Administration-time-dependency of the pharmacokinetic behavior and therapeutic effect of a once-a-day theophylline in asthmatic children.
Using a double-blind, placebo-control, crossover study design, 8 asthmatic children (8-15 years) were evaluated for temporal patterns in airways function throughout separate study periods when treatment was placebo or Theo-24 once-daily on separate occasions at 0600, 1500 or 2100 hr. During 39-hr in-hospital observations, pulmonary function and serum theophylline concentrations (STC) were assessed every 3 hr under all treatments. The pharmacokinetics of Theo-24 varied greatly depending on the dosing time. For the afternoon and evening dosings, the Cmax, Tmax, AUC, % swing, % fluctuation, % AUC fluctuation, % nocturnal excess and Cav(2-6 hr) were all statistically significantly greater than for the morning dosing. Compared with the placebo regimen, dosing patients with Theo-24 at 1500 hr disrupted circadian patterns of airways function, especially airways patency, while dosing at 2100 hr, reduced the amplitude and shifted the acrophase of several spirometric measures to a slightly earlier time. Theo-24 treatment irrespective of dosing time resulted in comparable enhancement of the group 24-hr mean, minimum and maximum values of airways patency with reference to placebo baselines. Theo-24 dosing at 1500 or 2100 hr, however, resulted in the best effect on the airways as assessed by the 24-hr mean FEV 1.0 level in 7 of the 8 asthmatic children. When the drug was given at 1500 hr, the time of lowest FEV 1.0 was shifted from the nighttime hours in 5 of 8 patients. These findings suggest that clinicians need to individualize the theophylline dosing schedule of patients to best control the symptoms of asthma.
Smolensky
M H
MH
School of Public Health, University of Texas Health Science Center, Houston 77225.
Scott
P H
PH
Harrist
R B
RB
Hiatt
P H
PH
Wong
T K
TK
Baenziger
J C
JC
Klank
B J
BJ
Marbella
A
A
Meltzer
A
A
D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002648:Child; D002940:Circadian Rhythm; D002986:Clinical Trials as Topic; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D012129:Respiratory Function Tests; D013806:Theophylline / Q000008:administration & dosage* / Q000493:pharmacokinetics
D003692:Delayed-Action Preparations; D013806:Theophylline