Differences in Theophylline Clearance between Patients with Chronic Hepatitis and those with Liver Cirrhosis.

BACKGROUND: Theophylline, a xanthine derivative drug, is used for the treatment of respiratory diseases, such as asthma, and is primarily eliminated by hepatic metabolism. There is marked interindividual variability in theophylline clearance. Therefore, the aim of this study was to evaluate the influence of chronic hepatitis (CH), liver cirrhosis (LC), and other covariates on theophylline clearance by population pharmacokinetic (PPK) analysis.

METHODS: The authors retrospectively obtained 496 trough concentrations of theophylline at steady-state from 226 adult patients with bronchial asthma. The liver functions of the patients were classified into three categories: normal hepatic function, CH, and LC. The PPK analysis was performed using the NONMEM program. CH, LC, age, smoking status, co-administration of clarithromycin (CAM) concentration, and sex were considered as covariates that affected theophylline clearance.

RESULTS: Theophylline clearance (CL/F/kg) was significantly influenced by CH, LC, smoking, and CAM. The final model of theophylline clearance was as follows: CL/F (L/hr/kg) = 0.0484 × 1.40 × 0.861 × 0.889 × 0.557.Smoking is a well-known factor that markedly enhances CL/F through the induction of CYP1A enzymes, whereas CAM has been reported to inhibit CYP3A4. The final model for hepatic function showed that theophylline clearanceCL/F in CH and LC patients was 11.1 and 44.3%0.043 and 0.027 L/hr/kg, respectively, and lower than that in patients with normal hepatic function. As theophylline clearance depends on intrinsic hepatic clearance, lower CL/F in patients with LC than in patients with CH may be due to a decrease in the metabolic enzymatic capability of LC patients.

CONCLUSIONS: Differences exist in theophylline clearance between CH and LC patients as per the PPK analysis.