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A Multiple-Dose Study of Sustained-Release Theophylline and Aminophylline
A Multiple-Dose Study of Sustained-Release Theophylline and Aminophylline· Marvin C. Meyer, Ph.D.;Arthur B. Straughn, Pharm.D.; and Philip Lieberman, M.D.
This study evaluated the relative bioavailabDity of a suslaIned-release capsule of theophylline, an elixir of theophylline, and a sustained-release tablet of aminophylline. Twelve healthy, nonsmoking, adult male subjects received nine doses of each of the three products in a crossover study conducted over a ten-day period. Each dosage form contained approximately 250 mg of theophylline and was administered every eight hours. Concentrations of theophylline in the plasma at steady state demonstrated the equivalence of the three dosage forms in terms of the percent of drug absorbed, including the tablet which had
A recent study! evaluated the relative bioavailabil-
ity of six sustained-release products containing theophylline or aminophylline, compared to several other dosage forms. The study concluded that three For editorial comment, see page 250
of the six sustained-release products were erratically and less completely absorbed, with one product containing aminophylline exhibiting a relative bioavailability of only 65 percent compared to a reference solution; however, this latter result was obtained using only five subjects, the study was not a crossover design, and only single doses of each product were administered. Thus, the study did not satisfy the requirement of the Food and Drug Administration that the bioavailability of sustained-release products must be evaluated using a multiple-dose steady-state protocol," It was therefore of interest to more thoroughly evaluate, via such a protocol, the relative bioavailability of the sustained-release tablet of aminophylline exhibiting the lowest bioavailability in the previous study. The present study also used an elixir of theophylline as a reference dosage form and evaluated a sustained-release capsule of theophylline, all marketed by the same company. The objectives of the study also include an evaluation of the study's design, which attempted to minimize the dose administered and the duration of the study. ·From the Department of Pharmaceutics, College of Pharmacy, and the Deparbnent of Medicine, College of Medicine, University of Tennessee Center for the Health Sciences,
Memphis. Manuscript received May 14; revision accepted September 4
300 MEYER, STRAUGHN, LIEBERMAN
exhibited reduced bioavailabllity in an earlier single-dose study of only five subjects. The steady-state average concentrations of theophylline in the plasma were 9.8 pgImI, 10.3 pglml and 10.8 p.g/mi for the tablet, capsule, and elixir, respectively. The areas under the curves of the plasma level vs time for the three dosage forms were with· in 9 percent of each other. These data indicate that a significant reduction in ftuctuations of the plasma level of theophylline was achieved with the two sustained-release dosage forms, compared to the elixir.
MATERIALS AND METHODS
Design of the Study Twelve healthy male subjects ranging in age from 21 to 32 years and ranging in weight from 68 to 93 kg (150 to 205 lb ) participated. All subjects were nonsmokers.vs All provided written informed consent and underwent an automated analysis of urinary, hematologic, and blood chemistry (SMA 18/ 90) prior to participation. A "Notice of Claimed Investigational Exemption for a New Drug" (IND) was also submitted,s and the study was approved by the institutional committee on human research. Subjects were randomly assigned to one of six groups. Each group received each of the three tested dosage forms in the sequence given in Table 1. The doses were administered with 4 oz of water at 7 AM, 3 PM, and 11 PM each day, for a
total of nine doses of each product. Morning and afternoon Table I-Experimental De,ign
Sequence of Administration *
Group Subjects
_-----A.------_ Day 1-3
Day 4-6
Day 7-9
1
1; 2
Product 1
Product 2
Product 3
2
3;4
Product 1
Product 3
Product 2
3
5;6
Product 2
Product 1
Product 3
4
7;8
Product 2
Product 3
Product 1
5
9; 10
Product 3
Product 1
Product 2
6
11; 12
Product 3
Product 2
Product 1
"Product 1 was tablets containing 300 mg of aminophylline (equivalent to 236 mg of anhydrous theophylline) (Aminodur Dura-Tabs; Cooper Laboratories lot R-80118); product 2 was capsules containing 250 mg of anhydrous theophylline (Elixophyllin S.R. Capsules; Cooper Laboratories lot W80317); and product 3 was elixir (47 ml, containing 250.7 mg of anhydrous theophylline) (Elixophyllin Elixir; Cooper Laboratories lot W-80541).
CHEST, 78: 2, AUGUST, 1980
REsuLTS Plasma Concentrations
doses were ingested at the site of the study, and each subject was contacted by telephone for the 11 PM dose, in order to ensure adherence to the protocol. Subjects were provided with a standard light breakfast at 9 AM, lunch at noon, sUpper at 6 PM, and a light snack at 9' PM. No other food was permitted, and the subjects refrained from ingestion of alcohol or xanthine-containing beverages during the study. Several subjects experienced headaches and were given doses of acetaminophen. No other drugs were permitted. Ten milliliter samples of blood were obtained just before and at one, two, three, four, six, and eight hours after the seventh dose of each of the three dosage forms. No breakfast was provided on the days when these samples were obtained. Samples of blood were also taken eight hours after the ninth dose of each product. This latter sample, as well as the zerotime and eight-hour samples for the seventh dose, represent steady-state minimum determinations. All samples of blood were immediately centrifuged, and the plasma was removed and frozen until the time of analysis. All samples were assayed using an enzymatic immunoassay procedure (Syva EMIT) sensitive and specific for theophylline.s The coefficient of variation was less than 10 percent for ten standard curves prepared during the analysis of the samples.
The mean concentrations of theophylline in the plasma at each sampling time are summarized in Table 2 and illustrated in Figure 1. Statistically signiBcant (P<0.05) differences were observed at 1, 2, 3,6, and 24 hours. The Newman-Keuls a posteriori analysis indicated that at one and two hours after administration, the elixir (product 3 ) exhibited higher plasma levels of theophylline than either of the two sustained-release products. Also, the mean level of theophylline in the plasma was lower for the elixir at the 24-hour sampling time. Out of the 108 steady-state minimum concentrations of theophylline determined during the course of this study, only four were less than 5p.gl mI, with three of these seen in one subject.
Maximum Concentration and Areaunder Curve
Analysis of Data
The mean peak concentration in the plasma was significantly higher (P<0.05) for the elixir than for the tablet and capsule. The highest plasma concentration observed in any subject during the study was 19.8,ug/ml for a two-hour sample in one subject receiving the elixir. Also, the time of the maximum concentration in the plasma was significantly shorter for the elixir than for the capsule but did not differ significantly from the time of the maximum concentration for the tablet. The mean difference between maximum and minimum concentrations of theophylline in the plasma at steady state was 3.4p.g/ml ±
Concentrations of theophylline in the plasma at each time were compared using an analysis of variance. In addition, the maximum level in the plasma, the time of this maximum level, the area under the curve of plasma level vs time, and this area normalized for the subject's weight were subjected to the same analysis. The areas under the curve were calculated using the trapezoidal rule. In instances where significant differences were noted, the data were further examined using a Newman- KeuIs a posteriori test. 8 All plasma levels of theophylline for the tablet, product 1, were adjusted by a factor of 1.059 in the statistical analysis to correct for the slightly lower content of theophylline in this dosage form.
Table 2-Mean Steady-SIGle 'Palue.lor Theophylline·
Measurement Plasma level of theophylline, I£g/ml o hr 1 hr 2 hr 3 hr 4hr 6 hr 8 hr 24 hr Maximum Time of maximum plasma theophylline level, hr Area under curve, I£g-hr/mlt Normalized area under curve, I£g-hr/ml-kgtt
Product 1**
9.2± 10.2± 10.5 ± 9.9± 9.9± 9.3± 9.4± 10.1 ± 11.1 ±
2.3 3.1 2.7 3.0 3.1 2.9 3.6 2.5 3.0
Product 2
Product 3
P Value#
8.8± 9.8± 10.2± 10.8± 10.5± 10.6± 9.6± 9.6 ± 11.7 ±
7.9± 13.0± 13.1 ± 11.9 ± 10.9± 9.5± 9.0± 8.3± 14.2±
2.4 2.5 2.7 2.1 3.1 2.2 2.9 2.7 3.0
0.056 0.010 <0.001 0.018 0.166 0.027 0.621 <0.001 <0.001
3.0 3.7 3.5 3.5 2.8 3.6 3.4 3.1 3.3
2.9± 1.9
3.5± 1.4
1.7 ± 1.0
0.026
78.2±23.1
82.0±26.0
86.2±17.8
0.101
1.0± 0.3
1.1 ± 0.3
1.1 ± 0.3
0.091
*Mean ± 1 SD. **Allievels of drug have been adjusted by factor of X 1.059 to correct for lower theophylline content of product I. [Curve of plasma level vs time. tNormalized for subject's weight. IP value indicates the level of significance for observed differences among the three products.
CHEST, 78: 2, AUGUST, 1980
SUSTAINED-RELEASE THEOPHRLINE AND AMINOPHYLLINE 301
14
12
-
•
10
....
~ 01
! ... ~
-0
8
raJ
Z
~
6
2
~
i
4
3 At
4
6
8
12 TIME(hours)
24
16
FiGURE 1. Mean concentrations of theophylline in plasma .of 12 subjects after seventh, eighth, and ninth doses of three different preparations given every eight hours; seventh dose was given at zero time (7 AM), eighth dose was given at eight hours (3 PM) and ninth dose was given at 16 hours (11 PM). Concentrations of theophylline were not determined between 8 and 24 hours. Open circles indicate tablet (product 1), solid circles indicate capsule (product 2), and squtJtes indicate elixir (product 3) .
1.31Ag/ml (+50), 2.7p.g/ml + 1.7p.g/ml, and 6.8 p.g/ml + 2.5pg/ ml for the capsule, the tablet, and the elixir, respectively. The mean areas under the curves of plasma level vs time, corrected for the smaller dose of theophylline in the tablet, were not significantly different (P>0.05), nor were these areas when normalized for the body weight of each subject. Subiect« and Sequence of Treatments
The statistical analysis indicated no significant differences (P>0.05) among the sequences of treatment. As may be anticipated because of the intersubject variability in clearance of theophylline," there were highly significant diHerences (P
An evaluation of the power of the design of the study" to permit the determination of statistically significant diHerences (a = 0.05; P = 0.2) indicated that, with the exception of the one-hour plasma level, a diHerence in means of 18 percent or more would have been statistically significant. Thus, 12 subjects were sufficientfor the design of the study. A comparison of the mean plasma levels at the zero, eight-hour, and 24-hour sampling times indicated no significant (P>O.05) diHerence among these values, suggesting that the steady state had been achieved with the first six doses during each 302 MEYER, STRAUGHN, LIEBERMAN
initial 48-hour period of treatment. Another measure of the appropriateness of the design of the study was the fact that all 12 subjects were able to tolerate the regimen. During the period of the study, the following side effects were reported: 13 instances of headache; five instances of insomnia; one report of cramps in the leg; and ten reports of nausea or anorexia. In addition, one subject vomited six hours after receiving his sixth dose of product 2 during the last sequence of administration. During this sequence the highest concentration observed in this subject was 7.1pg/ml. In addition, the occurrence of the side effects appeared to be randomly distributed among the subjects and among each of the three dosage forms. DISCUSSION
The results of this study indicate that the percentage of drug absorbed from the two sustainedrelease dosage forms was equivalent to the reference elixir at steady state. Over the eight-hour dosing interval, the areas under the curve were 91 percent and 95 percent for the tablet and the capsule, respectively, relative to the elixir. The average steadystate concentration in the plasma, calculated by dividing the area under the curve by the eight-hour dosing interval, 9 was 9.8p.g/ ml, "10.3p.g/ ml, and 10.8p.g/mlfor the tablet, the capsule, and the elixir, respectively. These data also demonstrated, as would be anticipated for well-formulated sustainedrelease dosage forms, that the maximum plasma levels for the sustained-release products were lower CHEST, 78: 2, AUGUST, 1980
and the minimum plasma levels were higher, compared to the more rapidly absorbed elixir. Sustainedrelease dosage forms are, of course, designed to minimize fluctuations between maximum and minimum plasma levels of the drug. Furthermore, the time of the maximum concentration of theophylline in the plasma was delayed with the sustained-release products. These data are particularly significant in view of the earlier single-dose study! using five subjects, which suggested incomplete bioavailability of the sustained-release tablet. It would appear that the protocol employed in this study is suitable for the assessment of the bioavailability of dosage forms of theophylline under steady-state conditions and that higher doses or longer sequences of treatment are not required. The 48-hour period of treatment should have been adequate to achieve 95 percent of steady state, even in subjects with half-lives of theophylline as long as 11 hours. The plasma concentrations of theophylline obtained at steady state demonstrated the equivalence of the percentage of drug absorbed from the tablets, capsules, and elixir, with the sustained-release preparations providing decreased fluctuation between peak and trough; however, it should be emphasized that regardless of the dosage form em-
CHEST, 78: 2, AUGUST, 1980
ployed clinically, individualization of the regimen will stilI be required. ACKNOWLEDGMENT: We thank Mrs. Vicki Proefrocle. Mrs. Cathie Grady, and Miss Laura Lucius for their technical assistance in the conduction of the clinical studies.
REFmmNCES 1 Weinberger M, Hendeles L, Bighley L. The relation of product formulation to absorption of oral theophylline. N Engl J Med 1978; 299:852-7. 2 Federal register. Bioavailability and bioequivalence requirements. 1977 (Jan 7); 42 (No.5, pt 3) :1651-2. 3 Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Coo Pharmacal Ther 1976; 19: 546-51~
4 Jenne J, Nagasawa H, McHugh R, et ale Decreased theophylline half-life in cigarette smokers. Life Sci 1975; 17: 195-8. 5 Koup JR, Brodsky B. Comparison of homogeneous enzyme immunoassay and high-pressure liquid chromatography for the determination of theophylline concentration in serum. Am Rev Respir Dis 1978; 117:1135-8. 6 Winer BJ. Statistical principles in experimental design. 2nd ed. New York: McGraw-Hill Book Co, 1962:261. 7 Ogilvie RI. Clinical pharmacokinetics of theophylline. Clin Pharmacokin 1978; 3:267-93. 8 Bowman KO. Tables of the sample size requirement. Biometrika 1972; 59:234. 9 Wagner JG. Fundamentals of clinical pharmacokinetics. 1st 00. Hamilton, Ill: Drug Intelligence Publications, Inc, 1975:134.
SUSTAINED-RELEASE THEOPHnUNE AND AMINOPHRUNE 303
This study evaluated the relative bioavailabDity of a suslaIned-release capsule of theophylline, an elixir of theophylline, and a sustained-release tablet of aminophylline. Twelve healthy, nonsmoking, adult male subjects received nine doses of each of the three products in a crossover study conducted over a ten-day period. Each dosage form contained approximately 250 mg of theophylline and was administered every eight hours. Concentrations of theophylline in the plasma at steady state demonstrated the equivalence of the three dosage forms in terms of the percent of drug absorbed, including the tablet which had
A recent study! evaluated the relative bioavailabil-
ity of six sustained-release products containing theophylline or aminophylline, compared to several other dosage forms. The study concluded that three For editorial comment, see page 250
of the six sustained-release products were erratically and less completely absorbed, with one product containing aminophylline exhibiting a relative bioavailability of only 65 percent compared to a reference solution; however, this latter result was obtained using only five subjects, the study was not a crossover design, and only single doses of each product were administered. Thus, the study did not satisfy the requirement of the Food and Drug Administration that the bioavailability of sustained-release products must be evaluated using a multiple-dose steady-state protocol," It was therefore of interest to more thoroughly evaluate, via such a protocol, the relative bioavailability of the sustained-release tablet of aminophylline exhibiting the lowest bioavailability in the previous study. The present study also used an elixir of theophylline as a reference dosage form and evaluated a sustained-release capsule of theophylline, all marketed by the same company. The objectives of the study also include an evaluation of the study's design, which attempted to minimize the dose administered and the duration of the study. ·From the Department of Pharmaceutics, College of Pharmacy, and the Deparbnent of Medicine, College of Medicine, University of Tennessee Center for the Health Sciences,
Memphis. Manuscript received May 14; revision accepted September 4
300 MEYER, STRAUGHN, LIEBERMAN
exhibited reduced bioavailabllity in an earlier single-dose study of only five subjects. The steady-state average concentrations of theophylline in the plasma were 9.8 pgImI, 10.3 pglml and 10.8 p.g/mi for the tablet, capsule, and elixir, respectively. The areas under the curves of the plasma level vs time for the three dosage forms were with· in 9 percent of each other. These data indicate that a significant reduction in ftuctuations of the plasma level of theophylline was achieved with the two sustained-release dosage forms, compared to the elixir.
MATERIALS AND METHODS
Design of the Study Twelve healthy male subjects ranging in age from 21 to 32 years and ranging in weight from 68 to 93 kg (150 to 205 lb ) participated. All subjects were nonsmokers.vs All provided written informed consent and underwent an automated analysis of urinary, hematologic, and blood chemistry (SMA 18/ 90) prior to participation. A "Notice of Claimed Investigational Exemption for a New Drug" (IND) was also submitted,s and the study was approved by the institutional committee on human research. Subjects were randomly assigned to one of six groups. Each group received each of the three tested dosage forms in the sequence given in Table 1. The doses were administered with 4 oz of water at 7 AM, 3 PM, and 11 PM each day, for a
total of nine doses of each product. Morning and afternoon Table I-Experimental De,ign
Sequence of Administration *
Group Subjects
_-----A.------_ Day 1-3
Day 4-6
Day 7-9
1
1; 2
Product 1
Product 2
Product 3
2
3;4
Product 1
Product 3
Product 2
3
5;6
Product 2
Product 1
Product 3
4
7;8
Product 2
Product 3
Product 1
5
9; 10
Product 3
Product 1
Product 2
6
11; 12
Product 3
Product 2
Product 1
"Product 1 was tablets containing 300 mg of aminophylline (equivalent to 236 mg of anhydrous theophylline) (Aminodur Dura-Tabs; Cooper Laboratories lot R-80118); product 2 was capsules containing 250 mg of anhydrous theophylline (Elixophyllin S.R. Capsules; Cooper Laboratories lot W80317); and product 3 was elixir (47 ml, containing 250.7 mg of anhydrous theophylline) (Elixophyllin Elixir; Cooper Laboratories lot W-80541).
CHEST, 78: 2, AUGUST, 1980
REsuLTS Plasma Concentrations
doses were ingested at the site of the study, and each subject was contacted by telephone for the 11 PM dose, in order to ensure adherence to the protocol. Subjects were provided with a standard light breakfast at 9 AM, lunch at noon, sUpper at 6 PM, and a light snack at 9' PM. No other food was permitted, and the subjects refrained from ingestion of alcohol or xanthine-containing beverages during the study. Several subjects experienced headaches and were given doses of acetaminophen. No other drugs were permitted. Ten milliliter samples of blood were obtained just before and at one, two, three, four, six, and eight hours after the seventh dose of each of the three dosage forms. No breakfast was provided on the days when these samples were obtained. Samples of blood were also taken eight hours after the ninth dose of each product. This latter sample, as well as the zerotime and eight-hour samples for the seventh dose, represent steady-state minimum determinations. All samples of blood were immediately centrifuged, and the plasma was removed and frozen until the time of analysis. All samples were assayed using an enzymatic immunoassay procedure (Syva EMIT) sensitive and specific for theophylline.s The coefficient of variation was less than 10 percent for ten standard curves prepared during the analysis of the samples.
The mean concentrations of theophylline in the plasma at each sampling time are summarized in Table 2 and illustrated in Figure 1. Statistically signiBcant (P<0.05) differences were observed at 1, 2, 3,6, and 24 hours. The Newman-Keuls a posteriori analysis indicated that at one and two hours after administration, the elixir (product 3 ) exhibited higher plasma levels of theophylline than either of the two sustained-release products. Also, the mean level of theophylline in the plasma was lower for the elixir at the 24-hour sampling time. Out of the 108 steady-state minimum concentrations of theophylline determined during the course of this study, only four were less than 5p.gl mI, with three of these seen in one subject.
Maximum Concentration and Areaunder Curve
Analysis of Data
The mean peak concentration in the plasma was significantly higher (P<0.05) for the elixir than for the tablet and capsule. The highest plasma concentration observed in any subject during the study was 19.8,ug/ml for a two-hour sample in one subject receiving the elixir. Also, the time of the maximum concentration in the plasma was significantly shorter for the elixir than for the capsule but did not differ significantly from the time of the maximum concentration for the tablet. The mean difference between maximum and minimum concentrations of theophylline in the plasma at steady state was 3.4p.g/ml ±
Concentrations of theophylline in the plasma at each time were compared using an analysis of variance. In addition, the maximum level in the plasma, the time of this maximum level, the area under the curve of plasma level vs time, and this area normalized for the subject's weight were subjected to the same analysis. The areas under the curve were calculated using the trapezoidal rule. In instances where significant differences were noted, the data were further examined using a Newman- KeuIs a posteriori test. 8 All plasma levels of theophylline for the tablet, product 1, were adjusted by a factor of 1.059 in the statistical analysis to correct for the slightly lower content of theophylline in this dosage form.
Table 2-Mean Steady-SIGle 'Palue.lor Theophylline·
Measurement Plasma level of theophylline, I£g/ml o hr 1 hr 2 hr 3 hr 4hr 6 hr 8 hr 24 hr Maximum Time of maximum plasma theophylline level, hr Area under curve, I£g-hr/mlt Normalized area under curve, I£g-hr/ml-kgtt
Product 1**
9.2± 10.2± 10.5 ± 9.9± 9.9± 9.3± 9.4± 10.1 ± 11.1 ±
2.3 3.1 2.7 3.0 3.1 2.9 3.6 2.5 3.0
Product 2
Product 3
P Value#
8.8± 9.8± 10.2± 10.8± 10.5± 10.6± 9.6± 9.6 ± 11.7 ±
7.9± 13.0± 13.1 ± 11.9 ± 10.9± 9.5± 9.0± 8.3± 14.2±
2.4 2.5 2.7 2.1 3.1 2.2 2.9 2.7 3.0
0.056 0.010 <0.001 0.018 0.166 0.027 0.621 <0.001 <0.001
3.0 3.7 3.5 3.5 2.8 3.6 3.4 3.1 3.3
2.9± 1.9
3.5± 1.4
1.7 ± 1.0
0.026
78.2±23.1
82.0±26.0
86.2±17.8
0.101
1.0± 0.3
1.1 ± 0.3
1.1 ± 0.3
0.091
*Mean ± 1 SD. **Allievels of drug have been adjusted by factor of X 1.059 to correct for lower theophylline content of product I. [Curve of plasma level vs time. tNormalized for subject's weight. IP value indicates the level of significance for observed differences among the three products.
CHEST, 78: 2, AUGUST, 1980
SUSTAINED-RELEASE THEOPHRLINE AND AMINOPHYLLINE 301
14
12
-
•
10
....
~ 01
! ... ~
-0
8
raJ
Z
~
6
2
~
i
4
3 At
4
6
8
12 TIME(hours)
24
16
FiGURE 1. Mean concentrations of theophylline in plasma .of 12 subjects after seventh, eighth, and ninth doses of three different preparations given every eight hours; seventh dose was given at zero time (7 AM), eighth dose was given at eight hours (3 PM) and ninth dose was given at 16 hours (11 PM). Concentrations of theophylline were not determined between 8 and 24 hours. Open circles indicate tablet (product 1), solid circles indicate capsule (product 2), and squtJtes indicate elixir (product 3) .
1.31Ag/ml (+50), 2.7p.g/ml + 1.7p.g/ml, and 6.8 p.g/ml + 2.5pg/ ml for the capsule, the tablet, and the elixir, respectively. The mean areas under the curves of plasma level vs time, corrected for the smaller dose of theophylline in the tablet, were not significantly different (P>0.05), nor were these areas when normalized for the body weight of each subject. Subiect« and Sequence of Treatments
The statistical analysis indicated no significant differences (P>0.05) among the sequences of treatment. As may be anticipated because of the intersubject variability in clearance of theophylline," there were highly significant diHerences (P
An evaluation of the power of the design of the study" to permit the determination of statistically significant diHerences (a = 0.05; P = 0.2) indicated that, with the exception of the one-hour plasma level, a diHerence in means of 18 percent or more would have been statistically significant. Thus, 12 subjects were sufficientfor the design of the study. A comparison of the mean plasma levels at the zero, eight-hour, and 24-hour sampling times indicated no significant (P>O.05) diHerence among these values, suggesting that the steady state had been achieved with the first six doses during each 302 MEYER, STRAUGHN, LIEBERMAN
initial 48-hour period of treatment. Another measure of the appropriateness of the design of the study was the fact that all 12 subjects were able to tolerate the regimen. During the period of the study, the following side effects were reported: 13 instances of headache; five instances of insomnia; one report of cramps in the leg; and ten reports of nausea or anorexia. In addition, one subject vomited six hours after receiving his sixth dose of product 2 during the last sequence of administration. During this sequence the highest concentration observed in this subject was 7.1pg/ml. In addition, the occurrence of the side effects appeared to be randomly distributed among the subjects and among each of the three dosage forms. DISCUSSION
The results of this study indicate that the percentage of drug absorbed from the two sustainedrelease dosage forms was equivalent to the reference elixir at steady state. Over the eight-hour dosing interval, the areas under the curve were 91 percent and 95 percent for the tablet and the capsule, respectively, relative to the elixir. The average steadystate concentration in the plasma, calculated by dividing the area under the curve by the eight-hour dosing interval, 9 was 9.8p.g/ ml, "10.3p.g/ ml, and 10.8p.g/mlfor the tablet, the capsule, and the elixir, respectively. These data also demonstrated, as would be anticipated for well-formulated sustainedrelease dosage forms, that the maximum plasma levels for the sustained-release products were lower CHEST, 78: 2, AUGUST, 1980
and the minimum plasma levels were higher, compared to the more rapidly absorbed elixir. Sustainedrelease dosage forms are, of course, designed to minimize fluctuations between maximum and minimum plasma levels of the drug. Furthermore, the time of the maximum concentration of theophylline in the plasma was delayed with the sustained-release products. These data are particularly significant in view of the earlier single-dose study! using five subjects, which suggested incomplete bioavailability of the sustained-release tablet. It would appear that the protocol employed in this study is suitable for the assessment of the bioavailability of dosage forms of theophylline under steady-state conditions and that higher doses or longer sequences of treatment are not required. The 48-hour period of treatment should have been adequate to achieve 95 percent of steady state, even in subjects with half-lives of theophylline as long as 11 hours. The plasma concentrations of theophylline obtained at steady state demonstrated the equivalence of the percentage of drug absorbed from the tablets, capsules, and elixir, with the sustained-release preparations providing decreased fluctuation between peak and trough; however, it should be emphasized that regardless of the dosage form em-
CHEST, 78: 2, AUGUST, 1980
ployed clinically, individualization of the regimen will stilI be required. ACKNOWLEDGMENT: We thank Mrs. Vicki Proefrocle. Mrs. Cathie Grady, and Miss Laura Lucius for their technical assistance in the conduction of the clinical studies.
REFmmNCES 1 Weinberger M, Hendeles L, Bighley L. The relation of product formulation to absorption of oral theophylline. N Engl J Med 1978; 299:852-7. 2 Federal register. Bioavailability and bioequivalence requirements. 1977 (Jan 7); 42 (No.5, pt 3) :1651-2. 3 Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Coo Pharmacal Ther 1976; 19: 546-51~
4 Jenne J, Nagasawa H, McHugh R, et ale Decreased theophylline half-life in cigarette smokers. Life Sci 1975; 17: 195-8. 5 Koup JR, Brodsky B. Comparison of homogeneous enzyme immunoassay and high-pressure liquid chromatography for the determination of theophylline concentration in serum. Am Rev Respir Dis 1978; 117:1135-8. 6 Winer BJ. Statistical principles in experimental design. 2nd ed. New York: McGraw-Hill Book Co, 1962:261. 7 Ogilvie RI. Clinical pharmacokinetics of theophylline. Clin Pharmacokin 1978; 3:267-93. 8 Bowman KO. Tables of the sample size requirement. Biometrika 1972; 59:234. 9 Wagner JG. Fundamentals of clinical pharmacokinetics. 1st 00. Hamilton, Ill: Drug Intelligence Publications, Inc, 1975:134.
SUSTAINED-RELEASE THEOPHnUNE AND AMINOPHRUNE 303