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Therapeutic effect and dosing strategies for theophylline in the treatment of chronic asthma
Therapeutic effect and dosing strategies for theophylline in the treatment of chronic asthma Miles Weinberger, Iowa
City,
Iowa,
M.D., and Leslie Hendeles,
and Gainesville,
Pharm.D.
Fla.
Theophylline has demonstrated a very high degree of clinical clfJicacy as a prophylactic maintenance drug for chronic asthma when dose levels maintain serum concentrations of 10 to ;70 pg,‘ml. Once established, such doses appear to be weli tolerated and free of clinically apparent side effects, although minor neuropsychological and physiologic abnormalities can be detected. In general, while there appears to be little clinical effect from these minor side effects, the possibility of bothersome symptoms in selected patients cannot be excluded and requires further study. The data argue strongly that formulations and dosage intervals should aim for the most stable serum concentrations practically attainable, even though clinicians will certainly make just$able compromises in individual clinical situations. The wide variability in theophylline elimination rate and the relationship between effect and serum concentration dictate that dosage be individualized and that jinal dosag? is best guided by measurement of serum concentration. Slow clinical titration decreases the frequency of caffeine-like side effects ji-om :>50% of patients when therapeutic levels are rapidly attained to only 1% or 2%. Finally, although some physiologic variables and drug interactions may alter theophylline elimination and thus pose clinical risks, it is reassuring that dosage requirements generally remain stable over extended periods. (J ALLERGYCLINIMMIINOL 1986;78:762-8.)
Theophylline has undergone a major transition in clinical use over the past 10 to 15 years. Used primarily for its cardiovascular effects in the early part of this century, theophylline was found in the 1920s to have clinically beneficial effects on acute bronchospasm. ’ In the 193Os, theophylline became popular as an oral agent, particularly in fixed-dose combination with ephedrine. Its predominant use continued in this manner into the early 1970s. Since then, definition of the pharmacodynamics and pharmacokinetics of theophylline has led to its present use as a major prophylactic agent for the prevention of chronic asthma. Several recent comprehensive reviews have discussed many aspects of the pharmacology and therapeutic use of theophylline.“4 The purpose of this article is to address three specific issues: (1) the ef-
From the Pediatric Allergy and Pulmonary Division, The University of Iowa, Iowa City, and University of Florida, Gainesville. Supported in part by grants from the National Institute of Allergy and Infectious Diseases (AI 16151-01) and the General Clinical Research Centers Program, Dvision of Research Resources (RR59), National Institutes of Health, United States Department of Health and Human Services. Reprint requests: Dr. Miles Weinberger, Department of Pediatrics, JCP, The University of Iowa, Iowa City, IA 52242. 762
ficacy of theophylline as prophylactic maintenance therapy for chronic asthma, (2) the relationship of the effect of theophylline to serum concentration, and (3) dosage :requirements of theophylline to obtain optimal safe eff;:ct for maintenance prophylactic therapy. EFFICACY OF THEOPHYLLINE Early studies by Turner-Warwick5 and Jenne et a1.6 suggested that clinical effect of theophylline appeared to be greatest when serum concentrations exceeded 10 p,g/ml. A subsequent double-blind, placebo-controlled :study on 12 children with asthma confirmed that doses reaching serum concentrations over 10 p.g/ml ‘were associated with marked suppression of asthmatic symptoms, whereas doses that reached lower serum concentrations did not result in symptoms that differed significantly from placebo in spite of measurable bronchodilator effect (Fig. 1). A subsequent double-blind, placebo-controlled study on a larger number of patients confirmed this high degree of efficacy,8 as did later studies comparing theophylline with cromo1yn,9 oral metaproterenol,‘(’ and inhaled albuterol. ” Theophylline’s efficacy for maintenance prophylactic therapy is sufficient to control chronic asthma when used as the only maintenance medication among
VOLUME NUMBER
78 4, PART 2
70% of patients referred to the Pediatric Allergy and Pulmonary Service at The University of lowa, a tertiary care referral center.” Even for the 30% of the referred patients who require maintenance corticosteroids because treatment with theophylline and other noncorticoid medication had failed, theophylline continues to have a (clinically important additive effect (Fig. 2). In spite of substantial doses of maintenance corticosteroids, a mean of 550 Fg/day of beclomethasone or 30 mg of oral prednisone on alternate momings, theophylline still significantly reduced the frequency and severity of symptoms. Cromolyn (an alternative to theophylline as maintenance prophylactic therapy for patients with less severe chronic asthma) appears not to have this degree of efficacy.14 Moreover, theophylline also significantly decreased the frequency with which patients had an inadequate clinical response to an inhaled sympathomimetic bronchodilator-the first line of defense for breakthrough symptoms-and therefore required a short course of oral corticosteroids (Table I). The observation that clinical responsiveness to inhaled bronchodilator was preserved and the need for short courses of oral corticosteroids because of progressive symptoms was thereby prevented was also reported in an earlier study.‘” However, theophylline also has a serious toxic potential. As serum concentrations increase above 20 kg/ml, the frequency and severity of adverse effects increase. Nausea, vomiting, headache, cardiac arrhythmias, seizures, and death can occur, and the literature is replete with the consequences of therapeutic misadventures. I5 Despite the toxic potential, adverse effects have not been seen in association with maintenance theophylline therapy when serum concentrations do not exceed 20 pg/ml (Fig. 3j.6-1o.” More careful neuropsychological evaluation, however, suggests various minor effects similar to those seen with caffeine.16. ”
RELATIONSHIP OF EFFECT TO SERUM CONCENTRATION Greater benefit can be obtained without an increase in adverse effects when doses are adjusted to maintain serum concentrations between 10 and 20 kg/ml. Moreover, the bronchodilatory effect from theophylline parallels changes in serum concentration (Fig. 4). A relationship between serum theophylline concentration and decrease in nonspecific airway reactivity can similarly be demonstrated by measuring the blocking of exercise-induced bronchospasm (Fig. 5). These and other data argue strongly for maintainenance of serum concentration at the most stable level possible (between 10 and 20 pgiml) to obtain maximal
TheoF;hylline
in the treatment
of chronic
60
asthma
763
I
Px05
t
; P< 05 u
Symptoms
m Isoproterenol :
q
Nebs
Eplnephrlne Inj. Substitute Meds
Placebo
Peak Serum Theophylline Averaging 6.5pg/ml
Peak Serum Theophylline Averaging 13pg/ml
FIG. 1. Frequency and severity of asthmatic symptoms among I:2 children with chronic asthma at residential treatment center. Each patient received, in double-blind randomized sequence, a l-week treatment with placebo, an ephedrine-theophylline combination in conventional doses that resulted in serum theophylline concentrations averaging 6.5 kg/ml, and individualized theophylline doses thar resulted in serum concentrations averaging 13 pg/ml. Asthma symptoms during each l-week period were promptly treated, when necessary, with inhaled isoproterenol; if symptoms were not rapidly relieved, epinephrine was administered subcutaneously. If patient was unrespons,ive to these measures, known drugs were substituted for double-blind medications.’ (Reproduced with permission from Weinberger M. Theophylline for treatment of asithma. J Pediatr 1978;92:1.)
safe beneft. However, asthma is a sufficiently variable disease that apparently adequate benefit may be obtained for some patients at lower serum concentrations. In Fig. 5 one patient had apparent blocking of exercise-induced bronchospasm at 0 kg/ml and, for many patients with asthma, a serum concentration of 0 kg/ml is fully adequate most of the time. Nonetheless, most evidence supports maintaining serum concentration:j within the range of 10 to 20 pg/ml when optimal likelihood of maximal safe effect is clinically indicated. Arguments have been made by some investigators” for routine use of lower serum concentrations. Most often the studies cited have been of questionable clinical relevance (i.e., examination of limited pulmonary function data only, or judgments based on detectable clinical effect at lower serum concentrations without examination for further clinical effect at h:!gher serum concentrations). 2’-23
DOSAGE REQUIREMENTS TO OBTAIN OPTIMAL. SAFE EFFECT A wide range of theophylline elimination rates is present at all ages with a continuum of elimination half-lives ranging from less than 3 hours to a maximum of 16 hours in normal, healthy subjects. Al-
764
Weinberger
and Hendeles
J ALLERGY
Beclomethasone
Dipropionate
Alternate
n = 21 Mean Days
Day n=
CLIN. IMMUNOL. OCTOBER 1986
Prednisone 10
Percent of Symptomatic
40 0
Transient
Symptoms
30
20
10
0
Nocturnal
Actlwiy
Cough
Wheeze
Nocturnal
Actwty
Cough
Wheeze
FIG. 2. Mean frequency of asthmatic symptoms with placebo (P) or theophylline (T) from daily diaries among children with chronic steroid-dependent astl-rma. The presence of nocturnal symptoms was recorded each morning, and interference witkl activity, cough, and wheezing were recorded each evening on a scale of 0 through 3 definlsd as absent, transient, repeated, or continuous symptoms, respectively. The graph at left refers to 21 patients receiving a mean dose of 550 pg/day of inhaled beclomethasone dipropioilate, and the graph at right refers to 10 patients receiving a mean dose of 30 mg of prednisone on alternate mornings. (Reproduced with permission from Nassif EG, Weinberger, MM, Thompson R, Huntley W. The value of maintenance theophylline for steroid dependent asthma. N Engl J Med 1981;304:71.)
2%
percent of Observation Periods
0
Insomnia
m
CNS Symptoms
m
GI Symptoms
‘5
10
Ephedrine Placebo
Hydmxyrine
Ephedrine
Thwphylline
Theop+hylline
Eph
Theophylline Hydr&yzine
FIG. 3. Frequency of symptoms compatible with adverse medication effects among 23 children with chronic asthma treated in a randomized, double-blirld, crossover study with theophylline, ephedrine, and hydroxyzine separately and in combination. Theophylline doses were individualized to attain peak levels between 10 pg/ml and 20 pgiml; the mean peak concentration was 16 pgiml. The frequency of these symptoms did not differ significantly between the theophylline and placebo regimens; adverse effects of medications were apparent only from the combination of ephedrine and theophylline. (Reproduced with permission from Weinberger M, Bronsky EA. Interaction of ephedrine and theophylline. Clin Pharmaccll Ther 1975;17:585.)
though the mean elimination half-life (under 4 hours) found in children is about half the mean half-life (8 hours) found in nonsmoking adults, there is considerable overlap. Moreover, there are no distinguishing clinical characteristics that enable the elimination half-
life, and thus the dosage requirement, to be identified. Doses, therefore, need to be individualized and guided by serum concentration if optimal likelihood of benefit without toxicity is to be obtained. Observations of a high frequency of caffeinelike
VOLUME NUMBER
78 4. PART 2
Theophylline
Serum Theophyllme Concentration (mcg/ml] .-.
100
in the treatment
12
14
sOi’
16
l
.
8l
.
V25
5
-20
5 a
-60
(Percent PredIctedI o---o
1
‘.
l
.
.
8
.
.
i I
a
.
.
(mcg/ml) -
.
-8Ot
l 9
5
10
15
20
Serum Theophylline
’
3 Time
(6hours)
’
drop tn vso
l .
.
6 8 10 Time (hrs)
765
. l
4
asthma
/.-JMean
s%PEFR (L/mm1 o____c
50
2
of chronic
25
@g/ml)
FIG. 5. Flelationship between maximal postexercise change in V, (flow rate at 50% of a forced vital capacity) and corresponding serum theophylline measurement. Superimposed, bar graph represents mean postexercise changes in V, for serum theophylline intervals indicated. Dotted line at 30% identifies response to exercise conventionally accepted as clinically important. (Reproduced with permission from Pollock J, Kiechel F, Cooper D, Weinberger M. Relationship of serum theophylline concentration to inhibition of exercise-induced bronchospasm and comparison with cromolyn. Pediatrics 1977; 60:840.)
l2
FIG. 4. A, Relationship between serum theophylline concentration and pulmonary function among 31 adult asthmatic subjects given 7.5 mgikg of a rapidly absorbed theophylline formulation.‘* B, Relationship between serum theophylline concentration and pulmonary function among 11 children treated with 100 mg Theo-Dur tablets (Key Pharmaceuticals) every 12 hours. Patients frequently became symptomatic: during last three hours of dosing interval.19
TABLE I. Frequency of requirements for additional daily prednisone due to exacerbations of asthma inadequately responsive to inhaled bronchodilators among 21 patients who required maintenance therapy with inhaled beclomethasone dipropionate (mean dose 550 pg/day) and 10 who required alternate-day prednisone (mean dose, 30 mg every other morning) during a randomized, placebo-controlled, month-long crossover study of iheophylline -
Event
Daily prednisonr: added Study period
Theophylline
Beclomethasone dipropionate
only Alternateday prednisone
Placebo Beclomethasone dipropionate
only
-
Alternateday prednisone
Both periods Beclomethasone dipropionate
Alternateday prednisone
P value*
1
0
6
2
1
1
0.02
1
0
5
1
0
0
0.06
termiantedt Reproduced with permission of The New England Journal of Medicine.‘4 *Analyses are for the therapeutic effect of theophylline among patients receiving both steroid regimens. ?A study period was terminated if more than 5 days of added prednisone were required during a regimen or when the investigator-clinician judged that contuation would be associated with excessive risk or discomfort to the patient. All decisions were made on a double-blind basis.
complaints when therapeutic serum concentrations are rapidly attained further influence dosing strategy. Since a slow clinical titration process appears to decrease the frequency of complaints of adverse effects
from more than 50%24 to a low of 1% to 2%,” we recommend beginning with low doses and subsequently increasing in increments of 25% to 50% (as long as increase is tolerated), until doses approach the
766
Weinberger
J. ALLERGY CLIN. IMMUNOL. OCTOBER 1986
and Hendeles
I
Adults and chlldren
INITIAL DOSE over 1 year old The lesger of 400 mg/day
or 16 mg/kg/day
I
after j days 4 FIRST INCREMENTAL INCREASE Adults and children t 45 kg 600mg/cay Children < 45 kg The lesser of 600 rrg/day 20 mg, kg/day 16 mg, kg’day
or-.
for ag,?s , to 9 for ag’?s >9
I
after 3 davs
SECOND INCREMENTAL INCREASE Adults and children 2 45 kg. 800mg Children < 45 kg The lesser of 800 mg/day 24 mglkg,day 20 mg:kgiday 18 mg kg/day
or
lor ages 1 lo 9 for ages 9 lo 12 for ages 12 10 16
I
Check Serum concentration about 4 hours affe, a dose when none have been mIssed or added for 3 days + DIRECTlIONS
SERUM CONCENTRATION lOto20~g/ml.
MaIntam dose tf tolerated. RECHECK SERUM THEOPHYLLINE CONCENTRATION AT 6 TO li! MONTH INTERVALS.*
20 to 25 Pgimf 25 to 30 &g/ml Over 30 Fg’m’.
Decrease dose at least 10% .Sklp next dose and decrease subsequent doses at least 25% .Sklp next 2 doses. decrease SulJsequent doses 50%. and RECHECK SERUM THEOPHYLLINE FOR GUIDANCE IN FURTHER DOSE ADJUSTMENT.
7.5 to 10 pg/ml. Below 7.5 pgiml
Increase dose about 25% If tolerated .Increase dose about 25%‘and RECHECK SERUMTHEOPHYLLINE FOR GUIDANCE IN FURTHER DOSE ADJUSTMENT.
FIG. 6. Scheme for establishing optimal oral theophylline dosage in ambulatory patientsz6 This is a conservative application of recommendations incorporated into Food and Drug Administration-approved package inserts. Ideal body weight should be used for obese patients. Dose recommendations are unique for infants under 1 year of age; clinician should review recommendations of Nassif et al.?’ before treating patients in this age group. (Reproduced with permission from Weinberger M, Hendeles L. Slow-release theophylline; Rationale and basis for product selection. N Engl J Med 1983;308:760.)
level where there is risk of exceeding 20 pg/ml. Measurement of serum concentration is then used to guide final dosage (Fig. 6). This dosing scheme has recently been evaluated over a 5-year period among patients followed by The University of Iowa Pediatric Allergy and Pulmonary Service.” Among 404 sequential patients interviewed by clinical phamracists regarding potential adverse effects of the medication regimen, none of 41 patients whose initial serum concentrations were under 10 pg/ml had any complaints in their responses to both open-ended and specific questions regarding theophylline side effects. Eight of 296 children and adults
had complaints when serum concentrations were between 10 and 20 kg/ml; the frequency of complaints increased to 21 out of 69 patients when initial serum concentrations exceeded 20 pg/ml (most were between 20 and 25 pg/ml and none exceeded 30 pg/ml). Moreover, an evaluation of the efficiency of this dosing scheme demonstrated that 78% of 701 patients in whom the titration procedure was used had initial serum concentrations in the 10 to 20 pg/ml therapeu.tic range, and 96% required no more than two measurements of serum concentration before documentation of therapeutic level was attained. Dosage requirements were examined among a total
VOLUME78 NUMBER4,PAHT2
Theophylline
of 745 patients. Average dose requirements were similar to those previously described by us in smaller patient samples.28 Although an average dose of 22 mgikglday was seen in children 1 year to 9 years of age, instead of the 24 mg/kg/day previously reported, this appeared to be a result of somewhat more conservative dosing rather than any substantial difference in the patient samples, since the mean estimated peak serum concentration was about 14 pg/ml for this larger sample as compared with about 16 kg/ml for the previously exa.mined smaller group (although all levels were between 10 and 20 kg/ml in both samples). Again, we confirmed the extensive range of dose requirements for both children and adults that reflects the wide range of elimination rates. Dosage requirements ranged from under 10 to over 22 mgikglday in adults and from about IO to over 34 mgikglday in children. Thus, there was considerable overlap, even though average weight-adjusted doses were almost twice as high for children as for adults. We also examined the stability of theophylline dosage requirements among 503 of our patients, who had been titrated initially to serum concentrations between 10 and 20 kg/ml and had then been subsequently followed at our clinic over periods of from 3 months to more than 2 years. The patients received the same product at the same: dose on the same dosing schedule. When serum concentrations were repeated, 67% were still within the therapeutic range and 9% were somewhat above 20 pg/ml, with only 1% over 25 kg/ml and none over 30 tLg/ml. A downward drift in serum concentrations was apparent among this predominantly pediatric population, who had grown somewhat during the mean 9-month interim. Some of the lower levels, of course, may also have been due to lesser compliance; some of the higher values may have reflected poor compliance at the time of the Hurst level. While there are identifiable clinical variables that alter serum concentration despite regularity of dosage, in general, the degree of stability of dosage requirements appears to be clinically acceptable. Of course, all of these results presume reliably complete absorption and thus cannot apply to those products that are incompletely absorbed under commonly encountered dosing conditions.:‘9-“2 While a dosing scheme could be adjusted to account for products that are consistently absorbed incompletely, it is impossible to do this for products that deliver highly variable amounts of drug. The work described in this article involved studies performed over a ISyear period at two institutions. The work was possible only through the encouragement of Dr. Elliot Ellis, who was chairman of the Pediatric Department at The National
Jewish Hospital
and Research Center. The earlier
in the treatment
of chronic
asthma
767
studies would not have been completed without the active and enthusiastic collaboration of Dr. Edwin Bronsky. Many fellows-in-training at both The National Jewish Hospital and Research Center and The University of Iowa Pediatric Allergy and Pulmonary Division made major contributions during this period of time. Noted for their efforts are Drs. Elliot Ginchansky, Fred Kiechel, James Pollock, Richard Wyatt, Edward Nassif, Michael Green, and Jesse Joad. Current active collaboration with my colleagues Dr. Richard
Ahrens and Dr. Gary Milavetz has permitted continued efforts to relate the pharmacodynamics and pharmacokinetics of theophylline to clinical use.
REFERENCES
1. Schultze-Weminghaus G, Meir-Sydow
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.I. The clinical and pharmacological history of theophylline: first report on the bronchospasmolytic action in man by S.R. Hirsch in Frankfurt (Main:’ 1922. Clin Allergy 1982;12:211. Hendeles L, Weinberger M. Theophylline. A state-of-the-art review. Pharmacotherapy 1983;3:2. Hendeles L, Iafrate RP, Weinbeger M. A clinical and pharmacokinetic basis for the selection and use of slow-release theophylline products. Clin Pharmacokinet 1984;9:95. Weinbssrger M. The pharmacology and therapeutic use of theophylhne. J ALLERGYCLIN IMMUNOL 1984;73:525. Turner-Warwick M. Study of theophylline plasma levels after oral ac!ministration of new theophylline compounds. Br Med J 1957;2:67. Jenne JW, Wyze E, Rood F, McDonald FM. Pharmacokinetics of theophylline: application to adjustment of the clinical dose of amiaophylline. Clin Pharmacol Ther 1972; 13:349. Weinberger M, Bronsky EA. Evaluation of oral bronchodilator therapy in asthmatic children. J Pediatr 1974;84:421. Weinberger M. Bronsky EA. Interaction of ephedrine and theophylline. Clin Pharmacol Ther 1975; 17:585 Hamblceton G, Weinberger M, Taylor J, Godfrey S, et al. Comparison of cromoglycate (cromolyn) and theophylline in controlling symptoms of chronic asthma. Lancet 1977; 1:381. Dusdieker L, Green M, Smith GD, Ekwo EE, Weinberger M. Comparison of orally administered metaproterenol and theophylline in the control of chronic asthma. J Pediatr 1982: 101:281. Joad J, Ahrens R, Weinberger ML. Relative efficacy of maintenance therapy with slow-release theophylline, inhaled aerosolized albuterol, and the combination for chronic asthma. J ALLERGY CLIN IMMUNOL (in press). Ekwo EI, Weinberger M. Evaluation of a program for the pharmacologic management of children with asthma. J ALLERGY CLIN IMMUNOL 1978;61:240. Nassif EG, Weinberger MM, Thompson R, Huntley W. The value ‘of maintenance theophylline for steroid dependent asthma N Engl J Med 1981;304:71. Toogood JH, Jennings B, Lefcoe NM. A clinical trial of combined cromolyn/beclomethasone treatment for chronic asthma. J ALLERGYCLIN IMMUNOL 1981;67:317. Hendel(:s L, Weinberger M. Theophylline. In: Ellis E, ed. Allergy: principles and practice. 2nd ed. St Louis: C V Mosby co, 1983:535-74. Joad J, Ahrens R, Lindgren S, Weinberger M. EXtrdpUhOIK+~ effects of maintenance therapy with theophylline and inhaled albuterol in patients with chronic asthma. J ALLERGY CLIN I~tduN0L (in press). Rapopcrt JL, Elkins R, Neims A, Zahn T, Berg CJ. Behavioral
Weinberger
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20. 21.
22.
23.
24.
25.
J. ALLERGY
and Hentleles
and autonomic effects of caffeine in normal boys. Dev Pharmacol Ther 1981;3:‘74. Richer C, Mathier M, Bah H, Thuillez C, Duroux P, Guidicelli J. Theophylline kinetics and ventilatory flow in bronchial asthma and chronic airflow obstruction: influence of erythromycin. Clin Pharmacol Ther 1982;31:579. Simons FER, Lucink GH, Simons KG. Sustained-release theophylline for treatment of asthma in preschool children. Am J Dis Child 1982; 136:790. Spector SL Advantages and disadvantages of 24.hour theophylline. J ALLERGY CLIN IMMUNDL 1985;76(pt 2):302. Katz RM, Rachelefsky GS, Siegel SC. Low-dose theophylline therapy in asthmatic children. From a publication distributed by Riker Laboratories, Inc, at the American Academy of Family Physicians Meeting, Las Vegas, Nev, Ott 10-14, 1977. Katz RM, Rachelefsky GS, Siegel S. The effectiveness of the short- and long-term use of crystallized theophylline in asthmatic children. .I Pcdiatr 1978;92:663. Rachelefsky GS, K.atz RM, Siegel SC. A sustained release theophylline preparation: efficacy in childhood asthma with low serum theophylline levels. Ann Allergy 1978;40:252. Hendeles L, Weinberger M, Bighley L. Disposition of theophylline following a single intravenous aminophylline infusion. Am Rev Respir Dis 1978;118:97. Milavetz G, Vaughan L, Hendeles L, Weinberger M. Evaluation of a scheme ‘for establishing and maintaining dosage of
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CLIN. IMMUNOL. OCTOBER 1986
theophylline in ambulatory patients with chronic asthma. J Pediatr 1986; 109;351. Hendeles L, Weinberger M, Wyatt R. Guide to oral theophylline therapy for the treatment of chronic asthma. Am J Dis Child 1078;132:876. Nassif EG, Weinberger M, Shannon D, Guiang SF, Jimenez D, Ekwo E. Theophylline disposition in infancy. J Pediatr 1981;98:158. Wyatt R, Weinberger M, Hendeles L. Oral theophylline dosage for the management of chronic asthma. J Pediatr 1978;92: 125. Weinberger M. Theophylline QID, TID, BID, and now QD? A report on 24 hour dosing with slow-release theophylline formulations with emphasis on analysis of data used to obtain Food and Drug Administration approval for Theo-24. Pharmacotherapy 1984;4: 18 1. Hendelcs L, Weinberger M, Milavetz G, Hill M, Vaughan L. Food-induced dose dumping from a “once-a-day” theophylline product as acause of theophylline toxicity. Chest 1985;87:758. Karim 4, Bums T, Wearley L, Streicher J, Palmer M. Foodinduced changes in theophylline absorption from controlledrelease formulations. Part I. Substantial increased and decreased absorption with Uniphyl tablets and Theo-Dur Sprinkle. Cln Pharmacol Ther 1985;38:77. Pedersen S, Moller-Petersen J. Erratic absorption of a slowrelease theophylline sprinkle product caused by food. Pediatrics 1934;74:534.
The Contin delivery system: Dosing considerations Stewart
Leslie, M.P.S. Cambridge,
England
The combination of hydrated cellulose with higher aliphatic alcohol forms the basis of the Contin delivery system, used in the development of tabletforms of sustained-release aminophylline, theophylline, morphine, and other drugs. Extensive clinical and pharmacokinetic evaluation of Vniphyl (anhydrous theophylline) tablets, 400 mg, shows that once-daily morning dosing is at least equivalent to twice-daily administration of theophylline. Ingestion of the once-daily product with a high-calorie-high-fat meal in volunteers increased the absorption of theophylline without accompanying “dose-dumping.’ ’ Extensive pharmacokinetic evaluation in patients with food intake not controlled has yielded bioavailability comparable to that of twice-daily theoph,ylline. Ongoing research suggests that evening administration of Uniphyl tablets may represent a rational dosing schedule for patients with asthma who often exhibit increased bronchoconstriction in the morning. In these studies patients demonstrate improved pulmonary function in the morning compared with use of twice-daily theophylline when once-daily Uniphyl is administered in the evening. Thus, evening administration of once-daily theophylline may block the morning dip in lung function commonly seen. (J .ALLERGYCLIN IMMUNOL 1986;78:
768-73.) Development of a tablet containing aminophylline in a cellulosic polymeric matrix introduced the Contin (Purdue Frederick, Norwalk, Conn.) delivery system From the Napp Research Centre, Cambridge, England. Reprint requests: Mr. Stewart Leslie, Napp Research Centre, Cambridge, England.
768
as a novel controlled-release preparation.’ In essence, drug is lirst blended with a hydrophilic cellulose followed b:y selective hydration with a polar solvent and fixation with a higher aliphatic alcohol to create the final Contin formulation. The desired in vivo release rate can be achieved for a variety of drugs (e.g., aminophylline, theophylline, morphine, potassium) by
City,
Iowa,
M.D., and Leslie Hendeles,
and Gainesville,
Pharm.D.
Fla.
Theophylline has demonstrated a very high degree of clinical clfJicacy as a prophylactic maintenance drug for chronic asthma when dose levels maintain serum concentrations of 10 to ;70 pg,‘ml. Once established, such doses appear to be weli tolerated and free of clinically apparent side effects, although minor neuropsychological and physiologic abnormalities can be detected. In general, while there appears to be little clinical effect from these minor side effects, the possibility of bothersome symptoms in selected patients cannot be excluded and requires further study. The data argue strongly that formulations and dosage intervals should aim for the most stable serum concentrations practically attainable, even though clinicians will certainly make just$able compromises in individual clinical situations. The wide variability in theophylline elimination rate and the relationship between effect and serum concentration dictate that dosage be individualized and that jinal dosag? is best guided by measurement of serum concentration. Slow clinical titration decreases the frequency of caffeine-like side effects ji-om :>50% of patients when therapeutic levels are rapidly attained to only 1% or 2%. Finally, although some physiologic variables and drug interactions may alter theophylline elimination and thus pose clinical risks, it is reassuring that dosage requirements generally remain stable over extended periods. (J ALLERGYCLINIMMIINOL 1986;78:762-8.)
Theophylline has undergone a major transition in clinical use over the past 10 to 15 years. Used primarily for its cardiovascular effects in the early part of this century, theophylline was found in the 1920s to have clinically beneficial effects on acute bronchospasm. ’ In the 193Os, theophylline became popular as an oral agent, particularly in fixed-dose combination with ephedrine. Its predominant use continued in this manner into the early 1970s. Since then, definition of the pharmacodynamics and pharmacokinetics of theophylline has led to its present use as a major prophylactic agent for the prevention of chronic asthma. Several recent comprehensive reviews have discussed many aspects of the pharmacology and therapeutic use of theophylline.“4 The purpose of this article is to address three specific issues: (1) the ef-
From the Pediatric Allergy and Pulmonary Division, The University of Iowa, Iowa City, and University of Florida, Gainesville. Supported in part by grants from the National Institute of Allergy and Infectious Diseases (AI 16151-01) and the General Clinical Research Centers Program, Dvision of Research Resources (RR59), National Institutes of Health, United States Department of Health and Human Services. Reprint requests: Dr. Miles Weinberger, Department of Pediatrics, JCP, The University of Iowa, Iowa City, IA 52242. 762
ficacy of theophylline as prophylactic maintenance therapy for chronic asthma, (2) the relationship of the effect of theophylline to serum concentration, and (3) dosage :requirements of theophylline to obtain optimal safe eff;:ct for maintenance prophylactic therapy. EFFICACY OF THEOPHYLLINE Early studies by Turner-Warwick5 and Jenne et a1.6 suggested that clinical effect of theophylline appeared to be greatest when serum concentrations exceeded 10 p,g/ml. A subsequent double-blind, placebo-controlled :study on 12 children with asthma confirmed that doses reaching serum concentrations over 10 p.g/ml ‘were associated with marked suppression of asthmatic symptoms, whereas doses that reached lower serum concentrations did not result in symptoms that differed significantly from placebo in spite of measurable bronchodilator effect (Fig. 1). A subsequent double-blind, placebo-controlled study on a larger number of patients confirmed this high degree of efficacy,8 as did later studies comparing theophylline with cromo1yn,9 oral metaproterenol,‘(’ and inhaled albuterol. ” Theophylline’s efficacy for maintenance prophylactic therapy is sufficient to control chronic asthma when used as the only maintenance medication among
VOLUME NUMBER
78 4, PART 2
70% of patients referred to the Pediatric Allergy and Pulmonary Service at The University of lowa, a tertiary care referral center.” Even for the 30% of the referred patients who require maintenance corticosteroids because treatment with theophylline and other noncorticoid medication had failed, theophylline continues to have a (clinically important additive effect (Fig. 2). In spite of substantial doses of maintenance corticosteroids, a mean of 550 Fg/day of beclomethasone or 30 mg of oral prednisone on alternate momings, theophylline still significantly reduced the frequency and severity of symptoms. Cromolyn (an alternative to theophylline as maintenance prophylactic therapy for patients with less severe chronic asthma) appears not to have this degree of efficacy.14 Moreover, theophylline also significantly decreased the frequency with which patients had an inadequate clinical response to an inhaled sympathomimetic bronchodilator-the first line of defense for breakthrough symptoms-and therefore required a short course of oral corticosteroids (Table I). The observation that clinical responsiveness to inhaled bronchodilator was preserved and the need for short courses of oral corticosteroids because of progressive symptoms was thereby prevented was also reported in an earlier study.‘” However, theophylline also has a serious toxic potential. As serum concentrations increase above 20 kg/ml, the frequency and severity of adverse effects increase. Nausea, vomiting, headache, cardiac arrhythmias, seizures, and death can occur, and the literature is replete with the consequences of therapeutic misadventures. I5 Despite the toxic potential, adverse effects have not been seen in association with maintenance theophylline therapy when serum concentrations do not exceed 20 pg/ml (Fig. 3j.6-1o.” More careful neuropsychological evaluation, however, suggests various minor effects similar to those seen with caffeine.16. ”
RELATIONSHIP OF EFFECT TO SERUM CONCENTRATION Greater benefit can be obtained without an increase in adverse effects when doses are adjusted to maintain serum concentrations between 10 and 20 kg/ml. Moreover, the bronchodilatory effect from theophylline parallels changes in serum concentration (Fig. 4). A relationship between serum theophylline concentration and decrease in nonspecific airway reactivity can similarly be demonstrated by measuring the blocking of exercise-induced bronchospasm (Fig. 5). These and other data argue strongly for maintainenance of serum concentration at the most stable level possible (between 10 and 20 pgiml) to obtain maximal
TheoF;hylline
in the treatment
of chronic
60
asthma
763
I
Px05
t
; P< 05 u
Symptoms
m Isoproterenol :
q
Nebs
Eplnephrlne Inj. Substitute Meds
Placebo
Peak Serum Theophylline Averaging 6.5pg/ml
Peak Serum Theophylline Averaging 13pg/ml
FIG. 1. Frequency and severity of asthmatic symptoms among I:2 children with chronic asthma at residential treatment center. Each patient received, in double-blind randomized sequence, a l-week treatment with placebo, an ephedrine-theophylline combination in conventional doses that resulted in serum theophylline concentrations averaging 6.5 kg/ml, and individualized theophylline doses thar resulted in serum concentrations averaging 13 pg/ml. Asthma symptoms during each l-week period were promptly treated, when necessary, with inhaled isoproterenol; if symptoms were not rapidly relieved, epinephrine was administered subcutaneously. If patient was unrespons,ive to these measures, known drugs were substituted for double-blind medications.’ (Reproduced with permission from Weinberger M. Theophylline for treatment of asithma. J Pediatr 1978;92:1.)
safe beneft. However, asthma is a sufficiently variable disease that apparently adequate benefit may be obtained for some patients at lower serum concentrations. In Fig. 5 one patient had apparent blocking of exercise-induced bronchospasm at 0 kg/ml and, for many patients with asthma, a serum concentration of 0 kg/ml is fully adequate most of the time. Nonetheless, most evidence supports maintaining serum concentration:j within the range of 10 to 20 pg/ml when optimal likelihood of maximal safe effect is clinically indicated. Arguments have been made by some investigators” for routine use of lower serum concentrations. Most often the studies cited have been of questionable clinical relevance (i.e., examination of limited pulmonary function data only, or judgments based on detectable clinical effect at lower serum concentrations without examination for further clinical effect at h:!gher serum concentrations). 2’-23
DOSAGE REQUIREMENTS TO OBTAIN OPTIMAL. SAFE EFFECT A wide range of theophylline elimination rates is present at all ages with a continuum of elimination half-lives ranging from less than 3 hours to a maximum of 16 hours in normal, healthy subjects. Al-
764
Weinberger
and Hendeles
J ALLERGY
Beclomethasone
Dipropionate
Alternate
n = 21 Mean Days
Day n=
CLIN. IMMUNOL. OCTOBER 1986
Prednisone 10
Percent of Symptomatic
40 0
Transient
Symptoms
30
20
10
0
Nocturnal
Actlwiy
Cough
Wheeze
Nocturnal
Actwty
Cough
Wheeze
FIG. 2. Mean frequency of asthmatic symptoms with placebo (P) or theophylline (T) from daily diaries among children with chronic steroid-dependent astl-rma. The presence of nocturnal symptoms was recorded each morning, and interference witkl activity, cough, and wheezing were recorded each evening on a scale of 0 through 3 definlsd as absent, transient, repeated, or continuous symptoms, respectively. The graph at left refers to 21 patients receiving a mean dose of 550 pg/day of inhaled beclomethasone dipropioilate, and the graph at right refers to 10 patients receiving a mean dose of 30 mg of prednisone on alternate mornings. (Reproduced with permission from Nassif EG, Weinberger, MM, Thompson R, Huntley W. The value of maintenance theophylline for steroid dependent asthma. N Engl J Med 1981;304:71.)
2%
percent of Observation Periods
0
Insomnia
m
CNS Symptoms
m
GI Symptoms
‘5
10
Ephedrine Placebo
Hydmxyrine
Ephedrine
Thwphylline
Theop+hylline
Eph
Theophylline Hydr&yzine
FIG. 3. Frequency of symptoms compatible with adverse medication effects among 23 children with chronic asthma treated in a randomized, double-blirld, crossover study with theophylline, ephedrine, and hydroxyzine separately and in combination. Theophylline doses were individualized to attain peak levels between 10 pg/ml and 20 pgiml; the mean peak concentration was 16 pgiml. The frequency of these symptoms did not differ significantly between the theophylline and placebo regimens; adverse effects of medications were apparent only from the combination of ephedrine and theophylline. (Reproduced with permission from Weinberger M, Bronsky EA. Interaction of ephedrine and theophylline. Clin Pharmaccll Ther 1975;17:585.)
though the mean elimination half-life (under 4 hours) found in children is about half the mean half-life (8 hours) found in nonsmoking adults, there is considerable overlap. Moreover, there are no distinguishing clinical characteristics that enable the elimination half-
life, and thus the dosage requirement, to be identified. Doses, therefore, need to be individualized and guided by serum concentration if optimal likelihood of benefit without toxicity is to be obtained. Observations of a high frequency of caffeinelike
VOLUME NUMBER
78 4. PART 2
Theophylline
Serum Theophyllme Concentration (mcg/ml] .-.
100
in the treatment
12
14
sOi’
16
l
.
8l
.
V25
5
-20
5 a
-60
(Percent PredIctedI o---o
1
‘.
l
.
.
8
.
.
i I
a
.
.
(mcg/ml) -
.
-8Ot
l 9
5
10
15
20
Serum Theophylline
’
3 Time
(6hours)
’
drop tn vso
l .
.
6 8 10 Time (hrs)
765
. l
4
asthma
/.-JMean
s%PEFR (L/mm1 o____c
50
2
of chronic
25
@g/ml)
FIG. 5. Flelationship between maximal postexercise change in V, (flow rate at 50% of a forced vital capacity) and corresponding serum theophylline measurement. Superimposed, bar graph represents mean postexercise changes in V, for serum theophylline intervals indicated. Dotted line at 30% identifies response to exercise conventionally accepted as clinically important. (Reproduced with permission from Pollock J, Kiechel F, Cooper D, Weinberger M. Relationship of serum theophylline concentration to inhibition of exercise-induced bronchospasm and comparison with cromolyn. Pediatrics 1977; 60:840.)
l2
FIG. 4. A, Relationship between serum theophylline concentration and pulmonary function among 31 adult asthmatic subjects given 7.5 mgikg of a rapidly absorbed theophylline formulation.‘* B, Relationship between serum theophylline concentration and pulmonary function among 11 children treated with 100 mg Theo-Dur tablets (Key Pharmaceuticals) every 12 hours. Patients frequently became symptomatic: during last three hours of dosing interval.19
TABLE I. Frequency of requirements for additional daily prednisone due to exacerbations of asthma inadequately responsive to inhaled bronchodilators among 21 patients who required maintenance therapy with inhaled beclomethasone dipropionate (mean dose 550 pg/day) and 10 who required alternate-day prednisone (mean dose, 30 mg every other morning) during a randomized, placebo-controlled, month-long crossover study of iheophylline -
Event
Daily prednisonr: added Study period
Theophylline
Beclomethasone dipropionate
only Alternateday prednisone
Placebo Beclomethasone dipropionate
only
-
Alternateday prednisone
Both periods Beclomethasone dipropionate
Alternateday prednisone
P value*
1
0
6
2
1
1
0.02
1
0
5
1
0
0
0.06
termiantedt Reproduced with permission of The New England Journal of Medicine.‘4 *Analyses are for the therapeutic effect of theophylline among patients receiving both steroid regimens. ?A study period was terminated if more than 5 days of added prednisone were required during a regimen or when the investigator-clinician judged that contuation would be associated with excessive risk or discomfort to the patient. All decisions were made on a double-blind basis.
complaints when therapeutic serum concentrations are rapidly attained further influence dosing strategy. Since a slow clinical titration process appears to decrease the frequency of complaints of adverse effects
from more than 50%24 to a low of 1% to 2%,” we recommend beginning with low doses and subsequently increasing in increments of 25% to 50% (as long as increase is tolerated), until doses approach the
766
Weinberger
J. ALLERGY CLIN. IMMUNOL. OCTOBER 1986
and Hendeles
I
Adults and chlldren
INITIAL DOSE over 1 year old The lesger of 400 mg/day
or 16 mg/kg/day
I
after j days 4 FIRST INCREMENTAL INCREASE Adults and children t 45 kg 600mg/cay Children < 45 kg The lesser of 600 rrg/day 20 mg, kg/day 16 mg, kg’day
or-.
for ag,?s , to 9 for ag’?s >9
I
after 3 davs
SECOND INCREMENTAL INCREASE Adults and children 2 45 kg. 800mg Children < 45 kg The lesser of 800 mg/day 24 mglkg,day 20 mg:kgiday 18 mg kg/day
or
lor ages 1 lo 9 for ages 9 lo 12 for ages 12 10 16
I
Check Serum concentration about 4 hours affe, a dose when none have been mIssed or added for 3 days + DIRECTlIONS
SERUM CONCENTRATION lOto20~g/ml.
MaIntam dose tf tolerated. RECHECK SERUM THEOPHYLLINE CONCENTRATION AT 6 TO li! MONTH INTERVALS.*
20 to 25 Pgimf 25 to 30 &g/ml Over 30 Fg’m’.
Decrease dose at least 10% .Sklp next dose and decrease subsequent doses at least 25% .Sklp next 2 doses. decrease SulJsequent doses 50%. and RECHECK SERUM THEOPHYLLINE FOR GUIDANCE IN FURTHER DOSE ADJUSTMENT.
7.5 to 10 pg/ml. Below 7.5 pgiml
Increase dose about 25% If tolerated .Increase dose about 25%‘and RECHECK SERUMTHEOPHYLLINE FOR GUIDANCE IN FURTHER DOSE ADJUSTMENT.
FIG. 6. Scheme for establishing optimal oral theophylline dosage in ambulatory patientsz6 This is a conservative application of recommendations incorporated into Food and Drug Administration-approved package inserts. Ideal body weight should be used for obese patients. Dose recommendations are unique for infants under 1 year of age; clinician should review recommendations of Nassif et al.?’ before treating patients in this age group. (Reproduced with permission from Weinberger M, Hendeles L. Slow-release theophylline; Rationale and basis for product selection. N Engl J Med 1983;308:760.)
level where there is risk of exceeding 20 pg/ml. Measurement of serum concentration is then used to guide final dosage (Fig. 6). This dosing scheme has recently been evaluated over a 5-year period among patients followed by The University of Iowa Pediatric Allergy and Pulmonary Service.” Among 404 sequential patients interviewed by clinical phamracists regarding potential adverse effects of the medication regimen, none of 41 patients whose initial serum concentrations were under 10 pg/ml had any complaints in their responses to both open-ended and specific questions regarding theophylline side effects. Eight of 296 children and adults
had complaints when serum concentrations were between 10 and 20 kg/ml; the frequency of complaints increased to 21 out of 69 patients when initial serum concentrations exceeded 20 pg/ml (most were between 20 and 25 pg/ml and none exceeded 30 pg/ml). Moreover, an evaluation of the efficiency of this dosing scheme demonstrated that 78% of 701 patients in whom the titration procedure was used had initial serum concentrations in the 10 to 20 pg/ml therapeu.tic range, and 96% required no more than two measurements of serum concentration before documentation of therapeutic level was attained. Dosage requirements were examined among a total
VOLUME78 NUMBER4,PAHT2
Theophylline
of 745 patients. Average dose requirements were similar to those previously described by us in smaller patient samples.28 Although an average dose of 22 mgikglday was seen in children 1 year to 9 years of age, instead of the 24 mg/kg/day previously reported, this appeared to be a result of somewhat more conservative dosing rather than any substantial difference in the patient samples, since the mean estimated peak serum concentration was about 14 pg/ml for this larger sample as compared with about 16 kg/ml for the previously exa.mined smaller group (although all levels were between 10 and 20 kg/ml in both samples). Again, we confirmed the extensive range of dose requirements for both children and adults that reflects the wide range of elimination rates. Dosage requirements ranged from under 10 to over 22 mgikglday in adults and from about IO to over 34 mgikglday in children. Thus, there was considerable overlap, even though average weight-adjusted doses were almost twice as high for children as for adults. We also examined the stability of theophylline dosage requirements among 503 of our patients, who had been titrated initially to serum concentrations between 10 and 20 kg/ml and had then been subsequently followed at our clinic over periods of from 3 months to more than 2 years. The patients received the same product at the same: dose on the same dosing schedule. When serum concentrations were repeated, 67% were still within the therapeutic range and 9% were somewhat above 20 pg/ml, with only 1% over 25 kg/ml and none over 30 tLg/ml. A downward drift in serum concentrations was apparent among this predominantly pediatric population, who had grown somewhat during the mean 9-month interim. Some of the lower levels, of course, may also have been due to lesser compliance; some of the higher values may have reflected poor compliance at the time of the Hurst level. While there are identifiable clinical variables that alter serum concentration despite regularity of dosage, in general, the degree of stability of dosage requirements appears to be clinically acceptable. Of course, all of these results presume reliably complete absorption and thus cannot apply to those products that are incompletely absorbed under commonly encountered dosing conditions.:‘9-“2 While a dosing scheme could be adjusted to account for products that are consistently absorbed incompletely, it is impossible to do this for products that deliver highly variable amounts of drug. The work described in this article involved studies performed over a ISyear period at two institutions. The work was possible only through the encouragement of Dr. Elliot Ellis, who was chairman of the Pediatric Department at The National
Jewish Hospital
and Research Center. The earlier
in the treatment
of chronic
asthma
767
studies would not have been completed without the active and enthusiastic collaboration of Dr. Edwin Bronsky. Many fellows-in-training at both The National Jewish Hospital and Research Center and The University of Iowa Pediatric Allergy and Pulmonary Division made major contributions during this period of time. Noted for their efforts are Drs. Elliot Ginchansky, Fred Kiechel, James Pollock, Richard Wyatt, Edward Nassif, Michael Green, and Jesse Joad. Current active collaboration with my colleagues Dr. Richard
Ahrens and Dr. Gary Milavetz has permitted continued efforts to relate the pharmacodynamics and pharmacokinetics of theophylline to clinical use.
REFERENCES
1. Schultze-Weminghaus G, Meir-Sydow
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.I. The clinical and pharmacological history of theophylline: first report on the bronchospasmolytic action in man by S.R. Hirsch in Frankfurt (Main:’ 1922. Clin Allergy 1982;12:211. Hendeles L, Weinberger M. Theophylline. A state-of-the-art review. Pharmacotherapy 1983;3:2. Hendeles L, Iafrate RP, Weinbeger M. A clinical and pharmacokinetic basis for the selection and use of slow-release theophylline products. Clin Pharmacokinet 1984;9:95. Weinbssrger M. The pharmacology and therapeutic use of theophylhne. J ALLERGYCLIN IMMUNOL 1984;73:525. Turner-Warwick M. Study of theophylline plasma levels after oral ac!ministration of new theophylline compounds. Br Med J 1957;2:67. Jenne JW, Wyze E, Rood F, McDonald FM. Pharmacokinetics of theophylline: application to adjustment of the clinical dose of amiaophylline. Clin Pharmacol Ther 1972; 13:349. Weinberger M, Bronsky EA. Evaluation of oral bronchodilator therapy in asthmatic children. J Pediatr 1974;84:421. Weinberger M. Bronsky EA. Interaction of ephedrine and theophylline. Clin Pharmacol Ther 1975; 17:585 Hamblceton G, Weinberger M, Taylor J, Godfrey S, et al. Comparison of cromoglycate (cromolyn) and theophylline in controlling symptoms of chronic asthma. Lancet 1977; 1:381. Dusdieker L, Green M, Smith GD, Ekwo EE, Weinberger M. Comparison of orally administered metaproterenol and theophylline in the control of chronic asthma. J Pediatr 1982: 101:281. Joad J, Ahrens R, Weinberger ML. Relative efficacy of maintenance therapy with slow-release theophylline, inhaled aerosolized albuterol, and the combination for chronic asthma. J ALLERGY CLIN IMMUNOL (in press). Ekwo EI, Weinberger M. Evaluation of a program for the pharmacologic management of children with asthma. J ALLERGY CLIN IMMUNOL 1978;61:240. Nassif EG, Weinberger MM, Thompson R, Huntley W. The value ‘of maintenance theophylline for steroid dependent asthma N Engl J Med 1981;304:71. Toogood JH, Jennings B, Lefcoe NM. A clinical trial of combined cromolyn/beclomethasone treatment for chronic asthma. J ALLERGYCLIN IMMUNOL 1981;67:317. Hendel(:s L, Weinberger M. Theophylline. In: Ellis E, ed. Allergy: principles and practice. 2nd ed. St Louis: C V Mosby co, 1983:535-74. Joad J, Ahrens R, Lindgren S, Weinberger M. EXtrdpUhOIK+~ effects of maintenance therapy with theophylline and inhaled albuterol in patients with chronic asthma. J ALLERGY CLIN I~tduN0L (in press). Rapopcrt JL, Elkins R, Neims A, Zahn T, Berg CJ. Behavioral
Weinberger
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and Hentleles
and autonomic effects of caffeine in normal boys. Dev Pharmacol Ther 1981;3:‘74. Richer C, Mathier M, Bah H, Thuillez C, Duroux P, Guidicelli J. Theophylline kinetics and ventilatory flow in bronchial asthma and chronic airflow obstruction: influence of erythromycin. Clin Pharmacol Ther 1982;31:579. Simons FER, Lucink GH, Simons KG. Sustained-release theophylline for treatment of asthma in preschool children. Am J Dis Child 1982; 136:790. Spector SL Advantages and disadvantages of 24.hour theophylline. J ALLERGY CLIN IMMUNDL 1985;76(pt 2):302. Katz RM, Rachelefsky GS, Siegel SC. Low-dose theophylline therapy in asthmatic children. From a publication distributed by Riker Laboratories, Inc, at the American Academy of Family Physicians Meeting, Las Vegas, Nev, Ott 10-14, 1977. Katz RM, Rachelefsky GS, Siegel S. The effectiveness of the short- and long-term use of crystallized theophylline in asthmatic children. .I Pcdiatr 1978;92:663. Rachelefsky GS, K.atz RM, Siegel SC. A sustained release theophylline preparation: efficacy in childhood asthma with low serum theophylline levels. Ann Allergy 1978;40:252. Hendeles L, Weinberger M, Bighley L. Disposition of theophylline following a single intravenous aminophylline infusion. Am Rev Respir Dis 1978;118:97. Milavetz G, Vaughan L, Hendeles L, Weinberger M. Evaluation of a scheme ‘for establishing and maintaining dosage of
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theophylline in ambulatory patients with chronic asthma. J Pediatr 1986; 109;351. Hendeles L, Weinberger M, Wyatt R. Guide to oral theophylline therapy for the treatment of chronic asthma. Am J Dis Child 1078;132:876. Nassif EG, Weinberger M, Shannon D, Guiang SF, Jimenez D, Ekwo E. Theophylline disposition in infancy. J Pediatr 1981;98:158. Wyatt R, Weinberger M, Hendeles L. Oral theophylline dosage for the management of chronic asthma. J Pediatr 1978;92: 125. Weinberger M. Theophylline QID, TID, BID, and now QD? A report on 24 hour dosing with slow-release theophylline formulations with emphasis on analysis of data used to obtain Food and Drug Administration approval for Theo-24. Pharmacotherapy 1984;4: 18 1. Hendelcs L, Weinberger M, Milavetz G, Hill M, Vaughan L. Food-induced dose dumping from a “once-a-day” theophylline product as acause of theophylline toxicity. Chest 1985;87:758. Karim 4, Bums T, Wearley L, Streicher J, Palmer M. Foodinduced changes in theophylline absorption from controlledrelease formulations. Part I. Substantial increased and decreased absorption with Uniphyl tablets and Theo-Dur Sprinkle. Cln Pharmacol Ther 1985;38:77. Pedersen S, Moller-Petersen J. Erratic absorption of a slowrelease theophylline sprinkle product caused by food. Pediatrics 1934;74:534.
The Contin delivery system: Dosing considerations Stewart
Leslie, M.P.S. Cambridge,
England
The combination of hydrated cellulose with higher aliphatic alcohol forms the basis of the Contin delivery system, used in the development of tabletforms of sustained-release aminophylline, theophylline, morphine, and other drugs. Extensive clinical and pharmacokinetic evaluation of Vniphyl (anhydrous theophylline) tablets, 400 mg, shows that once-daily morning dosing is at least equivalent to twice-daily administration of theophylline. Ingestion of the once-daily product with a high-calorie-high-fat meal in volunteers increased the absorption of theophylline without accompanying “dose-dumping.’ ’ Extensive pharmacokinetic evaluation in patients with food intake not controlled has yielded bioavailability comparable to that of twice-daily theoph,ylline. Ongoing research suggests that evening administration of Uniphyl tablets may represent a rational dosing schedule for patients with asthma who often exhibit increased bronchoconstriction in the morning. In these studies patients demonstrate improved pulmonary function in the morning compared with use of twice-daily theophylline when once-daily Uniphyl is administered in the evening. Thus, evening administration of once-daily theophylline may block the morning dip in lung function commonly seen. (J .ALLERGYCLIN IMMUNOL 1986;78:
768-73.) Development of a tablet containing aminophylline in a cellulosic polymeric matrix introduced the Contin (Purdue Frederick, Norwalk, Conn.) delivery system From the Napp Research Centre, Cambridge, England. Reprint requests: Mr. Stewart Leslie, Napp Research Centre, Cambridge, England.
768
as a novel controlled-release preparation.’ In essence, drug is lirst blended with a hydrophilic cellulose followed b:y selective hydration with a polar solvent and fixation with a higher aliphatic alcohol to create the final Contin formulation. The desired in vivo release rate can be achieved for a variety of drugs (e.g., aminophylline, theophylline, morphine, potassium) by