Theophylline Bioavailability A Comparison of the Oral Absorption of a Theophylline Elixir and Two Combination Theophylline Tablets to Intravenous Aminophylline'· •
MARK FIXLEY, DANNY D. SHEN, and DANIEL L. AZARNOFF
SUMMARY __________________________________________ ______________ The bioavailability of theophylline from single doses of an elixir (Elixophyllin®) and two different tablet formulations, as compared to intravenous aminophylline, was studied with a crossover design in 12 normal volunteers. Both tablet formulations (Marax® and Tedral®) contain ephedrine. Marax contains hydroxyzine hydrochloride, and Tedral contains phenobarbital. The absorption of theophylline was most rapid from the elixir, whereas that from Marax was faster than that from Tedral. The peak concentrations of theophylline after administration of the 3 oral dosage forms were in the order, elixir > Marax > Tedral; however, the time to achieve peak concentration was highly variable and did not differ significantly among the 3 products. On the basis of area under the serum concentration-time curves, the absorption of theophylline from the elixir and from Marax was essentially complete. The area under the serum concentration curve after administration of Tedral was significantly less than that after intravenous aminophylline, elixir, and Marax; however, when the individual areas under the concentration curves were adjusted for intrasubject variation in elimination rate constant, the mean area under the concentration curve after Tedral no longer differed significantly from those of the intravenous and other two oral products. A large degree of intersubject variation in the oral absorption of theophylline was observed in this study. Therefore, in addition to the well-documented, large individual variation in the serum clearance of theophylline, intersubject differences in the absorption of the drug is another factor that complicates proper adjustment of the dose in oral theophylline therapy.
Introduction The methylated xanthine, theophylline, is a mainstay of therapy in patients with acute and chronic obstructive airway disease. Numerous studies have shown that the efficacy of theophylline in relieving bronchospasm is dependent on the serum concentration of theophylline. It is
(Received in original form july 8,1976 and in revised form March 2, 1977) 1 From the Clinical Pharmacology-Toxicoloy Center, Departments of Medicine and Pharmacology, University of Kansas Medical Center, College of Health Sciences and Hospital, Kansas City, Kan. 66103. 2 Supported by grants from the United States Pub-
generally accepted that serum concentrations of at least lO p.g per ml are required to achieve adequate relief of bronchospasm, whereas concentrations greater than 20 p.g per ml are associated with frequent incidences of gastrointestinal disturbances and other toxic effects (1-3). Bioavailability is an important consideration in the optimal control of serum concentration with oral theophylline therapy. A number of reported studies (4-9) have focused on the bioavailability of theophylline from commercial oral liquid and tablet formulations; however, all of these previous studies merely compared theophyllie Health Service (GM 15956) and Pfizer Laboratories Pharmaceutical Company.
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 115, 1977
955
956
HXLJIE BIOA VAILABILITY
where t• is the time of the last recorded serum concentration (C•). The area up to t• was estimated by the trapezoidal rule. It should be noted that, because blood samples were not obtained during the infusion period, the AUC was underestimated; however, the error incurred was estimated to be less than 5 per cent of the total AUC. The serum clearance of theophylline (Cl) was calculated according to equation [3]: IV Dose AUC '
[3)
Cl=---
where IV Dose is the dose given intravenously. In addition, a total apparent volume of distribution (V) could be calculated: Cl
where F = bioavailability, and D =dose. The time at which peak concentration was observed (tP) was calculated by equation [6]: ka_ 2.303 tp = -(ka -K) log K +to
The maximal serum concentration (Cmax) was calculated on substitution of time to peak in equation [5]. Bioavailability (F) was calculated based on comparison of AUC values for the various oral and intravenous dosage forms. Correction for intrasubject variation in elimination rate constant was made according to equation [7] (10, 14):
[4)
V= K
The absorption of theophylline from the various oral dosage forms was characterized by an apparent first-order absorption rate constant (k8 ). In some cases, a more satisfactory fit of the observed data was obtained when an absorption lag time (t,) was introduced. Serum concentration of theophylline at any time after an oral dose was, therefore, fitted to equation 5 by means of nonlinear least-squares regression: means of nonlinear nonlinear of nonlinear means of nonlinear means of means
[6)
F' =
AUC p.o. K p.o. AUCi.v.
Ki.v.
[ 7)
where F' is the corrected bioavailability, p.o. denotes oral administration, and i.v. denotes intravenous administration. Statistit l analysis. Analysis of variance (15) was used in the statistical evaluation of areas, peak serum concentration of theophylline, and time to reach peak concentration. When significant differences between the products were found, a Duncan's multiple range test was carried out to find the source of the difference (16, 17). Comparisons between male and female mean V, K, and Cl were evaluated by 2·
TABLE 1 PHARMACOKINETIC PARAMETERS FOR THEOPHYLLINE DERIVED FROM THE INTRAVENOUS STUDY Subject
Sex
Body Weight (kg)
v (/iter/kg)
K
(hour-1 )
Cl (/iter/hour/kg)
84.1 69.5 76.8 65.9 86.4
0.438 0.463 0.523 0.449 0.513
0.142 0.112 0.162 0.099 0.119
0.0622 0.0518 0.0848 0.0445 0.0611
76.5
0.477* 0.014
0.127 0.010
0.0609 0.0068
52.3 63.6 44.5 54.5 54.5 68.2 68.2
0.502 0.400 0.372 0.418 0.394 0.430 0.382
0.098 0.103 0.130 0.173 0.188 0.122 0.076
0.0492 0.0412 0.0483 0.0723 0.0740 0.0524 0.0290
Mean ±SE IN= 7)
58.0
0.414* 0.014
0.127 0.010
0.0523 0.0061
Mean• ±SE (N = 121
67.3
0.440 0.015
0.127 0.010
0.0559 0.0045
JA
sc
ED TR RR
M M M M M
Mean ±SE (N = 5) MC AC LC PH
RN MR ER
F F F F F F F
Definition of abbreviations: V = volume of distribution, calculated by equation (4] in Materials and Methods; K = the apparent first-order elimination rate constant; Cl =serum clea'rance of theophylline, calculated by equation [3] in Materials and Methods; N = number of subjects. • Difference between the two means significant at P < 0.01.
958
FIXLEY, SHEN, AND AZAR:-.IOFF
tailed, unpaired "Student's" t test. A P value less than 0.05 was considered to be significant.
Results
Pharmacokinetic parameters of theophylline derived from the intravenous theophylline data are given in table I. The mean eliminiation rate constant was 0.127 ± 0.010 hour-1, which corresponds to an elimination half-life of 5.84 ± 0.44 hours. The apparent volume of distribution for the entire group ranged from 0.372 to 0.523 liter per kg. When the group was divided according to sex, there was a significant difference (P < 0.005) in the volume of distribution between male and female volunteers (0.477 versus 0.414 liter per kg), but no difference in the serum clearance of theophylline. For the entire group of 12 subjects, the mean serum clearance of theophylline was 0.0559 ± 0.0045 liter per hour per kg. It should be noted that there was a significant correlation (r = 0.67; P < 0.05) between serum clearance expressed as liter per hour and body weight, pointing to the necessity of adjusting theophylline dosage according to body size.
The time courses of changes in mean serum concentration of theophylline in our 12 volunteers after intravenous aminophylline and oral doses of the elixir and tablet formulations are shown in figure I. The absorption of theophylline from the hydroalcoholic solution was much faster than that from the tablet dosage forms. The mean calculated half-life of absorption of theophylline was 8.3 min for the elixir, 21 min for Marax, and 33 min for Tedral. The differences in the absorption half-lives were significant (F 2 , 20 = 4. H; P < 0.05). Similarly, the mean peak concentrations of the 3 products (table 2) were significantly different (F 2 , 20 = 44. I; P < 0.0005) from one another, with the elixir achieving the highest peak concentration, followed by Marax and Tedral. The mean time to reach peak concentration was not significantly different among the 3 products. The over-all range of peak time was 0.74 to 4.3 hours. The mean half-lives of elimination of theophylline were 5.82, 5.36, 5.68, and 5.38 hours after administration of intravenous aminophylline, the elixir, the Marax tablet, and the Tedral
1-
---
o-oA ·--· B o--oc A••••A D I
2
I
4
I
6
HOURS
I
8
I
10
Fig. 1. Serum theophylline concentration after administration of 260 mg of theophylline equivalent in the form of an aminophylline parenteral (A), an elixir (B), and each of 2 different commerical tablets, Marax (C) and Tedral (D). Each point represents the mean; bars, ±I SE, of 12 observations. The curves represent the nonlinear least-squares predictions based on equations [ 1] and [ 5] (see Materials and Methods).
959
THEOPHYLLINE BIOAVAILABILITY
TABLE 2 COMPARISON OF MEAN± SE SERUM CONCENTRATIONS AMONG 4 THEOPHYLLINE TREATMENTS Product Intravenous
Parameters
Aminophylline
Peak serum concentration, J,lg/m I*
Elixir
Marax Tablet
8.09±0.32
< 0. 0 1 t
7.18±0.28
Tedral Tablet
MARK FIXLEY, DANNY D. SHEN, and DANIEL L. AZARNOFF
SUMMARY __________________________________________ ______________ The bioavailability of theophylline from single doses of an elixir (Elixophyllin®) and two different tablet formulations, as compared to intravenous aminophylline, was studied with a crossover design in 12 normal volunteers. Both tablet formulations (Marax® and Tedral®) contain ephedrine. Marax contains hydroxyzine hydrochloride, and Tedral contains phenobarbital. The absorption of theophylline was most rapid from the elixir, whereas that from Marax was faster than that from Tedral. The peak concentrations of theophylline after administration of the 3 oral dosage forms were in the order, elixir > Marax > Tedral; however, the time to achieve peak concentration was highly variable and did not differ significantly among the 3 products. On the basis of area under the serum concentration-time curves, the absorption of theophylline from the elixir and from Marax was essentially complete. The area under the serum concentration curve after administration of Tedral was significantly less than that after intravenous aminophylline, elixir, and Marax; however, when the individual areas under the concentration curves were adjusted for intrasubject variation in elimination rate constant, the mean area under the concentration curve after Tedral no longer differed significantly from those of the intravenous and other two oral products. A large degree of intersubject variation in the oral absorption of theophylline was observed in this study. Therefore, in addition to the well-documented, large individual variation in the serum clearance of theophylline, intersubject differences in the absorption of the drug is another factor that complicates proper adjustment of the dose in oral theophylline therapy.
Introduction The methylated xanthine, theophylline, is a mainstay of therapy in patients with acute and chronic obstructive airway disease. Numerous studies have shown that the efficacy of theophylline in relieving bronchospasm is dependent on the serum concentration of theophylline. It is
(Received in original form july 8,1976 and in revised form March 2, 1977) 1 From the Clinical Pharmacology-Toxicoloy Center, Departments of Medicine and Pharmacology, University of Kansas Medical Center, College of Health Sciences and Hospital, Kansas City, Kan. 66103. 2 Supported by grants from the United States Pub-
generally accepted that serum concentrations of at least lO p.g per ml are required to achieve adequate relief of bronchospasm, whereas concentrations greater than 20 p.g per ml are associated with frequent incidences of gastrointestinal disturbances and other toxic effects (1-3). Bioavailability is an important consideration in the optimal control of serum concentration with oral theophylline therapy. A number of reported studies (4-9) have focused on the bioavailability of theophylline from commercial oral liquid and tablet formulations; however, all of these previous studies merely compared theophyllie Health Service (GM 15956) and Pfizer Laboratories Pharmaceutical Company.
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 115, 1977
955
956
HXLJIE BIOA VAILABILITY
where t• is the time of the last recorded serum concentration (C•). The area up to t• was estimated by the trapezoidal rule. It should be noted that, because blood samples were not obtained during the infusion period, the AUC was underestimated; however, the error incurred was estimated to be less than 5 per cent of the total AUC. The serum clearance of theophylline (Cl) was calculated according to equation [3]: IV Dose AUC '
[3)
Cl=---
where IV Dose is the dose given intravenously. In addition, a total apparent volume of distribution (V) could be calculated: Cl
where F = bioavailability, and D =dose. The time at which peak concentration was observed (tP) was calculated by equation [6]: ka_ 2.303 tp = -(ka -K) log K +to
The maximal serum concentration (Cmax) was calculated on substitution of time to peak in equation [5]. Bioavailability (F) was calculated based on comparison of AUC values for the various oral and intravenous dosage forms. Correction for intrasubject variation in elimination rate constant was made according to equation [7] (10, 14):
[4)
V= K
The absorption of theophylline from the various oral dosage forms was characterized by an apparent first-order absorption rate constant (k8 ). In some cases, a more satisfactory fit of the observed data was obtained when an absorption lag time (t,) was introduced. Serum concentration of theophylline at any time after an oral dose was, therefore, fitted to equation 5 by means of nonlinear least-squares regression: means of nonlinear nonlinear of nonlinear means of nonlinear means of means
[6)
F' =
AUC p.o. K p.o. AUCi.v.
Ki.v.
[ 7)
where F' is the corrected bioavailability, p.o. denotes oral administration, and i.v. denotes intravenous administration. Statistit l analysis. Analysis of variance (15) was used in the statistical evaluation of areas, peak serum concentration of theophylline, and time to reach peak concentration. When significant differences between the products were found, a Duncan's multiple range test was carried out to find the source of the difference (16, 17). Comparisons between male and female mean V, K, and Cl were evaluated by 2·
TABLE 1 PHARMACOKINETIC PARAMETERS FOR THEOPHYLLINE DERIVED FROM THE INTRAVENOUS STUDY Subject
Sex
Body Weight (kg)
v (/iter/kg)
K
(hour-1 )
Cl (/iter/hour/kg)
84.1 69.5 76.8 65.9 86.4
0.438 0.463 0.523 0.449 0.513
0.142 0.112 0.162 0.099 0.119
0.0622 0.0518 0.0848 0.0445 0.0611
76.5
0.477* 0.014
0.127 0.010
0.0609 0.0068
52.3 63.6 44.5 54.5 54.5 68.2 68.2
0.502 0.400 0.372 0.418 0.394 0.430 0.382
0.098 0.103 0.130 0.173 0.188 0.122 0.076
0.0492 0.0412 0.0483 0.0723 0.0740 0.0524 0.0290
Mean ±SE IN= 7)
58.0
0.414* 0.014
0.127 0.010
0.0523 0.0061
Mean• ±SE (N = 121
67.3
0.440 0.015
0.127 0.010
0.0559 0.0045
JA
sc
ED TR RR
M M M M M
Mean ±SE (N = 5) MC AC LC PH
RN MR ER
F F F F F F F
Definition of abbreviations: V = volume of distribution, calculated by equation (4] in Materials and Methods; K = the apparent first-order elimination rate constant; Cl =serum clea'rance of theophylline, calculated by equation [3] in Materials and Methods; N = number of subjects. • Difference between the two means significant at P < 0.01.
958
FIXLEY, SHEN, AND AZAR:-.IOFF
tailed, unpaired "Student's" t test. A P value less than 0.05 was considered to be significant.
Results
Pharmacokinetic parameters of theophylline derived from the intravenous theophylline data are given in table I. The mean eliminiation rate constant was 0.127 ± 0.010 hour-1, which corresponds to an elimination half-life of 5.84 ± 0.44 hours. The apparent volume of distribution for the entire group ranged from 0.372 to 0.523 liter per kg. When the group was divided according to sex, there was a significant difference (P < 0.005) in the volume of distribution between male and female volunteers (0.477 versus 0.414 liter per kg), but no difference in the serum clearance of theophylline. For the entire group of 12 subjects, the mean serum clearance of theophylline was 0.0559 ± 0.0045 liter per hour per kg. It should be noted that there was a significant correlation (r = 0.67; P < 0.05) between serum clearance expressed as liter per hour and body weight, pointing to the necessity of adjusting theophylline dosage according to body size.
The time courses of changes in mean serum concentration of theophylline in our 12 volunteers after intravenous aminophylline and oral doses of the elixir and tablet formulations are shown in figure I. The absorption of theophylline from the hydroalcoholic solution was much faster than that from the tablet dosage forms. The mean calculated half-life of absorption of theophylline was 8.3 min for the elixir, 21 min for Marax, and 33 min for Tedral. The differences in the absorption half-lives were significant (F 2 , 20 = 4. H; P < 0.05). Similarly, the mean peak concentrations of the 3 products (table 2) were significantly different (F 2 , 20 = 44. I; P < 0.0005) from one another, with the elixir achieving the highest peak concentration, followed by Marax and Tedral. The mean time to reach peak concentration was not significantly different among the 3 products. The over-all range of peak time was 0.74 to 4.3 hours. The mean half-lives of elimination of theophylline were 5.82, 5.36, 5.68, and 5.38 hours after administration of intravenous aminophylline, the elixir, the Marax tablet, and the Tedral
1-
---
o-oA ·--· B o--oc A••••A D I
2
I
4
I
6
HOURS
I
8
I
10
Fig. 1. Serum theophylline concentration after administration of 260 mg of theophylline equivalent in the form of an aminophylline parenteral (A), an elixir (B), and each of 2 different commerical tablets, Marax (C) and Tedral (D). Each point represents the mean; bars, ±I SE, of 12 observations. The curves represent the nonlinear least-squares predictions based on equations [ 1] and [ 5] (see Materials and Methods).
959
THEOPHYLLINE BIOAVAILABILITY
TABLE 2 COMPARISON OF MEAN± SE SERUM CONCENTRATIONS AMONG 4 THEOPHYLLINE TREATMENTS Product Intravenous
Parameters
Aminophylline
Peak serum concentration, J,lg/m I*
Elixir
Marax Tablet
8.09±0.32
< 0. 0 1 t
7.18±0.28
Tedral Tablet
