Theophylline pharmacokinetics with concomitant steroid and gold therapy

Theophylline has been used for several decades in the treatment of asthma. In recent years, however, with the appreciation of the importance of inflammation in the pathogenesis of asthma, new therapeutic approaches have arisen, including beta2-agonists, steroid and nonsteroidal anti-inflammatory drugs, such as gold salts.

In the present work we studied the kinetic behaviour of theophylline administered concomitantly with methylprednisolone (steroid compound) and auranofin (oral gold) in six adult female patients.

Drug concentration data for patients under routine care were collected. The kinetic analysis (Bayesian Approach) was done using two different commercial software packages, PKS (Abbott Diagnostics) and CAPCIL (SIMKIN Inc., courtesy of Dade-Behring). A one-compartment open model with first-order absorption (ka for PKS=0. 5/h; ka for CAPCIL=0.3/h ) and first- order elimination. Default CL, t1/2 and Vd values were used for each program was assumed. The measured and predicted theophylline concentrations were used to calculate percentage prediction errors defined as %PE=[(predicted conc. - measured conc.)/measured conc.] x 100. A linear regression analysis was also carried out for the observed concentrations and those predicted by each method (PKS vs. CAPCIL).

The predicted concentrations indicating persistently over-predicted the observed theophylline serum levels (results expressed as median and interquartile range; %PE for PKS=58.1 [37.1-126.0]; %PE for CAPCIL=34.0 [12.5-93.8]). The regression analysis confirmed the same tendency, showing an intercept significantly different from zero using both PKS and CAPCIL.

The results suggest a possible interaction between theophylline and auranofin. Both PKS and CAPCIL failed to predict theophylline serum levels based exclusively on population pharmacokinetic parameters. The lower observed concentrations than expected have obvious implications in practice. Periodic theophylline serum determinations are advisable until further studies provide the necessary clarification about the kinetic profile of theophylline in patients taking concomitant steroids and gold salts.