Formulations and dosage requirements for theophylline in the treatment of asthma

Summary

Theophylline has been marketed in many formulations. Fixed-dose combinations with ephedrine have been popular, but synergistic toxicity with only a modest degree of added effect has been demonstrated. The formulation of theophylline with strong bases as so-called ‘salts’ has been inappropriately claimed to improve absorption and/or decrease adverse effects, and stable theophylline derivatives such as dihydroxypropyl-theophylline (diprophylline) are less effective bronchodilators. The high degree of efficacy recently demonstrated for theophylline in controlling symptoms of chronic asthma has resulted from an appreciation of the relationship between the maintenance of serum theophylline concentrations within a defined therapeutic range of 10 to 20 μg/ml, the need to individualize dosage because of variable rates of elimination, and the appreciation of the relationship between formulation and absorption of oral theophylline. Single-dose bioavailability studies in adults have confirmed the inherently complete and rapid absorption of theophylline when administered in forms that allow rapid dissolution. Products with decreased rates of in vitro dissolution have variable rates and completeness of absorption that do not correlate well with predictions based on conventional in vitro methodology. Examination of children receiving multiple doses of a sustained-release formulation confirm that more stable serum theophylline concentrations are maintained with longer dosing intervals in comparison with a plain uncoated tablet. Dosage is best initiated with an appropriate controlled oral delivery system at the lesser of 16 mg/kg/day or 400 mgjday to assure the absence of adverse effects. An appropriate formulation for children should then allow small dose increments until median dose requirements are attained {24 mg/kg/day for children 1 to 9 years, 20 mg/kg/day for children 9 to 12 years, 18 mg/kg/day for children 12 to 16 years, and 13 mg/kg/day for those over 16 years of age). Final dosage should then be guided by serum theophylline concentrations, taking care to consider the potential for dose-dependent kinetics of elimination resulting in disproportionately large changes in serum concentration with relation to changes in dosage.

Key Words::

• Theophylline
• pharmacology
• asthma