Administration-Time-Dependency of the Pharmacokinetic Behavior and Therapeutic Effect of a Once-A-Day Theophylline in Asthmatic Children

Abstract

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 C_maxT_max, AUC₁%swing,%fluctuation,%AUC fluctuation,%nocturnal excess and C_av(2,6hr)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 group24-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_1.0level in 7 of the 8 asthmatic children. When the drug was given at 1500 hr, the time of lowest FEV_1.0was 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.

Key Words:

• Once-a-day theophylline
• pharmacokinetics
• pharmacodynamics
• asthma
• children
• chrono-pharmacology