Monitoring Serum Theophylline Levels

Summary

Recent definition of the pharmacodynamics and pharmacokinetics of theophylline have increased the safety and efficacy of the drug for acute bronchodilator therapy and have greatly expanded its potential as a prophylactic agent in the management of chronic asthmatic symptoms. Specifically, benefit and risk from theophylline have been demonstrated to relate directly to serum theophylline concentration, which is itself a function of not only the dose but also the elimination characteristics of the drug in the individual patient.

When used to treat acute symptoms, an initial loading dose of theophylline based on a volume of distribution of 0.5L/kg (range — 0.3 to 0.7L/kg) is required to rapidly attain maximum bronchodilator effect. There are wide interpatient differences in elimination rate. Dosage for continued therapy must be matched to the rate of elimination in the individual patient, which can be expressed as clearance. Under normal circumstances, this can only be done empirically by monitoring serum theophylline concentration at intervals and adjusting dosage until a steady state is reached with the serum theophylline concentration within the 10 to 20μg/ml therapeutic range.

During long term therapy, product formulation must be carefully considered; sustained release preparations, if completely and reliably absorbed, offer therapeutic advantage, particularly for children. The most acceptable way to determine final dosage for long term therapy is to begin with doses sufficiently low to allow virtually universal acceptance of the medication, although optimum benefit will be obtained in very few. Gradual increases in dose at 3 day intervals until average doses are reached, if tolerated, minimises the frequency with which serum theophylline concentrations need to be measured. These doses should then, however, not be maintained or increased further without measurement of serum theophylline concentration. Final dosage adjustment can then be made. Serum theophylline measurement is therefore essential for optimum management of chronic asthma and, when rapidly available, increases the utility of theophylline for acute therapy.

Six different basic methods for measuring theophylline in serum or plasma have been developed and multiple modifications of many of these have been utilised in various laboratories. Of greatest relevance are: (I) modifications of the traditional extraction methodology and measurement of ultraviolet absorbance first reported by Schack and Waxler in 1949; (2) high pressure liquid chromatography of which the reverse phase technology has become the most popular because of its commercial availability; and (3) the enzyme immunoassay which has recently been released and appears to have distinct advantage for the average clinical laboratory with regard to cost, specificity, ease of operation, speed of the assay and potential application of the equipment for assaying drugs other than theophylline.