APPLICATION OF POPULATION PHARMACOKINETICS TO THE OPTIMIZATION OF THEOPHYLLINE THERAPY

The aim of this study was to determine theophylline clearance (Cl) val ues in adult patients using serum concentrations gathered from routine clinical care. This information was used to estimate an a priori dosi ng regimen that would permit steady-state concentrations of 5-15 mg/li tre, now recommended for the treatment of chronic asthma, and to evalu ate the need to establish monitoring strategies when theophylline is g iven at these lower doses and when it can be expected that almost no a dverse effects are likely. Retrospective data from 204 asthmatic and C OPD 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 o f the following factors on theophylline CZ were investigated: body wei ght (TBW, IBW and LBM) and age as continuous variables, and gender, sm oking habit and the presence of congestive heart failure (CHF) as indi cator variables. To validate the results of the population pharmacokin etic analysis, a second independent group of 63 patients was studied p rospectively. Hypothesis testing to evaluate potentially significant f actors produced a final model in which CI was based on IBW (kg) and ag e (years), and was reduced by 25% in patients with moderate CHF and in creased by 28% in patients who smoked (Cl (litres/h)=(0.037 IBW - 0.00 6 age) x 1.284 smoker x 0.751 CHF). The variability in Cl, expressed a s the coefficient of variation, was 3.6%. In adult non-smoker and non- CHF patients, application of a maintenance dosing regimen calculated f rom IBW and age using the final model for Cl would theoretically affor d only 1.5% of patients with potentially toxic concentrations. Thus, m easurement of serum theophylline concentrations (STC) would only be re quired when other conditions known to alter theophylline metabolism ex ist, such as smoking or disease factors. These appreciations could hav e important clinical implications at a time when the potential immunom odulatory activity of theophylline is being emphasized and health reso urces should be allocated properly.