Application of population pharmacokinetics to the optimization of theophylline therapy

The aim of this study was to determine theophylline clearance (Cl) values in adult patients using serum concentrations gathered from routine clinical care. This information was used to estimate an a priori dosing regimen that would permit steady-state concentrations of 5-15 mg/litre, now recommended for the treatment of chronic asthma, and to evaluate the need to establish monitoring strategies when theophylline is given at these lower doses and when it can be expected that almost no adverse effects are likely. Retrospective data from 204 asthmatic and COPD patients, with a total of 517 serum concentrations, were studied. Population pharmacokinetic analysis was performed with the MULTI(ELS) computer program according to a one-compartment model. The influence of the following factors on theophylline Cl were investigated: body weight (TBW, IBW and LBM) and age as continuous variables, and gender, smoking habit and the presence of congestive heart failure (CHF) as indicator variables. To validate the results of the population pharmacokinetic analysis, a second independent group of 63 patients was studied prospectively. Hypothesis testing to evaluate potentially significant factors produced a final model in which Cl was based on IBW (kg) and age (years), and was reduced by 25% in patients with moderate CHF and increased by 28% in patients who smoked (Cl (litres/h) = (0.037 IBW-0.006 age) x 1.284 smoke x 0.751 CHF). The variability in Cl, expressed as the coefficient of variation, was 36%. In adult non-smoker and non-CHF patients, application of a maintenance dosing regimen calculated from IBW and age using the final model for Cl would theoretically afford only 1.5% of patients with potentially toxic concentrations. Thus, measurement of serum theophylline concentrations (STC) would only be required when other conditions known to alter theophylline metabolism exist, such as smoking or disease factors. These appreciations could have important clinical implications at a time when the potential immunomodulatory activity of theophylline is being emphasized and health resources should be allocated properly.