- Email: [email protected]
Intrasubject variation in sustained-release theophylline absorption
knee Et&e
A. Dwktrtch, Pharm.D., Stsnky J. Ft. Green, Phsrm.0. Bu&lo, N. Y.
r, M.D., and
Intrasubject variability in the absorption characteristics of two sustained-release theophylline products was examined. Eight healthy, nonsmoking, adult volunteers received a single 250 mg Slo-Phyllin Gyrocap on two separate study days and a single 300 mg Theo-dur tablet on two other study days. Plasma samples were collected over a 24-hr period aftPr each dose and were assayed for theophylline content. Absorption parameters were determined, including peak plasma concentration, peak time, absorption rate, time until 90% absorbed, and wea under the plasma concentration time curve. Marked intrasubject variation in these absorption paramters was ,found by examination of duplicate plasma concentration time curves. These d#erences ure not apparent from examination of mean data only. The implications of this dose-to-dose variation for the individual patient are discussed.
Tke recognition of a narrow optimal range for serum concentrations (10 to 20 pg/ml) in control of chronic a&male3 has prompted develapent of oral sustained-release theophylline preparatkms. These products are designed to avoid large fIucW&ions in serum concentrations while avoiding short and inconvenient administration intervals. The idea! product should release its theophylline into the @es&al tract at a controlled rate over a readuration with predictability and should have
thWuations (B 10 pg/ml) centrtions over a steady while taking tions . +s In a6h&kn, IGel y consistency in the times at trollgh (lowest) serum curred within that
theqhyl&e
e bioavailability .
‘ihe bioavailability of most sustained-action theoph#ine is said to be complete, on the basis of in vivo test&g of commercially available products.4-5 However, data on the predictability of the release charact&w in individual patients are not apparent from a revtiw of the available literature. Several investigators have reported individual subjects who encounter large
and Theo-dur tablets.
men, 4 women), ages 20 to 27 yr. AIEore termined by history, physical e~~~~, sad routi laboratory tests (blood count, urinalysis, and biaclrtn%xl profile); informed cansent was c&&ted. The subjects were assignedby mean of a &Me of random numbers to two study grope. C&x@ A received a single 300 mg Theo-dur tablet* on stiy day& 1 and 2 followed by a single 250 mg Slo-Rryffin Gym? on SDudy days 3 and 4. Group B received these sametreatments in the
-From the Departments of Pharmacy and Pediatrics of the State Unaversity of New York at Buffalo and Children’s Hospital of Buffalo, Buffalo, N. Y. by a Pharmaceutical Manufacturer’s Association Fellowship for S. J. S. pubkatim Aug. 29, 1980. publication Feb. 19, 1981. Repr&t quests to: Elaine R. Green, Pharm.D., Division of Clinica~:Pharmacology and Fhammcokinetics, Children’s Hospital of Buffalo, 219 Bryant St., Buffalo, NY 14222. 0691~74$!811660466+07$00.70/0
0
1981
The
C. V. Mosby
*Key Pharmaceuticals, Inc., Miami, Fla., l’Wo&r 300 mg, Lot No. 85551, expimtion date be 1980. ?Dooner Jaimatories, Inc. Hav&&l, W., SI+-R$WI 250 Gyrocaps, Lot No. 40632, expiration date Ma& 1980. Co.
Vol.
67, No. 6, pi.
@WI71
466
Dederich et al.
J. ALLERGY CLIN. IMMUNOL. JUNE 1981
SLO-PHYLLIN GYROCAP
THEO-OUR
TABLET
o second dose
5
IO
15
TIME FIG. 1. Mean theophylline (250 mg) and a Theo-dur
20
25
30
5
IO
plasma concentrations Tablet (300 mg).
opposite sequence. This generated a total of four pharmacokinetic profiles for each subject, i.e., two profiles for each product in each subject. At least 1 wk separatedeach of the study days. Subjects were instructed to avoid xanthine-containing food (i.e. coffee, tea, or chocolate) for 48 hr before each study day. All participants fasted overnight for 8 hr prior to each investigation. Between 7:00 and 8:00 A.M., after a light breakfast consisting of orange juice, cereal, toast, and milk, subjects were given the specified test dose with 240 ml of water. The identical breakfast meal was given on each study day. Blood samples (2 ml) were collected immediately prior to dosing; at 30, 60, 90, and 120 min after; and then at hourly intervals until 12 hr after ingestion. An additional blood sample was obtained at 24 hr. An indwelling heparin lock in a forearm vein was used to allow multiple sampling for the first 12 hr. Saliva sampleswere obtained at 1, 4, 12, 18, and 24 hr after ingestion. Xanthine-free meals and fluids were administered ad libitum beginning 4 hr after the dose. Plasma and saliva theophylline concentrations were determined by a modification of the high-pressure liquid chromatography method of Jusko and Poliszczuk.g This assay had a sensitivity of 0.3 pug/ml and a coefficient of variation of <5% on duplicate samples in our laboratory. Measured concentrations were used to calculate absorption parameters for each of the four doses in individual subjects. The 18-hr plasma concentration was extrapolated from the saliva-to-plasma ratio for each subject on each study day. A zero-order pharmacokinetic absorption model was used for Theo-dur,‘” and a first-order pharmacokinetic absorption model was used for Slo-Phyllin Ciyrocaps.4The following absorption parameters were calculated: peak plasma concentration (Cp; pg/ml), time of peak plasmaconcentration (Tp; hours), absorptionrate constant (Ka; hours-‘) for Slo-Phyllin or absorption rate (AR; mg/hr) for Theodur, time until 90% absorbed (90%; hours), and area under
15
TIME
Ihrs)
after duplicate
20
25
30
(hrs)
doses of a So-Phyllin
Gyrocap
the plasma concentration time curve (AUC; pg-hr/ml).* The rate of absorption was examined by the Wagner-Nelson equation, l1 which allowed calculation for the fraction remaining to be absorbed at each time point. The first-order Ka for Slo-Phyllin was calculated from the slope of the logarithm of the fraction unabsorbed over time plot, with least-squaresregression over the first 90% absorbed.” The AR for Theo-dur was calculated by dividing the dose (300 mg) by the time needed to absorb the first 90%. Intrasubject variability in absorption parameters was determined by calculating the percent change between duplicate doses of the products for each subject. The percent change was defined as follows: % change = largestobservation - smallestobservation x 1oo largest observation
RESULTS The mean plasma concentration vs time profiles for the two products are illustrated in Fig. 1. Inspection reveals that the products differed in absorption characteristics, with Slo-Phyllin Gyrocaps reaching their peak concentration earlier than the Theo-dur tablets (5
to 6 hr vs 11 to 12 hr). Absorption was 90% complete for Slo-Phyllin at approximately 6 hr, whereas this was not achieved with Theo-dur until approximately 15 hr after ingestion. Absorption parameters for indi*Sinceno cleareliminationphasewasevident24 hr after a Theodur dose, the best estimateof half-life for eachsubject(i.e., meanobtainedfrom the Slo-Phyllindata)wasusedto extrapolate the terminalportionsof the Theo-durAUC from the trapazoidal rule. This methodhasbeenusedin other similarstudies.(Data availablefrom Key Pharmaceuticals, Inc.)
Variation
VOLUMI 61 NUMBEIH 6
in theophylline
absorption
467
TAB&E I. Absorption parameters for duplicate doses of Slo-Phyllin Gyrocaps” -..
Ctidml) 1
2
1
E; _. ;,
2.98 7.92 4.58 6.50
3.85 7.03 5.40 4.35
6.0 6.0 7.01 7.0t
It. I’ Ci l-l
8.06 4.72 4.43 6.53
7.08 3.86 6.27 6.21
Me;in SD
5.72 1.82
5.51 1.35
-
Kathr-1)
Tp(hr) 2
so%(hr)
AWJ~~hrlrntI
1
2
1
2
1
2
8.0 6.0 4.0t 6.0
0.441 0.891 0.473 0.348
0.301 0.611 0.391 0.348
5.0 4.0 7.0 6.0
7.0 5.0 7.0 6.0
45.45 112.93 81.48 82.65
55.11 96.23 80.89 85.67
5.0 6.0 6.0t 5.0
6.0 6.0t 3.0 5.0
0.304 0.450 0.322 0.496
0.334 0.408 0.817 0.530
7.0 5.0 6.0 6.0
7.0 6.0 3.0 5.0
125.37 62.83 75.40 109.20
96.63 53.30 79.70 120.94
6.0 0.8
5.5 1.5
0.466 0.186
0.468 0.176
5.6 0.9
5.8 1.4
86.92 27.08
83.56 22.30
Subject A
--. *Paired Student’s t tests were used to compare duplicate doses. No significant differences were found. tNo Ifl hr sample obtained. TAStL -a.
H. Absorption
parameters
for duplicate Tdhr)
CPWmu
doses
of Theo-dur
tablets*
ARbwlhrI
SW% fhrl
~~~mil
1
2
1
2
1
2
1
2
1
Sub,ject A H C II E; F Ci H:’
3.11 4.89 4.71 5.84 5.54 3.45 5.86 -
1.86 5.16 3.73 6.71 6.45 2.95 5.54 -
8.0 8.0 10.0 7.0 12.0 10.0t 9.01 -
26.0t 10.0 6.0 10.0 9.0t 18.0 18.0 -
28.08 14.85 29.19 16.87 19.44
14.15 18.90 15.50 24.48 23.76
9.6 18.2 9.3 16.0 13.9
18.36
13.14
14.7
23.94 -
14.33 -
11.3 -
19.1 14.3 17.4 11.0 11.4 20.6 18.8 -
50.58 124.42 85.14 126.71 126.06 75.05 94.96 -
53.60 108.80 103.86 99.73 110.70 72.22 103.91 -
Mean SD
4.77 1.11
4.63 1.83
9.1 1.7
13.9 7.0
21.53 5.60
17.75 4.72
13.28 3.35
16.08 3.86
97.56 29.56
93.26 21.71
-.. *Paired Student’s t tests were used to compare doses. No significant differences were found. _ duplicate _ tNo
18-ju
sample
2
obtained.
$Did no. complete Theo-dur portion of study
viduJ subjects with Slo-Phyllin Gyrocaps and Theodur taM%s are shown in Tables I and II. Paired Student’s t tests were used to compare the duplicate doses of each product with respect to Tp, Cp, Ka or AR, !X%, and AUC. No statistically significant differences were found (p > 0.05). The individual subject plasma concentration vs time profiles for duplicate single doses are depicted in Figs. 1A to 2D. Large intrasubject variations in the absoqion profiles are apparent from visual inspection of’ the data. The range of intrasubject percent chan@s ia the absorption parameters is shown in Table III. With both products the wide range of intrasub&ct percent change in each parameter indicates that alkough some subjects exhibited rather minor or
no variation, others showed considerable di&mnces in their dose-to-dose absorption pro@Ies. This variability in absorption patterns products is minimized when des or group data.
There is little argument with tk c sustained-rebase d pletely absorbed, asthma therapy b and lesser fluctu&.ion in se trations during long-term theophylline products have been eqamincsf for campleteness of absorption or bioav~l~li~ by several
488
Dederich
J. ALLERGY CLIN. IMMUNOL. JUNE 1981
et al.
7
SUBJEC; SLO-PHYLLIN GYROCAP
A THEO-DUR
TABLET
THEO-DUt?
TABLET
t
SUBJEC; SLO-PHYLLIN GYROCAP
B
t
I
,
5
lo
15
M
25
M TIME
5
IQ
L5
20
25
3Q
(hrsl
FIGS. 2A to 2D. Theophylline plasma concentrations after duplicate doses of a Slo-Phyllin Gyrocap (280 mg) and a Theo-Dur Tablet (300 mg) to eight individual subjects. l , First dose; o, second dose; dotted line, no 18-hr sample obtained to connect 12- and 25hr concentrations. FIG. 2A. Subjects A and B.
TAELE III. Range of intrasubject in absorption parameters Parameter CP TP Ka or AR 90% AUC
percent
Slo-Phyilin 5-29 o-so 6-61 O-50 O-23
change* Theodur S-40 O-70 18-50 18-50 4-21
*Percent change calculated by equation in text.
investigators.4’ 5 Their results show that although there is substantial variation among products, several products, including Theo-dur tablets and Slo-Phyllin Gyrocaps, are nearly 100% bioavailable. A second factor to consider in evaluating sustained-release dosage forms is the reliability of the release pattern and the resulting absorption profile within a subject; this had not been carefully examined until our investigation . The products used in this study are each promoted by their respective manufacturers as being specially
formulated to provide a prolonged therapeutic effect. Product information describes Theo-dur as a sustainedrelease formulation with constant or zero-order absorption.* The average peak-trough difference for Theo-dur is stated in the package insert to be only 4 pg/ml at steady state on a 12-hr dosing interval. The range of peak-trough differences is not specified. The manufacturer further states that Theo-dur provides “smooth and stable maintenance therapeutic theophylline levels throughout a q12h dosing interval” and “the predictability of an IV infusion . . . in a tablet. ’ ‘t Slo-Phyllin Gyrocaps arc described by their manufacturer as anhydrous theophylline in a special base that provides a prolonged therapeutic effect with predictable absorption. $ Data collected in this study suggest that there may be rather large intrasubject fluctuations in absorption profiles (Figs. 2A to 2D and Table III) for both SloPhyllin Gyrocaps and Theo-dur tablets despite the fact *Theo-dur product information, Key Phamwceuticals, Inc. Theo-dur advertisement, 1979, Key Pharmaceuticals, Inc. $Slo-Phyllin product information, Dooner Laboratories, Inc.
VOCUM:. 67 NUMBE.4 6
Variation
SUBJECf
E
1’
absorption
489
C
6
THEO-OUR
SLO-PHYLLIN GYROCAP
5t
in theophylline
TdBLET
t
5
IO
15
20
25
30
I 5
10
15
20
25
30
5
IO
15
20
25
30
5
IO
15
20
25
x1
I
TIME FIG.
26.
Subjects
that these products have been shown to be nearly 100% bioavaiiable on the basis of mean subject data.** 5 Figs. 2A to 2D clearly illustrate the variations in serum concentration vs time profiles generated from ined after duplicate single doses in the same data individual. It is also readily apparent that for most subje&s, no clear elimination phase is discernible during 24 hr of sampling after a single dose of Theo-dur. a detectable elimination phase implies n is continuing from the Theo-dur tablet ut our sampling period. In fact, in Subject A, a w sample obtained approximately 26 hr after admktistration contained the highest theophylline concentration. In Subjects F and G, the 18-hr nted the peak theophylline serum conprolonged absorption of Theo-dur, as r variations in absorption characteristics occurring with both products, are obscured when mean serum concentration data only are used to generate concentration vs time profiles (Fig. 1). formuktion of a sustained-release product that wi iminate both intraindividual and interindividual varia&m in absorption is technically very difficult. In ad n to possible tablet-to-tablet or lot-to-lot variab in dissolution characteristics, physiologic factors kuch as gastric emptying, intestinal motility, and tram& time of food must also be considered in ex-
(hrsl
C and
D.
plaining any lack of reproducibility in in viva absorption profiles. The data from this Ives allow us to identify the spec resulted in the intrasubject found with both Theo&r tablets &ml ~l~~~~in Gyrocaps. Several other investigators have tuations in theophylline serum steady-state dosing intervai and Bigley,6 in a study of fluctuations in serum th 2.0 to 11.4 pg/ml over Gyrocaps and 2.3 to 8 tablets. Dasta et al.* reported ences ranging from 1.3 to 11.8 dosing regimen with Theo-dur obstructive pulmonary disease. in another study of Theodttr in found peak-to-trough differences a 12-hr dosing schedule. These inv ported little consistency in t trough serum the~I.&yMe served. In that study, study dose at steady state) sew were found to be at their whereas six of the 19 were four& to be at their ‘pale concentration. The remaining six patknts were at
470
Dederich et al.
J. ALLERGY CLIN. IMMUNOL. JUNE 1991
THEO-OUR
5
IO
I5
20
25
30
TIME
5
IO
15
TABLET
20
25
lhrsl
FIG. X. Subjects E and F.
THEO- DUR
SLO-PHYLLIN
:6 15
SLO-PHYLLIN
5
IO
I5 TIME
20
25
fhrsl
Fig. 2B. Subjects G end H.
%J
30
VOLUNC 67 NUMBt 3 6
concentrations between the eventual peak and trough. In addition, at least one patient was at the observed trough concentration at each of the four sampling times studied (0, 4, 6, and 10 hr after a dose). Conversejy , at least three subjects were at their observed peak
Variation
in theophyliine
absorption
471
2. Weinberger MM, Bronsky EA: Evaluation of oral bronchodilator therapy in asthmatic children. J pediatr 84~421, 1974. 3. Hambleton G, Weinberger MM, Taylor J, et al.: Comparison of cromoglycate (cromofyn) and tbe@phyUine in controlling symptoms of chronic asthma. Lagcet 18381, 1977. 4. Weinbqer M, Hendeles L, Bighlrey L: The relation of product formulation to absorption of oral theophylIine. N Engl J Med 299:852, 1978. 5. Spangler DL, Kalof DD, Bloom FL, Wittig M: Theophyliine bioavailabiiity following oral administration of six sustainedrelease preparations. Ann Allergy 4&6, 1978. 6. Bell T, Sigley J: Sustained &ease tbeophylline therapy for chronic childhood asthma. Pediatrics 62:352, 1978. 7. Kelly HW, Murphy S: Serum theqhyltine levels in asthmatic children receiving sustained-reteaae theophylline tablets. Am J Hosp pharm M:l698, 1979. 8. 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. 9. Jusko WJ, Poliszczuk A: High-pressure liquid chromatographic and spectrophotometric assaysfor theophylline in biological fluids. Am J Hosp Pharm 33:1193, 1976. 10. RiegeIman S: Achieving stationary state th~yli~n~ plasma levels in the therapeutic range with zero-order dosage forms. in Proceedings of the 25th Annual Congress of the American College of Allergists, January, 1979, San Francisco, Calif. (Abst.) 11. Gibaldi M, Perrier D: Pharmaccrkinetics. in Dnrgs and the pharmacokinetic sciences, Vol. 1. New York. 1975, Marcel Dekker, Inc.
A. Dwktrtch, Pharm.D., Stsnky J. Ft. Green, Phsrm.0. Bu&lo, N. Y.
r, M.D., and
Intrasubject variability in the absorption characteristics of two sustained-release theophylline products was examined. Eight healthy, nonsmoking, adult volunteers received a single 250 mg Slo-Phyllin Gyrocap on two separate study days and a single 300 mg Theo-dur tablet on two other study days. Plasma samples were collected over a 24-hr period aftPr each dose and were assayed for theophylline content. Absorption parameters were determined, including peak plasma concentration, peak time, absorption rate, time until 90% absorbed, and wea under the plasma concentration time curve. Marked intrasubject variation in these absorption paramters was ,found by examination of duplicate plasma concentration time curves. These d#erences ure not apparent from examination of mean data only. The implications of this dose-to-dose variation for the individual patient are discussed.
Tke recognition of a narrow optimal range for serum concentrations (10 to 20 pg/ml) in control of chronic a&male3 has prompted develapent of oral sustained-release theophylline preparatkms. These products are designed to avoid large fIucW&ions in serum concentrations while avoiding short and inconvenient administration intervals. The idea! product should release its theophylline into the @es&al tract at a controlled rate over a readuration with predictability and should have
thWuations (B 10 pg/ml) centrtions over a steady while taking tions . +s In a6h&kn, IGel y consistency in the times at trollgh (lowest) serum curred within that
theqhyl&e
e bioavailability .
‘ihe bioavailability of most sustained-action theoph#ine is said to be complete, on the basis of in vivo test&g of commercially available products.4-5 However, data on the predictability of the release charact&w in individual patients are not apparent from a revtiw of the available literature. Several investigators have reported individual subjects who encounter large
and Theo-dur tablets.
men, 4 women), ages 20 to 27 yr. AIEore termined by history, physical e~~~~, sad routi laboratory tests (blood count, urinalysis, and biaclrtn%xl profile); informed cansent was c&&ted. The subjects were assignedby mean of a &Me of random numbers to two study grope. C&x@ A received a single 300 mg Theo-dur tablet* on stiy day& 1 and 2 followed by a single 250 mg Slo-Rryffin Gym? on SDudy days 3 and 4. Group B received these sametreatments in the
-From the Departments of Pharmacy and Pediatrics of the State Unaversity of New York at Buffalo and Children’s Hospital of Buffalo, Buffalo, N. Y. by a Pharmaceutical Manufacturer’s Association Fellowship for S. J. S. pubkatim Aug. 29, 1980. publication Feb. 19, 1981. Repr&t quests to: Elaine R. Green, Pharm.D., Division of Clinica~:Pharmacology and Fhammcokinetics, Children’s Hospital of Buffalo, 219 Bryant St., Buffalo, NY 14222. 0691~74$!811660466+07$00.70/0
0
1981
The
C. V. Mosby
*Key Pharmaceuticals, Inc., Miami, Fla., l’Wo&r 300 mg, Lot No. 85551, expimtion date be 1980. ?Dooner Jaimatories, Inc. Hav&&l, W., SI+-R$WI 250 Gyrocaps, Lot No. 40632, expiration date Ma& 1980. Co.
Vol.
67, No. 6, pi.
@WI71
466
Dederich et al.
J. ALLERGY CLIN. IMMUNOL. JUNE 1981
SLO-PHYLLIN GYROCAP
THEO-OUR
TABLET
o second dose
5
IO
15
TIME FIG. 1. Mean theophylline (250 mg) and a Theo-dur
20
25
30
5
IO
plasma concentrations Tablet (300 mg).
opposite sequence. This generated a total of four pharmacokinetic profiles for each subject, i.e., two profiles for each product in each subject. At least 1 wk separatedeach of the study days. Subjects were instructed to avoid xanthine-containing food (i.e. coffee, tea, or chocolate) for 48 hr before each study day. All participants fasted overnight for 8 hr prior to each investigation. Between 7:00 and 8:00 A.M., after a light breakfast consisting of orange juice, cereal, toast, and milk, subjects were given the specified test dose with 240 ml of water. The identical breakfast meal was given on each study day. Blood samples (2 ml) were collected immediately prior to dosing; at 30, 60, 90, and 120 min after; and then at hourly intervals until 12 hr after ingestion. An additional blood sample was obtained at 24 hr. An indwelling heparin lock in a forearm vein was used to allow multiple sampling for the first 12 hr. Saliva sampleswere obtained at 1, 4, 12, 18, and 24 hr after ingestion. Xanthine-free meals and fluids were administered ad libitum beginning 4 hr after the dose. Plasma and saliva theophylline concentrations were determined by a modification of the high-pressure liquid chromatography method of Jusko and Poliszczuk.g This assay had a sensitivity of 0.3 pug/ml and a coefficient of variation of <5% on duplicate samples in our laboratory. Measured concentrations were used to calculate absorption parameters for each of the four doses in individual subjects. The 18-hr plasma concentration was extrapolated from the saliva-to-plasma ratio for each subject on each study day. A zero-order pharmacokinetic absorption model was used for Theo-dur,‘” and a first-order pharmacokinetic absorption model was used for Slo-Phyllin Ciyrocaps.4The following absorption parameters were calculated: peak plasma concentration (Cp; pg/ml), time of peak plasmaconcentration (Tp; hours), absorptionrate constant (Ka; hours-‘) for Slo-Phyllin or absorption rate (AR; mg/hr) for Theodur, time until 90% absorbed (90%; hours), and area under
15
TIME
Ihrs)
after duplicate
20
25
30
(hrs)
doses of a So-Phyllin
Gyrocap
the plasma concentration time curve (AUC; pg-hr/ml).* The rate of absorption was examined by the Wagner-Nelson equation, l1 which allowed calculation for the fraction remaining to be absorbed at each time point. The first-order Ka for Slo-Phyllin was calculated from the slope of the logarithm of the fraction unabsorbed over time plot, with least-squaresregression over the first 90% absorbed.” The AR for Theo-dur was calculated by dividing the dose (300 mg) by the time needed to absorb the first 90%. Intrasubject variability in absorption parameters was determined by calculating the percent change between duplicate doses of the products for each subject. The percent change was defined as follows: % change = largestobservation - smallestobservation x 1oo largest observation
RESULTS The mean plasma concentration vs time profiles for the two products are illustrated in Fig. 1. Inspection reveals that the products differed in absorption characteristics, with Slo-Phyllin Gyrocaps reaching their peak concentration earlier than the Theo-dur tablets (5
to 6 hr vs 11 to 12 hr). Absorption was 90% complete for Slo-Phyllin at approximately 6 hr, whereas this was not achieved with Theo-dur until approximately 15 hr after ingestion. Absorption parameters for indi*Sinceno cleareliminationphasewasevident24 hr after a Theodur dose, the best estimateof half-life for eachsubject(i.e., meanobtainedfrom the Slo-Phyllindata)wasusedto extrapolate the terminalportionsof the Theo-durAUC from the trapazoidal rule. This methodhasbeenusedin other similarstudies.(Data availablefrom Key Pharmaceuticals, Inc.)
Variation
VOLUMI 61 NUMBEIH 6
in theophylline
absorption
467
TAB&E I. Absorption parameters for duplicate doses of Slo-Phyllin Gyrocaps” -..
Ctidml) 1
2
1
E; _. ;,
2.98 7.92 4.58 6.50
3.85 7.03 5.40 4.35
6.0 6.0 7.01 7.0t
It. I’ Ci l-l
8.06 4.72 4.43 6.53
7.08 3.86 6.27 6.21
Me;in SD
5.72 1.82
5.51 1.35
-
Kathr-1)
Tp(hr) 2
so%(hr)
AWJ~~hrlrntI
1
2
1
2
1
2
8.0 6.0 4.0t 6.0
0.441 0.891 0.473 0.348
0.301 0.611 0.391 0.348
5.0 4.0 7.0 6.0
7.0 5.0 7.0 6.0
45.45 112.93 81.48 82.65
55.11 96.23 80.89 85.67
5.0 6.0 6.0t 5.0
6.0 6.0t 3.0 5.0
0.304 0.450 0.322 0.496
0.334 0.408 0.817 0.530
7.0 5.0 6.0 6.0
7.0 6.0 3.0 5.0
125.37 62.83 75.40 109.20
96.63 53.30 79.70 120.94
6.0 0.8
5.5 1.5
0.466 0.186
0.468 0.176
5.6 0.9
5.8 1.4
86.92 27.08
83.56 22.30
Subject A
--. *Paired Student’s t tests were used to compare duplicate doses. No significant differences were found. tNo Ifl hr sample obtained. TAStL -a.
H. Absorption
parameters
for duplicate Tdhr)
CPWmu
doses
of Theo-dur
tablets*
ARbwlhrI
SW% fhrl
~~~mil
1
2
1
2
1
2
1
2
1
Sub,ject A H C II E; F Ci H:’
3.11 4.89 4.71 5.84 5.54 3.45 5.86 -
1.86 5.16 3.73 6.71 6.45 2.95 5.54 -
8.0 8.0 10.0 7.0 12.0 10.0t 9.01 -
26.0t 10.0 6.0 10.0 9.0t 18.0 18.0 -
28.08 14.85 29.19 16.87 19.44
14.15 18.90 15.50 24.48 23.76
9.6 18.2 9.3 16.0 13.9
18.36
13.14
14.7
23.94 -
14.33 -
11.3 -
19.1 14.3 17.4 11.0 11.4 20.6 18.8 -
50.58 124.42 85.14 126.71 126.06 75.05 94.96 -
53.60 108.80 103.86 99.73 110.70 72.22 103.91 -
Mean SD
4.77 1.11
4.63 1.83
9.1 1.7
13.9 7.0
21.53 5.60
17.75 4.72
13.28 3.35
16.08 3.86
97.56 29.56
93.26 21.71
-.. *Paired Student’s t tests were used to compare doses. No significant differences were found. _ duplicate _ tNo
18-ju
sample
2
obtained.
$Did no. complete Theo-dur portion of study
viduJ subjects with Slo-Phyllin Gyrocaps and Theodur taM%s are shown in Tables I and II. Paired Student’s t tests were used to compare the duplicate doses of each product with respect to Tp, Cp, Ka or AR, !X%, and AUC. No statistically significant differences were found (p > 0.05). The individual subject plasma concentration vs time profiles for duplicate single doses are depicted in Figs. 1A to 2D. Large intrasubject variations in the absoqion profiles are apparent from visual inspection of’ the data. The range of intrasubject percent chan@s ia the absorption parameters is shown in Table III. With both products the wide range of intrasub&ct percent change in each parameter indicates that alkough some subjects exhibited rather minor or
no variation, others showed considerable di&mnces in their dose-to-dose absorption pro@Ies. This variability in absorption patterns products is minimized when des or group data.
There is little argument with tk c sustained-rebase d pletely absorbed, asthma therapy b and lesser fluctu&.ion in se trations during long-term theophylline products have been eqamincsf for campleteness of absorption or bioav~l~li~ by several
488
Dederich
J. ALLERGY CLIN. IMMUNOL. JUNE 1981
et al.
7
SUBJEC; SLO-PHYLLIN GYROCAP
A THEO-DUR
TABLET
THEO-DUt?
TABLET
t
SUBJEC; SLO-PHYLLIN GYROCAP
B
t
I
,
5
lo
15
M
25
M TIME
5
IQ
L5
20
25
3Q
(hrsl
FIGS. 2A to 2D. Theophylline plasma concentrations after duplicate doses of a Slo-Phyllin Gyrocap (280 mg) and a Theo-Dur Tablet (300 mg) to eight individual subjects. l , First dose; o, second dose; dotted line, no 18-hr sample obtained to connect 12- and 25hr concentrations. FIG. 2A. Subjects A and B.
TAELE III. Range of intrasubject in absorption parameters Parameter CP TP Ka or AR 90% AUC
percent
Slo-Phyilin 5-29 o-so 6-61 O-50 O-23
change* Theodur S-40 O-70 18-50 18-50 4-21
*Percent change calculated by equation in text.
investigators.4’ 5 Their results show that although there is substantial variation among products, several products, including Theo-dur tablets and Slo-Phyllin Gyrocaps, are nearly 100% bioavailable. A second factor to consider in evaluating sustained-release dosage forms is the reliability of the release pattern and the resulting absorption profile within a subject; this had not been carefully examined until our investigation . The products used in this study are each promoted by their respective manufacturers as being specially
formulated to provide a prolonged therapeutic effect. Product information describes Theo-dur as a sustainedrelease formulation with constant or zero-order absorption.* The average peak-trough difference for Theo-dur is stated in the package insert to be only 4 pg/ml at steady state on a 12-hr dosing interval. The range of peak-trough differences is not specified. The manufacturer further states that Theo-dur provides “smooth and stable maintenance therapeutic theophylline levels throughout a q12h dosing interval” and “the predictability of an IV infusion . . . in a tablet. ’ ‘t Slo-Phyllin Gyrocaps arc described by their manufacturer as anhydrous theophylline in a special base that provides a prolonged therapeutic effect with predictable absorption. $ Data collected in this study suggest that there may be rather large intrasubject fluctuations in absorption profiles (Figs. 2A to 2D and Table III) for both SloPhyllin Gyrocaps and Theo-dur tablets despite the fact *Theo-dur product information, Key Phamwceuticals, Inc. Theo-dur advertisement, 1979, Key Pharmaceuticals, Inc. $Slo-Phyllin product information, Dooner Laboratories, Inc.
VOCUM:. 67 NUMBE.4 6
Variation
SUBJECf
E
1’
absorption
489
C
6
THEO-OUR
SLO-PHYLLIN GYROCAP
5t
in theophylline
TdBLET
t
5
IO
15
20
25
30
I 5
10
15
20
25
30
5
IO
15
20
25
30
5
IO
15
20
25
x1
I
TIME FIG.
26.
Subjects
that these products have been shown to be nearly 100% bioavaiiable on the basis of mean subject data.** 5 Figs. 2A to 2D clearly illustrate the variations in serum concentration vs time profiles generated from ined after duplicate single doses in the same data individual. It is also readily apparent that for most subje&s, no clear elimination phase is discernible during 24 hr of sampling after a single dose of Theo-dur. a detectable elimination phase implies n is continuing from the Theo-dur tablet ut our sampling period. In fact, in Subject A, a w sample obtained approximately 26 hr after admktistration contained the highest theophylline concentration. In Subjects F and G, the 18-hr nted the peak theophylline serum conprolonged absorption of Theo-dur, as r variations in absorption characteristics occurring with both products, are obscured when mean serum concentration data only are used to generate concentration vs time profiles (Fig. 1). formuktion of a sustained-release product that wi iminate both intraindividual and interindividual varia&m in absorption is technically very difficult. In ad n to possible tablet-to-tablet or lot-to-lot variab in dissolution characteristics, physiologic factors kuch as gastric emptying, intestinal motility, and tram& time of food must also be considered in ex-
(hrsl
C and
D.
plaining any lack of reproducibility in in viva absorption profiles. The data from this Ives allow us to identify the spec resulted in the intrasubject found with both Theo&r tablets &ml ~l~~~~in Gyrocaps. Several other investigators have tuations in theophylline serum steady-state dosing intervai and Bigley,6 in a study of fluctuations in serum th 2.0 to 11.4 pg/ml over Gyrocaps and 2.3 to 8 tablets. Dasta et al.* reported ences ranging from 1.3 to 11.8 dosing regimen with Theo-dur obstructive pulmonary disease. in another study of Theodttr in found peak-to-trough differences a 12-hr dosing schedule. These inv ported little consistency in t trough serum the~I.&yMe served. In that study, study dose at steady state) sew were found to be at their whereas six of the 19 were four& to be at their ‘pale concentration. The remaining six patknts were at
470
Dederich et al.
J. ALLERGY CLIN. IMMUNOL. JUNE 1991
THEO-OUR
5
IO
I5
20
25
30
TIME
5
IO
15
TABLET
20
25
lhrsl
FIG. X. Subjects E and F.
THEO- DUR
SLO-PHYLLIN
:6 15
SLO-PHYLLIN
5
IO
I5 TIME
20
25
fhrsl
Fig. 2B. Subjects G end H.
%J
30
VOLUNC 67 NUMBt 3 6
concentrations between the eventual peak and trough. In addition, at least one patient was at the observed trough concentration at each of the four sampling times studied (0, 4, 6, and 10 hr after a dose). Conversejy , at least three subjects were at their observed peak
Variation
in theophyliine
absorption
471
2. Weinberger MM, Bronsky EA: Evaluation of oral bronchodilator therapy in asthmatic children. J pediatr 84~421, 1974. 3. Hambleton G, Weinberger MM, Taylor J, et al.: Comparison of cromoglycate (cromofyn) and tbe@phyUine in controlling symptoms of chronic asthma. Lagcet 18381, 1977. 4. Weinbqer M, Hendeles L, Bighlrey L: The relation of product formulation to absorption of oral theophylIine. N Engl J Med 299:852, 1978. 5. Spangler DL, Kalof DD, Bloom FL, Wittig M: Theophyliine bioavailabiiity following oral administration of six sustainedrelease preparations. Ann Allergy 4&6, 1978. 6. Bell T, Sigley J: Sustained &ease tbeophylline therapy for chronic childhood asthma. Pediatrics 62:352, 1978. 7. Kelly HW, Murphy S: Serum theqhyltine levels in asthmatic children receiving sustained-reteaae theophylline tablets. Am J Hosp pharm M:l698, 1979. 8. 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. 9. Jusko WJ, Poliszczuk A: High-pressure liquid chromatographic and spectrophotometric assaysfor theophylline in biological fluids. Am J Hosp Pharm 33:1193, 1976. 10. RiegeIman S: Achieving stationary state th~yli~n~ plasma levels in the therapeutic range with zero-order dosage forms. in Proceedings of the 25th Annual Congress of the American College of Allergists, January, 1979, San Francisco, Calif. (Abst.) 11. Gibaldi M, Perrier D: Pharmaccrkinetics. in Dnrgs and the pharmacokinetic sciences, Vol. 1. New York. 1975, Marcel Dekker, Inc.