stream. After intravenous bolus administration,
`drug concentration in the blood is given by:
`
`C = Co exp( — kt)
`
`(7-1)
`
`where Co is the initial drug concentration and k is
`the first-order elimination rate constant. Under
`these conditions, MRT is given by:
`
`MRTiv = 1/k
`
`(7-2)
`
`The persistence of drug in the body and the duration
`of drug effect is a function of drug elimination
`kinetics.
`Following oral administration of the drug, as-
`suming first-order absorption, concentration in the
`blood is given by:
`
`C = C*F[exp( — kt) — exp( — kat)]
`
`(7-3)
`
`where C* is a complex constant, F is the fraction
`of the oral dose reaching the systemic circulation,
`and ka is the first-order absorption rate constant.
`The MRT is given by the following equation:
`
`MRTora, = MRT + 1/ka
`
`(7-4)
`
`Page 3
`
`

`

`Prolonged-Release Medication
`
`125
`
`The time course of drug concentration in the blood
`is affected by the absorption process, i.e., MRTO„
`> MRT;,. But, for most drugs, absorption from
`conventional dosage forms is so rapid that MRTora,
`is not substantially greater than MRT;,. Accord-
`ingly, even after oral administration the duration
`of effect is largely a function of the elimination
`kinetics of the drug.
`However, if the release rate of drug from the
`dosage form is decreased (i.e., decrease ka), we
`simultaneously increase MRTara,. The MRT be-
`comes more dependent on the release rate and less
`dependent on the drug molecule's kinetics. Using
`this approach, a situation is reached where the
`MRT and the duration of effect are largely con-
`trolled by the release rate of drug from the dosage
`form.
`
`Frequency of Dosing and Therapeutic Index
`The therapeutic index of a drug is most usefully
`defined in man as the ratio of the maximum drug
`concentration in blood that can be tolerated to the
`minimum drug concentration needed to produce a
`satisfactory clinical response. Therapeutic concen-
`tration ranges for certain drugs in man have been
`identified. In some cases, these ranges are narrow,
`resulting in small therapeutic indices.
`The average therapeutic range of theophylline
`concentration in blood is about 8 to 20 µg/ml; the
`therapeutic index of theophylline is 2.5. Estimates
`of therapeutic index for other drugs are 2.0 for
`digoxin and valproic acid, 2.7 for procainamide,
`and 4.0 for lidocaine. We seek to maintain drug
`concentrations in blood well within the therapeutic
`range during drug therapy. This requires not only
`the selection of an appropriate daily dose; the drug
`must also be given with sufficient frequency so as
`to minimize the range of blood concentrations that
`are produced. The ratio of maximum to minimum
`drug concentrations at steady state should not ex-
`ceed the therapeutic index of the drug. This con-
`centration ratio is a function of the half-life of a
`drug and the frequency of dosing.
`For drugs that are both absorbed and distributed
`rapidly, Theeuwes and Bayne' have demonstrated
`the following relationship:
`
`7 < tit (In TI)/(ln 2)
`
`(7-5)
`
`where T is the dosing interval, ttt is the half-life,
`and TI is the therapeutic index. A drug with a
`therapeutic index of 2 and a half-life of 3 hr must
`be given no less frequently than every 3 hr to avoid
`
`excessive or subtherapeutic concentrations. A drug
`with a similar half-life but a therapeutic index of
`4 may be given every 6 hr.
`When drug effects are directly related to con-
`centration in blood but distribution is slow, the drug
`must be given even more frequently than suggested
`by Equation 7-5. In such cases, a better estimate
`of dosing interval may be obtained by replacing
`t1/2 with 0.693(MRT) where MRT is the mean res-
`idence time.
`
`Steady-State Concentrations and
`Release Rate
`Dosing regimens for rapidly absorbed drugs are
`a function of the pharmacodynamic and pharma-
`cokinetic characteristics of the drug molecule; they
`must be based on the therapeutic index and half-
`life or MRT of the drug itself. Reducing the ab-
`sorption rate of a drug by controlling its release
`rate from the dosage form, however, can dramat-
`ically affect drug concentrations at steady state.
`For a given dosage regimen, the slower the release
`rate of drug; the smaller is the ratio of maximum
`to minimum drug concentrations at steady state.
`Under these conditions, we can give larger doses
`at less frequent intervals and still stay within the
`therapeutic concentration range of the drug; this is
`the rationale for prolonged-release medication.
`Prolonged-release medication offers obvious ad-
`vantages for drugs with short half-lives and small
`therapeutic indices. These specialized dosage
`forms permit such drugs to be given at more rea-
`sonable intervals throughout the day; implications
`include more optimal therapy, patient convenience,
`and improved patient compliance with the pre-
`scribed regimen. The application of prolonged-
`release medication, however, is not limited to such
`drugs Since these dosage forms offer the potential
`of reducing the peak-to-trough drug concentration
`ratio, they may be useful for many more drugs 2
`Reducing the peak-to-trough concentration ratio
`has been found to improve the benefit-to-risk ratio
`of some drugs. The potassium-depleting effect of
`hydrochlorothiazide disappears, while its diuretic
`effect is slightly enhanced, when the drug is given
`every 3 hr rather than once a day.3 The nephrotox-
`icity of gentamicin is substantially reduced when
`steady-state concentrations are maintained in a nar-
`row range of about 1 to 4 itg/m1.4 The safety of
`certain anticancer drugs, including bleomycin5 and
`methotrexate,' is increased when given continu-
`ously by infusion rather than intermittently.
`
`Page 4
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`

`

`126
`
`Biopharmaceutics and Clinical Pharmacokinetics
`
`By minimizing fluctuations in blood levels we
`may be able to reduce the dosage required, improve
`the effectiveness, and decrease the adverse effects
`of a drug. For instance, pilocarpine administered
`continuously by an ocular insert reduces elevated
`intraocular pressure in patients with glaucoma
`without the marked myopia commonly seen in pa-
`tients using pilocarpine eyedrops every six hours.
`White' compared intraoperative and postopera-
`tive effects of fentanyl and ketamine administered
`by continuous intravenous infusion with those pro-
`duced by intermittent iv bolus doses. Continuous
`infusion minimized the peaks and valleys of drug
`concentration in blood and, presumably, brain that
`ordinarily result from intermittent dosage.
`Women scheduled for elective outpatient gyne-
`cologic surgery received either fentanyl or keta-
`mine as an intravenous adjunct to nitrous oxide for
`maintenance of general anesthesia after induction
`with thiopental. The drugs were given either by
`continuous iv infusion or intermittent iv bolus. The
`method of drug administration resulted in important
`differences.
`Only about one-half the dosage of fentanyl or
`ketamine was needed to maintain anesthesia when
`the drugs were given by continuous infusion rather
`than by intermittent bolus. The use of less drug
`resulted in more rapid recovery from anesthesia
`and in substantially less postoperative sedation, and
`minimized postoperative psychomotor dysfunc-
`tion. Excessive sedation was noted in about 50%
`of the patients in the bolus groups but in less than
`10% of the patients in the infusion groups.
`Continuous infusion also improved intraopera-
`tive conditions. Respiratory depression and mus-
`cular rigidity occurred less frequently with contin-
`uous rather than intermittent administration of
`fentanyl. Hypertension and tachycardia occurred
`less frequently with continuous rather than inter-
`mittent ketamine.
`
`Zero-Order Release
`
`Continuous, constant-rate intravenous infusion
`leads to constant blood levels. Under these con-
`ditions, blood levels are invariant with time; there
`are no peaks or troughs. Provided that the constant
`drug concentration is within the therapeutic range,
`this is an ideal situation for many drugs. The only
`way to achieve constant blood levels is to admin-
`ister the drug at a constant (zero-order) rate over
`the entire dosing interval. The concentration of
`
`drug at steady state is given by the following equa-
`tion:
`
`C. = ko/C1
`
`(7-6)
`
`where lc is the zero-order delivery or release rate
`of drug, and Cl is the clearance of the drug. Fluc-
`tuations in blood levels do occur under these con-
`ditions, because of temporal variations in clearance
`or in the delivery rate, but they are usually small.
`Until recently, constant rate intravenous infu-
`sion, by means of a carefully controlled drip or
`mechanical pump, was the only way to attain con-
`stant blood or tissue levels of drug. Today, there
`are dosage forms intended for oral, ocular, intra-
`vaginal, or intramuscular administration that re-
`lease drug in a zero-order or near zero-order fash-
`ion. These dosage forms are discussed in other
`sections of this chapter.
`
`ORAL MEDICATION
`Most prolonged-release dosage forms are in-
`tended for oral administration. A prolonged-release
`dosage unit contains more drug than a conventional
`dosage unit but is intended to be given less fre-
`quently. A drug that is ordinarily given at a dose
`of 250 mg 4 times a day in a conventional tablet
`or capsule may be given at a dose of 500 mg twice
`a day, or 1 g once a day, in a prolonged-release
`dosage form. The ultimate criteria for evaluating
`such dosage forms are: (1) the amount of drug
`intended to be absorbed is indeed absorbed in a
`predictable and consistent manner; and (2) the
`steady-state ratio of maximum to minimum drug
`concentrations is no greater than or, optimally, less
`than that produced by the more frequently admin-
`istered conventional dosage form.
`The early history of the prolonged-release oral
`dosage form is probably best forgotten. Products
`were developed empirically, often with little ra-
`tionale, and bioavailability problems were com-
`mon. Many people viewed these dosage forms as
`little more than marketing inducements. Today, the
`situation has improved; many of the available prod-
`ucts are well designed drug delivery systems and
`have a defined therapeutic goal. In some cases, the
`prolonged-release dosage form is the most impor-
`tant and most frequently used form of the drug.
`A wide variety of techniques have been used to
`develop prolonged-release oral dosage forms.
`These techniques include the use of drug sub-
`stances of decreased solubility or dissolution rate,
`accomplished by increasing particle size or substi-
`
`Page 5
`
`

`

`Prolonged-Release Medication
`
`127
`
`tuting less soluble salts or complexes, ion exchange
`resins to bind the drug substance, porous, nondis-
`integrating, inert carriers as matrices for the drug,
`slowly eroding coatings or matrices, and coatings
`that serve as membranes for drug diffusion.
`Most oral prolonged-release dosage forms can
`be characterized as either subdivided or single
`units. Subdivided prolonged-release dosage forms,
`exemplified by the hard gelatin capsule containing
`numerous drug-impregnated beads, present the
`drug to the gastrointestinal tract in the form of many
`slowly-dissolving particles or granules. Often, sev-
`eral kinds of beads are found in the capsule, some
`releasing the drug rapidly, others releasing the drug
`over a period of several hours, still others releasing
`the drug at intermediate rates. Spansule is a trade
`name historically associated with this dosage form.
`More details of these and other formulations can
`be found in a recent review by Longer and Robin-
`son.' Phenothiazines, antihistamines, iron, and
`many other drugs are available in this kind of dos-
`age form. In general, the release and absorption of
`drugs from slow-release beads can be described by
`first-order kinetics.
`The single-unit prolonged-release dosage form
`remains more or less intact throughout the gastro-
`intestinal tract, releasing the drug continuously dur-
`ing its passage down the tract. An example of this
`dosage form is the inert plastic matrix, a dosage
`form that has been used widely in Europe. The
`drug is mixed with inert, insoluble, powdered ma-
`trix material consisting of plastic resins and other
`ingredients and compressed. In the gastrointestinal
`tract, drug particles from the surface of the matrix
`system dissolve and leave pores through which
`drug from within the tablet leaches out. The matrix
`retains its shape during the leaching process and is
`eliminated in the feces. The release rate of drug
`decreases with time and, in this sense, resembles
`a first-order process.9
`The steady-state plasma levels and pharmaco-
`logic effects of a daily dose of 0.2-g metoprolol,
`a cardioselective 13-blocker, in a prolonged-release
`matrix tablet and in regular 0.1-g tablets were stud-
`ied in healthy subjects. The following dosing reg-
`imens were used: (1) one prolonged-release tablet
`once a day; (2) two 0.1-g regular tablets once a
`day; and (3) one 0.1-g regular tablet every 12 hr.
`The peak-to-trough concentration ratio of meto-
`prolol was, on the average, about 10 for the matrix
`tablet and the twice-a-day regimen and about 40
`for the once-a-day administration of the regular
`
`tablets (Fig. 7-1). Metoprolol in the matrix tablet
`produced a more uniform effect on heart rate and
`systolic blood pressure during exercise than the
`corresponding daily dose of metoprolol given as
`two 0.1-g tablets once daily or as one 0.1-g tablet
`twice a day. '° Although metoprolol has a relatively
`short half-life, about 3 hr, a once-a-day regimen
`can be developed with a prolonged-release dosage
`form. The same is true for propranolol."
`Some pharmaceutical scientists judge subdi-
`vided prolonged-release dosage forms to be poten-
`tially safer than intact or single-unit dosage forms
`because a mechanical failure of the coating or ma-
`trix would result in the immediate release of only
`a small fraction of the entire dose. Mechanical fail-
`ure is unlikely to occur with the matrix tablet, but
`it may occur in those single-unit dosage forms that
`rely on a continuous membrane to control release.
`A failure in this case may result in the immediate
`dumping of the entire dose, a quantity of drug that
`is 2 or 3 times the amount given as a single dose
`in a conventional dosage form.
`Because prolonged-release products are complex
`dosage forms, substantial differences in perform-
`ance among different products of the same drug
`may occur. Although the prolonged-release matrix
`tablet of metoprolol, previously described, has a
`longer duration of effect than the same dose of the
`drug given as regular tablets,''- this is not true for
`a different prolonged-release product of metopro-
`lol. '3,14 One product shows a significant improve-
`ment over conventional metoprolol whereas the
`other does not.
`Considerable differences among prolonged-
`release products of theophylline have also been
`reported. Studies in adult subjects indicate that the-
`ophylline is slowly but completely and consistently
`absorbed from three of six prolonged-release for-
`mulations. Theophylline absorption from the other
`three products is more erratic and less complete. '5
`In another study, theophylline absorption from
`three commercial products labeled as prolonged-
`release was compared to the absorption from a
`standard uncoated tablet. Two of the prolonged-
`release products showed considerably slower ab-
`sorption of theophylline than did the regular tablet,
`but the third product did not.16
`To determine whether clinically important
`changes in serum theophylline concentrations
`occur when patients switch their brand of pro-
`longed-release theophylline, 10 subjects with
`asthma were given the same dose of four different
`
`Page 6
`
`

`

`128
`
`Biopharmaceutics and Clinical Pharmacokinetics
`
`1000
`
`800
`
`600
`
`400
`
`200
`
`Fig. 7-1. Mean steady-state plasma concentrations of metoprolol after repetitive dosing of a prolonged-release tablet
`(0.2 g) once a day (0), two 0.1 g regular tablets once a day (0), and one 0.1 g regular tablet every 12 hr (0). (From
`Johnsson, G., et al.'°)
`
`commercially available products for 2-week peri-
`ods in a random, double-blinded, crossover fash-
`ion. "
`On at least one occasion in every subject, switch-
`ing between brands of theophylline resulted in
`serum theophylline levels outside the accepted ther-
`apeutic range, and this was associated with toxic
`symptoms in 5 of the subjects. Worsening pul-
`monary function was observed in two subjects
`when switching resulted in lowered theophylline
`levels. Many of the changes in theophylline con-
`centrations on switching from one brand to another
`could not be predicted by the bioavailability dif-
`ferences between the products. The investigators
`concluded that "these results argue against the
`open substitution of these formulations and suggest
`that if patients are switched between different
`brands of SR theophylline, their serum theophyl-
`line concentration needs to be closely monitored."
`Much has been published concerning prolonged-
`release theophylline during the past 10 years. The
`drug has a relatively short half-life, particularly in
`children, and a small therapeutic index. Clinical
`studies suggest that 40% of all children receiving
`conventional products of theophylline in the usual
`every 6-hr manner will have excessive or subther-
`apeutic blood levels of the drug. '8
`Although no well-controlled clinical trials have
`been published showing that prolonged-release the-
`ophylline preparations are more effective than plain
`theophylline tablets or solutions, many clinicians
`
`report that the long-acting formulations are more
`effective in controlling symptoms, especially dur-
`ing the night. Furthermore, compliance is likely to
`improve when patients take medication only twice
`a day, rather than 3 or 4 times a day. On the other
`hand, some clinicians have found that when ad-
`verse effects occur with prolonged-release theo-
`phylline, they persist longer. Some patients taking
`the long-acting preparations complain of insomnia,
`a known adverse effect of theophylline.
`Adult smokers and children, who metabolize
`theophylline rapidly, may benefit most from treat-
`ment with prolonged-release preparations. In many
`patients, it may be necessary to individualize the
`daily dose and, in some patients, it may be nec-
`essary to give the product more frequently than
`twice a day.
`Individual variability in dosing requirements is
`clearly seen in the results of a study evaluating one
`of the more commonly prescribed prolonged-
`release theophylline preparations, Theodur. '9 In a
`panel of 20 asthmatic patients, 6 to 18 years of
`age, receiving the long-acting theophylline product
`twice a day, the daily doses needed to produce an
`average blood level of about 15 µg/m1 ranged from
`6.1 to 16.3 mg/kg. The blood levels resulting from
`these individualized regimens, as estimated from
`4 to 5 blood samples taken over the course of each
`of 2 consecutive steady-state dosing intervals,
`showed surprisingly little fluctuation. Peak and
`trough values and peak-to-trough ratios for the 20
`
`Page 7
`
`

`

`Prolonged-Release Medication
`
`129
`
`Table 7-1. Peak and Trough Serum Concentrations
`of Theophylline During 24 hr at Steady State in
`Children Receiving, on the Average, 10 mg/kg Twice
`a Day in a Prolonged-Release Product. *
`Trough concn.
`Peak concn.
`(µg/ml)
`(µg/ml)
`
`Patient
`
`Peak-to-trough
`ratio
`1.7
`1.8
`1.4
`1.5
`1.5
`1.5
`2.5
`1.3
`1.6
`1.2
`1.2
`2.1
`1.7
`1.6
`1.7
`1.3
`1.5
`1.4
`1.9
`1.6
`
`10.3
`17.6
`12.7
`22.7
`2
`12.0
`3
`17.0
`14.8
`22.9
`4
`16.4
`11.2
`5
`12.4
`18.9
`6
`7.0
`17.2
`7
`16.3
`21.8
`8
`8.7
`13.7
`9
`12.6
`15.5
`10
`20.3
`16.6
`11
`9.0
`18.5
`12
`10.6
`18.4
`13
`12.1
`19.7
`14
`10.5
`17.6
`15
`15.4
`20.3
`16
`17.5
`11.8
`17
`16.7
`23.5
`18
`7.6
`14.5
`19
`10.4
`16.8
`20
`*Data from Kelly, H.W., and Murphy, S.',
`
`patients are shown in Table 7-1. Average blood
`levels are shown in Figure 7-2. If twice-a-day
`doses of regular theophylline, sufficient to produce
`average levels of about 15 µ,g/ml, were given to
`these patients we would expect to find peak-to-
`trough concentration ratios of about 10.
`A circadian variation in theophylline levels in
`
`serum is quite evident during treatment with certain
`twice-a-day slow-release theophylline products.
`Steady-state theophylline concentrations for the 12-
`hr period following the morning dose are different
`from those following the evening or night dose. In
`one study, peak concentration at steady state after
`an 11 AM dose occurred at about 3 hr after dosing,
`whereas peak level was observed at about 9 hr
`following the 11 PM dose, which was taken im-
`mediately before retiring.20 The area under the con-
`centration-time curve during a dosing interval at
`steady state was also smaller after the night dose
`than following the morning dose. These differences
`reflect a circadian variation in theophylline ab-
`sorption rather than in theophylline metabolism.
`A change in posture could be a simple expla-
`nation of the circadian variation in theophylline
`pharmacokinetics.2' This was examined in healthy
`human subjects who took 450 mg slow-release ami-
`nophylline orally at the same time of day on two
`separate occasions. On one day the subjects re-
`mained standing and on the other, they lay supine
`throughout the study. Theophylline levels in plasma
`were measured hourly for 6 hr after the dose.
`At each sampling time, theophylline levels were
`higher during the standing experiment than during
`the supine study. Peak concentration of theophyl-
`line with the subjects standing occurred at 5 hr and
`was 6.4 mg/L. Theophylline levels were ascending
`for the entire 6-hr study period in the supine group;
`
`ti
`
`2300
`
`0200
`
`0500
`
`t Dose
`0800
`
`TIME(hours)
`
`1100
`
`1400
`
`1700
`
`2000
`
`26
`24
`22
`20
`18
`16
`14
`12
`10
`8
`6
`4
`2
`
`Dose
`2000
`
`SERUM THEOPHYLLINE LEVELS(ag/m1)
`
`Fig. 7-2. Mean steady-state serum concentrations of theophylline in children receiving an average dosage of 10 mg/kg
`in a prolonged-release product every 12 hr. (From Kelly, H.W., and Murphy, S.: Efficacy of a 12-hour sustained-release
`preparation in maintaining therapeutic serum theophyl line levels in asthmatic children. Pediatrics, 66:100, 1980. Copyright
`American Academy of Pediatrics 1980.)
`
`Page 8
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`

`130
`
`Biopharmaceutics and Clinical Pharmacokinetics
`
`......................................
`
`A Capsule
`B Controlled
`Release Tablet
`
`0.9 .,
`
`OA.
`
`0.7.
`
`04.
`
`Os•
`
`OA.
`
`oa•
`
`02
`
`0.1.
`
`Serum Lithium Levels mEg/Liter
`
`0
`• am.
`
`2
`
`4
`
`6
`
`•
`
`10
`
`12
`Hours
`
`14
`
`16
`
`19
`
`20
`
`22
`
`24
`
`Fig. 7-3. Mean steady-state serum levels of lithium in healthy subjects who received a 300-mg capsule 3 times a day
`or a 450-mg prolonged-release tablet twice a day. (From Caldwell, H.C., et al.24)
`
`mean concentration at 6 hr was 5.4 mg/L. The
`investigators concluded that the supine position as-
`sumed at bedtime may be an adequate explanation
`for the diurnal variation seen with twice-a-day pro-
`longed-release theophylline products.
`Theophylline is widely used in children, so it is
`not surprising that slow-release tablets are some-
`times chewed or crushed to facilitate swallowing.
`This practice may result in a loss of the prolonged-
`release characteristic of the product. To examine
`this question, Theo-Dur, a widely used formula-
`tion, was given to healthy adult subjects on three
`occasions, at least 1 week apart.22 On the first day,
`subjects were randomly allocated to either swallow
`intact or chew, and then swallow, a 300 mg tablet.
`Subjects were then crossed over for the second
`dose. The effects of crushing the tablet prior to
`ingestion were studied at the third dose. Swallow-
`ing the tablets intact resulted in a significantly
`longer time to peak concentration compared with
`chewing or crushing (i.e., 6 hr vs about 3 hr) and
`the peak concentration was somewhat lower, 35.6
`µmol/L, compared with chewing (43.1 µ,mol/L) or
`crushing (41.9 µmon). Area under the curve,
`however, was about the same for all three modes
`of administration. Chewing or crushing Theo-Dur
`tablets does not appear to have a substantial effect
`on the bioavailability characteristics of the product,
`suggesting that it may be a suitable preparation for
`use in young children.
`A prolonged-release liquid theophylline prepa-
`
`ration, aimed at the pediatric population and de-
`signed for twice-daily administration, is under in-
`vestigation.23 The suspension was compared with
`aminophylline solution (administered every 8 hr)
`in 27 asthmatic children less than 12 years of age.
`Average steady-state levels of theophylline were
`about 10% lower during treatment with the sus-
`pension than with the solution. Peak levels were
`also lower (11.2 vs 14.2 µ,g/m1) and the difference
`between Cmax and C„„„ was smaller (6.9 vs 10.0
`µg/ml) with the suspension. The investigators con-
`cluded that the slow-release suspension should
`prove to be useful in patients who require main-
`tenance theophylline therapy, but who cannot take
`solid oral dosage forms.
`Lithium carbonate is the drug of choice in treat-
`ing certain phases of manic depression. Although
`the drug has a long half-life, about 24 hr, it also
`has a narrow therapeutic index and must be given
`3 or 4 times a day. Steady-state serum level fluc-
`tuations of lithium were compared following reg-
`ular capsules (300 mg 3 times a day) or prolonged-
`release tablets (450 mg every 12 hr) of lithium
`carbonate.24 Average blood levels are shown in Fig-
`ure 7-3. The degree of fluctuation (Fl) of serum
`levels was assessed by the following equation:
`
`Fl = (Cmax — Cn,in)/C
`
`(7-7)
`
`where Cmax and Cm,„ are the maximum and mini-
`mum drug concentrations over the 24-hr steady-
`state dosing cycle, and C is the mean concentration
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`

`Prolonged-Release Medication
`
`131
`
`over the cycle. C is estimated from the ratio of
`area under the curve to dosing interval. This fluc-
`tuation index is analogous to the coefficient of var-
`iation; small values are desired for the prolonged-
`release preparation. This index may be more stable
`than the peak-to-trough concentration ratio, which
`could be highly unstable in the presence of error
`for small values of C„,,„. In this study, the index
`was 0.46 for the prolonged-release tablet regimen
`and 0.66 for the regular capsule regimen, sug-
`gesting that the regular product produces about
`40% more fluctuation in serum lithium levels than
`the slow-release formulation.
`Fluctuations in serum levels are related not only
`to the release rate of drug from the dosage form
`and the frequency of administration (dosage inter-
`val), but also vary with drug elimination rate.
`Steady-state studies with a prolonged-release the-
`ophylline product found a linear relationship be-
`tween percent fluctuation and theophylline clear-
`ance in individual subjects.25
`Weinberger and Hendeles26 also calculated the
`percent fluctuation in steady-state serum levels of
`theophylline for different products. With one pro-
`longed-release product, percent fluctuation was
`57% in slow metabolizers of theophylline (half-life
`= 7.7 hr) but increased to 154% in rapid metab-
`olizers (half-life = 3.7 hr).
`Several antiarrhythmic drugs are plagued with
`the undesirable characteristics of short half-life and
`narrow therapeutic index. Procainamide is an ex-
`ample; its half-life is about 3 hr. Therapeutic and
`toxic effects have been related to drug concentra-
`tions in plasma. The therapeutic range is 4 to 8
`µg/ml but can often extend to 10 µg/m1 without
`toxicity. To maintain safe, adequate blood levels,
`the regular tablet form of the drug must be given
`every 3 to 4 hr.
`Steady-state levels of procainamide were deter-
`mined in patients receiving about 20 mg/kg per day
`in the form of prolonged-release matrix tablets of
`the drug every 8 hr.27 Mean procainamide blood
`levels are plotted in Figure 7-4. In 17 of the 26
`patients, blood levels were maintained above a
`level of 4µg/ml for at least 75% of the time. Of
`the 9 patients showing blood levels below the min-
`imum level for more than 25% of the time, 8 would
`have benefited from an increased daily dose or im-
`proved compliance with the regimen. In 4 of th