Inconsistent absorption from a susstained-release theophylline preparation during continuous therapy in asthmatic children

Inconsistent absorption from a sustained-release theophylline preparation during continuous therapy in asthmatic children During routine monitoring o f hospitalized children with asthma receiving a sustained-release theophylline formulation, we frequently observe unpredictable fluctuations in serum theophylline concentration (STC). We evaluated eight asthmatic patients (ages 4 to 17 years) with inconsistent STCs to determine the cause o f this phenomenon. Only minimal variation i'n S T C and thereJore theophylline clearance was noted during a 24-hour period o f continuous intravenous aminophylline infusion. However, marked variability in S T C was observed when measured every 2 hours for 48 hours after 6 days o f continuous therapy orally. In addition, the time required to teach peak and trough STCs variedJ?om dose to dose. Inasmuch as clearance was shown to be constant, the variability was attributed to inconsistent theophylline absorption. Unpredictable fluctuations o f S T C secondary to variable absorption fi'om this sustained-release theophylline preparation may occur in certain patients. Appreciation of this potential variability is necessary for the proper interpretation o f S T C measurements and subsequent dosage adjustment. (J PEDIATR 106:4961 1985)

Robert J. Rogers, M.D., Albert Kalisker, Ph.D., Matthew B. Wiener, Pharm.D., and Stanley J. Szefler, M.D. Denver, Colorado

BECAUSE THEOPHYLLINE is rapidly absorbed from both liquid and plain tablet formulations, ~ clinicians often experience difficulty maintaining serum theophylline concentration within the narrow therapeutic range when these rapidly absorbed products are prescribed, especially in patients in whom theophylline has a short elimination half-life. Sustained-release theophylline preparations have been formulated in an attempt to minimize this problem. The goals for design of an effective SRT formulation

From the Department oJ" Pediatrics, National Jewish Hospital and Research Center/National Asthma Center, and the Departments o f Pediatrics and Pharmacology, University o f Colorado Health Sciences Center. Supported in part by Grant HL-30513 from the National Heart, Lung, and Blood Institute. Submitted for publication June 7, 1984; accepted Aug. 17, 1984. Reprint requests." Stanley J. Szefler, M.D., Department o f Pediatrics, National Jewish Hospital and Research Center, 3800 E. Colfax Ave., Denver, CO 80206.

496

The Journal o f P E D I A T R I C S

include complete absorption within the dosing interval, predictable dose-to-d0se release of theophylline from the preparation, resulting in minimal fluctuations of STC, and a frequency of dosing that would facilitate compliance with the prescribed dosage regimens. Among the multiple SRT preparations presently available, Theo-Dur (Key Pharmaceuticals, Miami, Fla.) is one of the most widely prescribed. It exhibits 100% bioavaila-

SRT STC

Sustained-release theophylline Serum theophylline concentration

bility, t-6 and evaluation of mean patient data suggests that there is a consistent pattern of absorption and elimination. 4,s,7 WeinlJerger et al., 5 using data derived from single-dose administration of Theo-Dur to adult volunteers as a basis for computer simulation of multiple-dose therapy, predicted that fluctuations of STC in patients taking Theo-Dur 200 mg or 300 mg tablets every 12 hours would

Volume 106 Number 3

be minimal, even in patients in whom theophylline half-life was 3.7 hours. Our experience with asthmatic children and adolescents receiving Theo-Dur suggested greater variability in STC than was expected. This study was designed to determine whether the variability in STC was secondary to inconsistent theophylline absorption or elimination or a combination of both.

METHODS Eight pediatric patients (ages 4 to 17 years; five boys) in our hospital were selected for study. All were noted prior to inclusion in the study to have unpredictable variations in random STCs measured during the hospitalization while receiving Theo-Dur on a regular basis. All patients were nonsmokers, none was receiving any medication known to alter theophylline pharmacokinetics, and none had had a clinically apparent viral infection within 1 month of the study period. All were free of cardiac, hepatic, and gastrointestinal abnormality. Concurrent medications included alternate-day prednisone (four patients), cromolyn (seven), inhaled steroids (three), brompheniramine maleate (one), nystatin (one), tetracycline (one), Mylanta (one), and inhaled metaproterenol (six), albuterol (two), and atropine (fiye). The study protocol was approved by the Institutional Review Board; informed consent was obtained from the patients and their parents or guardians. Study medications. Aminophylline Injection USP (Searle Pharmaceuticals, Chicago; lot number 3942) was used during the intravenous phase of the study. This preparation contains 25 mg/ml aminophylline, Which is equivalent to 1917 mg/ml anhydrous theophylline. All doses of aminophylline for intravenous administration are expressed as the theophylline equivalent for comparison with the orally administered preparation studied. TheoDur (Key) 200 mg (lot number 320331) and 300 mg (lot number 31331) tablets were used throughout the oral study. The tablets were given in the combination of whole or half tablets necessary to provide the appropriate dose. We did not use 100 mg tablets because they have different absorption characteristics, as demonstrated in a singledose study. ~ Intravenous study protocol. The intravenous phas e of the study was conducted over 4 days. At 6:00 AM on day 1, administration of the SRT preparation was discontinued and an immediate-release theophylline tablet was substituted at an equivalent total daily dose until midmorning on day 2. At that time an intravenous Catheter was l~laced, a blood sample obtained for measurement of STC, and the Catheter connected to an intravenous infusion pump. A

Theophylline absorption

497

constant infusion of aminophylline was started as follows: the total daily aminophylline dose (estimated from previous dosage requirements to produce STC in the range of 10 to 15 ~g/ml) was divided evenly into 24 hourly doses; each hourly dose was placed in a graduated cylinder (part of the intravenous infusion apparatus) along with sufficient intravenous solution (5% dextrose 0.25NS) to infuse 20 ml (for smaller children) or 30 ml (for largeI children) fluid each hour. The aminophylline was mixed well with the intravenous fluid prior to each hourly infusion. In this manner, complete administration of the drug was verified every hour. A second blood sample for measurement of STC was obtained by venipuncture on the afternoon of day 2. The second sample was compared with the preinfusion sample obtained earlier in the day to assure that the aminophylline dose provided STC between 10 and 15 #g/ml. A single change in dose was made if necessary. No further dosage adjustment was made during the remainder of the intravenous study. At 6:00 AMOn day 3, an intravenous catheter was placed in the contralateral hand from the infusion site for ease of blood sampling. Patency of the catheter was maintained with heparin. Blood samples were Obtained from the sampling catheter every 2 hours from 6:00 AM on day 3 to 6:00 AM on day 4 for determination of STC during the continuous aminophylline infusion. The aminophylline infusion was discontinued at 6:00 AM o n d a y 4, and blood samples were obtained at 0, 1/2, 1,2, 3, 4, 6, 8, 10, and 12 hours for STC measurement in order to calculate elimination pharmacokinetics. Oral study protocol. Immediately on completion of the intravenous study, the patients were administered TheoDur orally every 12 hours (at 6:00 AM and 6:00 PM). The dose was selected to produce a mean STC of 10 to 15 #g/ml, based on previous intravenous and oral dosage requirements. After a minimum of 6 days of Theo-Dur therapy with no change in dose, an intravenous catheter was placed as described above. Blood samples for STC assay were obtained every 2 hours for 48 hours, beginning at 6:00 AM and ending at 6:00 AM 2 days later. Theo-Dur administration continued during the sampling period. The study was completed when the final blood sample was drawn. The total amount of blood drawn during the entire study period was
498

Rogers et al.

The Journal o f Pediatrics March 1985

25

20

100

Patient 8

3 E 20

0=,,-s

!00 ~

,- 15 0

g.o

a~,~ 1 0

E 10

e-

o

100 o.

o o e-

Eg

g,

o

5

|

0

0

0

6AM

I

I

I

12N

6PM

12MN

0 6AM

6PM

I

6AM

6PM

6AM

Time

6AM

Time

Fig. l, Summary (mean _+ SEM) of STCs measured every 2 hours during 24-hour continuous aminopbylline infusion in eight patients.

25

300

Patient 1

3 o

E 20 "

t-

~i~ii!~i~!!iiiiii~i~iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii!iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii~iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii!!iiiii!iiiii!iiii~ii~i~i 200

,-

15

o

o .m

ambulatory but relatively quiet during the intravenous phase because of the physical restrictions of intravenous infusion. Activity was unrestricted during the oral study, with the exception of swimming, which was not permitted in order to protect the indwelling intravenous catheter. Assay procedure. The assay of STC was performed by high-performance liquid chromatography using a modification of the method of Franconi et al, 8 Serum samples (100/zl) were miXed witfi an equal volume of acetonitrile to precipitate proteins. The acetonitrile contained fl-hydroxyethyl theophylline (135 #g/ml) as an internal standard. Injections of the deproteinized, diluted serum samples were repeated every 7 minutes with a Waters Associates (Millford, Mass.) WISP automatic sample injector into a Waters RadialPak uBondapak C~8 reverse-phase cartridge placed in a Z-module compression chamber connected to a model 6000A pump. The separation procedure was performed with a mobile phase consisting of 0.0l M sodium acetate buffer, pH 4.0, containing 10% acetonitrile at a flow rate of 4 ml/min, Detection of eluting peaks was achieved at 280 nm with a model 440 UV detector. The detector output was processed on a Waters Data Module integrating recorder. The STC was calculated by the method of ratios of areas under the theophylline and internal standard peaks. The ratios of areas under the peaks follow a linear relationship from 2 to 200/~g/ml; the average coefficient of variation in this range of concentrations is less than 5%. All serum samples were assigned a code number so that the technician performing the assay was unaware of the order of sample collection. All samples from one study phase were assayed together, with high and

10

loo

o ro

@"

8~ Qo

o 6AM

6PM

6AM

6PM

6AM

Time

Fig. 2. STC (o) and calculated amount of theophytline absorbed in each 2 hours (bar graphs) in each patient during continuous treatment with TheorDur. All doses were administered at 6:00 AM and 6:00 PM. Shaded area, Recognized therapeutic range for theophyiline. A, Diurnal pattern. B, Highly variable STC profile.

low reference standards assayed before and after each run.

PHARMACOKINETIC

ANALYSIS

Intravenous study. The area under the serum concentration-time curve (AUC) during the 24-hour infusion was calculated by the trapezoidal rule. The clearance was derived by the equation Clearance = Dose/AUC, where dose is milligrams of theophylline infused in 24 hours. The STCs Obtained after discontinuation of the aminophylline infusion were applied to log-linear regression analysis to derive the elimination rate constant (Ke0. The serum theophylline half-life was determined from the equation t89 = 0.693/Ko~: The Volume of distribution (Vd) was calculated by dividing the clearance by Ko The clearance and volume of distribution were normalized for body

Volume 106 Number 3

Theophylline absorption

weight. Because patient 7 was markedly obese, lean body weight was used to normalize the clearance and volume of distribution data in this patient. Oral study. The serum concentration-time curve for each 12-hour dosing interval was analyzed to determine the highest (peak) and lowest (trough) STC of each interval and the time required to reach peak and trough STCs after the dose. The highest and lowest STCs of the entire 48-hour period were also noted; the difference between the highest and lowest STC during the 48 hours is expressed as ASTC. Because the patients did not have the same range of STCs during the oral study, 2xSTC for each patient was also expressed as %2xSTC, in a manner similar to that of other studies4,s,9: %LxSTC =

ASTC X 100 Lowest STC

Bioavailability of Theo-Dur was determined by comparing the AUC of the 24-hour intravenous study with the AUC of each 24-hour period of oral study: Bioavailability= AUCo~ • - -Dose~ • 100 AUC~v Doseora~ The amount of theophylline absorbed (A) during each 2-hour period of the oral study was calculated using the modified Wagner-Nelson equation for multiple-dose drug administration~~ A = Vd(Cn2 + Ko~f2Cndt - Cnl) 1

where Cnl and Cn2 are the first and second STCs, respectively. As suggested by Wagner, the linear trapezoidal rule was used to calculate f~ Cndt when Cnl was less than Cn2; the logtrapezoidal rule was used when Cnl was more than Cn2. The accuracy of the absorption data was verified by comparing the total amount of theophylline absorbed during the 48 hours as calculated by the modified Wagner-Nelson equation with the amount of theophylline absorbed during the 48 hours as calculated using the bioavailability data. A theoretical "ideal" absorption amount for a 2-hour period was calculated as the amount of theophylline that would be absorbed every 2 hours if the dose were absorbed consistently and completely throughout the 12-hour dosing interval. For example, if a 600 mg dose were absorbed in the "ideal" manner, 100 mg would be absorbed every 2 hours for 12 hours. The ideal absorption (Abs) amount was compared with the actual amount absorbed in each 2-hour period and expressed as a percentage of the ideal: % ldeal Abs -

Actual Abs - Ideal Abs • 100 Ideal Abs

499

In this manner, comparisons between the variability of absorption in different patients could be made regardless of interpatient differences in dosage r e quirements. RESULTS Intravenous study. The STC remained essentially constant during the 24-hour period of continuous intravenous aminophylline infusion in each patient (Fig. 1). The %ASTC was 22.6% +_ 7.5% SD and randomly distributed with no diurnal pattern. Because aminophylline was delivered at a constant rate and there was minimal variation in STC, the elimination of theophylline was considered to be consistent throughout the 24-hour study. The pharmacokinetic parameters calculated from the intravenous study are presented in Table I. Oral study. During the 48-hour study period of oral administration of Theo-Dur, patients 5 through 8 (Fig. 2, A) were noted to have a diurnal pattern of fluctuation in STC, with higher values after the morning dose compared with those after the evening dose; these patients absorbed more theophylline during the day than at night. Patients 1 through 4, however, did not have this diurnal pattern. Data from patient 1 (Fig. 2 B) are presented as an example of the marked inconsistency in STC observed in some patients. A summary of the data obtained from this study is included in TabIe I. The time required to reach peak and trough STCs after each dose varied widely, both between patients and from dose to dose in individual patients (Table II). The total amount of theophylline absorbed during the 48-hour oral study, calculated by the modified Wagner-Nelson method, was essentially the same as that predicted by the oral bioavailability equation (no greater than 5.8% difference between the two methods in any patient). Although the average bioavailability was 95%, there was considerable dose-to-dose variability in percentage of the dose absorbed during a dosing interval. We observed unpredictable fluctuations in STC in these pediatric patients during continuous therapy with TheoDur. If we assume consistent elimination of theophylline during the oral study (based on the results of the intravenous infusion study), the fluctuation in STC was considered secondary to variable absorption of theophylline from the SRT formulation. The variation of absorption was significant in each patient, ranging from 32% to 208% of the theoretical ideal amount absorbed in the patient with least variation (patient 3) to 9% to 287% in the patient with the greatest v~.riation (patient 5). The pattern of variation in absorption was unpredictalSIe from dose to dose within individual patients.

500

Rogers et al.

The Journal of Pediatrics March 1985

Table I. Summary of patient data

Patient

Dose (mg/kg/day)

Clearance (ml/hr/kg)

tile (hr)

l 2 3 4 5 6 7 8

26.3 33.3 30.8 20.4 23.1 24.2 21,8 21.1

96.1 101.0 95.4 80.6 83.8 79.0 59.7 59.4

2.2 2.7 2.7 3.5 3.9 4.0 6.0 6.2

Bioavailability (%)

V~ (ml/kg) I Day 1 !

306 390 371 403 476 451 524 530

89 122 102 101 110 101 77 104

Day 2

ASTC (tzg/ml)

%AS TC *

Ideal Abs~ (mg/2 hr)

94 78 99 89 91 99 80 79

9.4 13.5 11.3 6.4 10.7 11.2 6.9 1l.l

157 171 149 97 157 126 82 135

83.3 58.3 100.0 91.8 100.0 66.7 66.7 100.0

Actual Abs (rag~2 hr) 14 to 21 to 32 to 0.7 to 9 to 25 to 0 to 0 to

165 123 208 174 287 186 153 192

Ideal Absr (%) 17 to 36 to 32 to 0.7 to 9 to 38 to 0 to 0 to

198 212 208 190 287 274 230 192

Peak STC - Trough STC • 100. Trough STC tldeal Abs, Amount of theophyllinc absorbed in each 2-hour period if dose were absorbed consistently over 12 hours. Actual Abs ~:% Ideal Abs = -• 100. Ideal Abs *%ASTC

Table II. Frequency of peak and trough S T C at each sampling time Time after dose (hr)

Peak (n)

Trough (n)

0 2 4 6 8 l0 12

6 7 6 3 5 2 3

5 3 4 5 3 6 6

DISCUSSION The advantages of an S R T formulation that could provide predictable and reliable absorption are obvious, especially for those patients in whom theophylline has a short half-life. Many asthmatic patients, usually children, would require doses of theophylline every 2 to 4 hours to maintain a therapeutic S T C if rapidly absorbed theophylline preparations were used. Patients have difficulty complying with medications requiring administration every 6 hours; a 12-hour dosing schedule improves compliance. TM ~2 The ideal S R T formulation should provide predictable delivery of theophylline with minimal fluctuation of S T C when administered no more frequently than twice daily. Other investigators have noted a similar degree of fluctuation in S T C in patients receiving Theo-Dur on a continuous basis. Dasta et al. 4 and Menendez et al. 9 noted %ASTC of 65% _+ 46% and 65% _+ 30%, respectively, when S T C was measured at 2-hour intervals over 12 hours. Our data, when analyzed in 12-hour segments, reveal %ASTC of 67% _+ 38%. Weinberger et al. s noted a larger

%ASTC of 87% _+ 49% when S T C was measured every hour for 12 hours. Evaluation of data presented by Kelly and Murphy 7 reveals a smaller %ASTC of 38% _+ 23% in their patients when S T C was measured every 3 hours for 12 hours, increasing to 59% _+ 34% when measured over 24 hours. We noted %ASTC of 95 _+ 41% when the data were analyzed in 24-hour segments, and %ASTC of 134% + 31% when data from the entire 48-hour study were evaluated. Therefore, it appears that the %ASTC observed is correlated to both the frequency of sampling and the duration of observation. Because of the nature of our institution, all patients involved in this study were referred because their asthma was difficult to control. However, in these patients asthma was clinically stable throughout the study period. During the periods of measurement of STC, no patients required medications in addition to regularly scheduled medications, even when their S T C was <10 # g / m l . Therefore, although many studies have reported that theophylline is most effective when S T C is >10 u g / m l , it may not be clinically significant if the S T C occasionally falls below that limit. If the fluctuation of S T C observed was not of obvious clinical significance in the control of wheezing in this study population, of what importance are our findings? O f greatest significance is the implication for accurate interpretation of therapeutic drug monitoring results. Based on previous dat a produced by analyzing the average pattern of fluctuations in S T C after a dose of Theo-Dur, it has been suggested that Theo-Dur will produce the peak S T C of the dosing interval 4 to 6 hours after the dose? 3'~4 An S T C measured 4 to 6 hours after the dose in an individual patient is interpreted to be the highest of the dosing

Volume 106 Number 3

interval, and dosage adjustments are made with the assumption that all other STCs would be less than the one measured. However, because absorption of theophylline from this S R T product may be unpredictably inconsistent in the individual patient, it would appear inappropriate to assume that a single S T C represented a "peak" or "trough" concentration, regardless of the time the sample was obtained during the dosing interval. The time required to reach peak S T C after a dose ranged from 0 to 12 hours. Of the 32 dosing intervals tested (four intervals in eight patients), the sample obtained 4 hours after the dose was the peak S T C in only six of 32 intervals. Thus, if it were assumed that S T C measured 4 hours after a dose was the highest of the dosing interval, there would be less than a 1:5 chance that the assumption was correct. The S T C measured at 6 and 8 hours after the dose was even less predictive of the actual peak STC. Other investigators have noted wide variability in the time required to reach peak S T C in patients taking Theo-Dur. 9' ~5.~6Although the 4-hour postdose S T C obtained after the morning dose may approximate the peak STC, an isolated S T C measurement must be interpreted with care. It must be compared with previous determinations, and the patient's clinical status closely evaluated, including an attempt at judging compliance, before a change in dose is considered. W e were unable to identify specific factors that influence the absorption of theophylline. Four of eight patients had evidence of diurnal variation of absorption, with less absorption at night, but the reason for this is unclear. Absorption essentially stopped in the middle of the dosing interval in some patients, and then started again without an additional dose. No consistent influence of food on absorption was noted. There was no significant difference in fluctuation of S T C between patients taking systemi c corticosteroids and those who were not. In conclusion, considerable variability in S T C secondary to inconsistent absorption of theophylline from Theo-Dur, a commonly prescribed sustained-release theophylline preparation, was observed in our patients. The unpredictable nature of absorption within and between patients has important implications in the proper interpretation of a single S T C measurement and subsequent dosage adjustment. It is important to investigate the factors that may influence absorption of theophylline from S R T formulations, such as intestinal motility, intestinal transit time, digestive enzymes, maturity of the gastrointestinal tract, absorption capacity of various segments of the intestinal tract, diet, other medications, and physical activity, to design drug delivery systems that are minimally affected by these factors.

Theophylline absorption

50 1

We thank the nurses of the Pediatric Special Care Unit and the technicians in the Clinical Laboratories for their meticulous attention to detail; Ms. Judy Franconi and Ms. Julia Gunnerson for secretarial assistance; and Duane Bloedow, Ph.D., Danny Shen, Ph.D., and Martin Lefkowitz, M.S., for their thoughtful advice. REFERENCES

1. Weinberger M, Hendeles L, Bighley L: The relation of product formulation to absorption of oral theophylline. N Engl J Med 299:852, 1978. 2. Bell T, Bigley J: Sustained-release theophylline therapy for chronic childhood asthma. Pediatrics 62:352, 1978. 3. Spangler DL, Kalof DD, Bloom FL, Wittig H J: Theophylline bioavailability following oral administration of six sustainedrelease preparations. Ann Allergy 40:6, 1978. 4. Dasta J, Mirtallo JM, Altman M: Comparison of standard and sustained-release theophylline tablets in patients with chronic obstructive pulmonary disease. Am J Hosp Pharm 36"613, 1979. 5. Weinberger M, Hendeles L, Wong L, Vaughan L: Relationship of formulation and dosing interval to fluctuation of serum theophylline concentration in children with chronic asthma. J PEDIATR99:145, 1981. 6. Williams RL, Upton RA, Bostrom A: Relative bioavailability of two sustained-release theophylline formulations versus an immediate-release preparation. J Asthma 20:27, 1983. 7. Kelly HW, Murphy S: Efficacy of a 12-hour sustained-release preparation in maintaining therapeutic serum theophylline levels in asthmatic children. Pediatrics 66:97, 1980. 8. Franconi LC, Hawk GL, Sandmann BJ, Haney WG: Determination of theophylline in plasma ultrafiltrate by reversed phase high pressure liquid chromatography. Anal Chem 48:372, 1976. 9. Mcnendez R, Kelly HW, Howick J, MeWilliams BC: Sustained-release theophylline: Pharmacokinetic and therapeutic comparison of two preparations. Am J Dis Child 137:469, 1983. 10. Wagner JG: Modified Wagner-Nelson absorption equations for multiple dose regimens. J Pharm Sci 72:578, 1983. 1t. Eney RD, Goldstein EO: Compliance of chronic asthmatics with oral administration of theophylline as measured by serum and salivary levels. Pediatrics 57:513, 1976. 12. Tinkelman DG, Vanderpool GE, Carroll MS, Page EG, Spangler DL: Compliance differences following administration of theophyltine at six- and twelve-hour intervals. Ann Allergy 44:283, 1980. 13. Weinberger M, Hendeles L: Slow-release theophylline: Rationale and basis for product selection. N Engl J Med 308:760, 1983. 14. Hendeles L, Weinberger M, Wyatt R: Guide to oral theophylline therapy for the treatment of chronic asthma. Am J Dis Child 132:876, 1978, 15. Domson JF, Hein EW, Sheen A, Sly RM: Comparison of Theolair SR and Theo-Dur tablets. Ann Allergy 43"220, 1979. 16. Dederich RAiSzefler S J, Green ER: lntrasubject variation in sustained-release theophyltine absorption. J Allergy Clin Immunol 67:465, t98I.