European Journal of
Eur J Clin Pharmacol (1983) 25:667-672
Bioavailability and Diurnal Variation in Absorption of Sustained
Release Theophylline in Asthmatic Children
K._P.Coulthard, D.J. Birkett, D. R. Lines, N. Grgurinovich, and J. J. Grygiel
Departments of Pharmacy, Clinical Pharmacology and Paediatrics, Hinders Medical Centre, Hinders University of South Australia,
Adelaide, South Australia, Australia 5042
Summary. The absolute oral bioavailability of a sus-
tained release theophylline tablet (Nuelin-SR250),
given 12 hourly was determined in 14 asthmatic chil-
dren aged 5 to 13 years. In 4 of the patients, mean
bioavailability of the fourth dose was 38.9+8.4%
and that of the sixth dose was 67.9 + 25.9% (p < 0.05)
in the other ten patients. This suggests steady-state
had not been achieved after four doses. In the initial
study with 9 patients, a significant diurnal variation
in predose plasma theophylline concentrations was
observed, as the mean morning predose concentra-
tions were 2.9 fold greater than the mean evening
predose concentrations (p < 0.005). Dual peak plas-
ma concentrations occurred in 5 out of the 9 patients.
The mechanism of this diurnal variation was investi-
gated in a further 5 asthmatic children (10.8 years
+ 1.6). Morning and night steady-state plasma the-
ophylline concentrations during a continuous intra-
venous infusion of aminophylline were not different
(14.9 + 5.3 mg/1 vs. 15.6 + 5.9 mg/l), demonstrating
that there was no diurnal variation in the plasma
clearance of theophylline. The diurnal variation in
predose concentrations with Neulin-SR250 was con-
firmed with the morning concentrations again being
2.6 fold greater than those in the evening. However,
bioavailability was not significantly different for day
(09.00-21.00) and night (21.00-09.00) dosing inter-
vals after doses 6 and 7 respectively of Nuelin-
SR250. The plasma concentration versus time pro-
files suggested that the diurnal variation in predose
concentrations was due to slower absorption of the
evening dose.
Key words: theophylline, asthma; children, sus-
tained-release, diurnal, absorption, bioavailability
Oral theophylline therapy has been demonstrated to
be effective in reducing the number of acute attacks
in children with chronic asthma [1]. There appears to
be a correlation between plasma theophylline con-
centrations and both clinical toxicity [2] and thera-
peutic response as measured by pulmonary function
Clinical Pharmacology
© Springer-Verlag 1983
testing [3, 4]. A range of 10-20 mg/l (55-110 ~tmol/1)
is usually quoted as the therapeutic plasma concen-
tration.
Maintenance of such plasma concentrations is
difficult in children administered rapidly absorbed
theophylline preparations because of the higher rate
of theophylline metabolism exhibited by children as
compared with adults [5]. As a consequence of the
higher clearance and the narrow therapeutic index, it
is necessary to dose frequently over a 24-h period to
maintain plasma concentrations in the 10-20 mg/1
range and this may have a detrimental effect on com-
pliance. An alternative to frequent dosing is to em-
ploy sustained-release theophylline preparations.
Previous reports have suggested there may be con-.
siderable variations in the pharmacokinetic efficacy
of sustained-release theophylline preparations [6, 7].
Nuelin-SR250, a sustained-release theophylline
preparation manufactured by Riker Laboratories
Australia, was the first theophylline sustained-re-
lease preparation to be marketed and manufactured
in Australia. It is manufactured according to specifi-
cations for a similar USA product (Ilaeolair). The
aim of these studies was to investigate the absolute
oral bioavailability of Nuelin-SR250 in asthmatic
children and to determine the plasma theophylline
concentration profile achieved over a 24-h period.
Methods and Materials
Subjects
Fourteen children, with ages ranging from 5 years to
13 years, participated. All children were admitted to
the paediatric wards at Flinders Medical Centre with
an exacerbation of their asthma severe enough to re-
quire intravenous aminophylline therapy as well as
the standard medications such as inhaled salbuta-
mol, oxygen and intravenous fluid. Parental consent
and, where possible, patient assent were obtained.
The study was approved by the Clinical Investiga-
tion Committee of Flinders Medical Centre.
668 K.E Coulthardet al.: Bioavaitabilityof Theophyllinein AsthmaticChildren
Protocols
Study A: The first study with 9 patients was designed
to determine the steady state bioavailability of Nue-
lin-SR250. Patients were treated with intravenous
theophylline (as aminophylline) for 12 to 36 h prior
to collection of the first blood sample. An intrave-
nous cannula was inserted into the arm opposite that
used for the aminophylline infusion to allow collec-
tion of venous blood samples. Two blood samples
(2 ml) were collected at least 3 h apart and the amino-
phylline infusion was ceased immediately after col-
lection of the second sample. Further blood samples
were collected at 4, 6 and 8 h after ceasing the infu-
sion to allow determination of the theophylline elim-
ination half-life.
Oral theophylline therapy was then begun using
Nuelin-SR250 at a dose based on either the steady
state plasma theophylline concentrations during the
aminophylline infusion or 20 mg/kg body weight per
24 h. Doses were administered 12 hourly at 09.00 and
21.00 h.
Prior to the 09.00 h dose corresponding to dose
number 4 (Subjects 1-4) or dose 6 (Subjects 5-9) of
Nuelin-SR250, (i. e. after 36 or 60 h oral therapy) an
intravenous cannula was inserted for sampling. This
was kept patent for the duration of the study by I to
2 hourly flushes of 1 ml of 10 units/ml of heparinized
saline. Blood samples (2 ml) were collected prior to
dose 4 or 6, and at 1, 2, 4, 6, 8, t0, 12, 16, 20 and 24h
after the dose. No further theophylline therapy was
administered during this 24-h period (the evening
dose was omitted).
StudyB: As studyA showed a diurnal variation in
predose plasma theophylline concemrations, a sec-
ond study with 5 patients (Subjects 10-14) was de-
signed to investigate the plasma theophylline con-
centration profile over day and night dosage inter-
vals. Two blood samples were again collected at
steady state during an aminophylline infusion but in
this case they were collected at 09.00 and 21.00 h to
investigate whether the diurnal variation was due to
changes in theophylline clearance. Treatment was
then commenced with an appropriate dose of Nue-
lin-SR250 given at 09.00 and 21.00 h. After 6 doses
(60 h oral treatment) samples were collected 2 hourly
commencing at 09.00 for 24h over day (after the
sixth dose) and night (after the seventh dose) dosage
intervals.
Where appropriate, the data from the subjects
studied after 6 doses (Patients 5-14) were analysed
together.
Analytical Methods
Plasma was separated by centrifugation and stored
at -20 °C until analysed. Plasma theophylline con-
centrations were determined in duplicate by high
pressure liquid chromatography [8].
Analysis of Data
Theophylline elimination rate constant k~ was deter-
mined from the slope of the tog theophylline concen-
tration versus time curve after ceasing the amino-
phylline infusion. Theophylline half-life was calcu-
lated from 0.693/ke.
Theophylline plasma clearance was calculated
from the average of the two steady state theophylline
concentrations during intravenous aminophylline
therapy using the relationship:
DRiv = C1 x Cp~,.,
where Dl~v is the infusion rate of theophylline
(mg/h) assuming that aminophylline comprises 80%
theophylline; C1 is the theophylline plasma clear-
ance (l/h) and Cp~vis the steady state plasma the-
ophylline concentration (mg/1) during intravenous
administration.
Mean plasma theophylline concentration CPo
over a dosage interval on oral therapy was calculated
from:
CPo= AUC/T,
where AUC is the area under the plasma concentra-
tion versus time curve (nag. h/l) over a theophylline
dosage interval and T is the dosage interval (h).
Oral bioavailability (f) was then calculated from
f = Cpo. D R i v / C E • DRo,
where DRo is the dose rate on oral therapy (mg/h).
Significance of differences between groups or study
phases were determined using Student's t-test for
paired or unpaired data as appropriate. Values of
p < 0.05 were regarded as significant.
Results
Subject characteristics, intravenous and oral doses of
theophylline per 24 hours, steady-state theophylline
plasma concentrations during intravenous amino-
phylline therapy and the mean concentration after
oral dosing with Nuelin-SR250 are presented in
Table 1. There were no significant differences in the
parameters between the 4 dose and 6 dose groups.
Table 2 shows various pharmacokinetic parame-
ters for theophylline in the fourteen subjects. The
mean plasma theophylline clearance (1.17 _+0.55 ml/
min/kg) and half-life (3.9 + 1.6 h) are similar to those
reported by other investigators [3, 5, 9, 10]. When cor-
rected for dose, the mean Ceo was markedly lower
than m e a n Cpi v in both groups of subjects (p < 0.001).