Reduced theophylline clearance due to hepatic congestion secondary to right heart failure - A population pharmacokinetic study.

Theophylline, a beneficial drug with bronchodilatory and anti-inflammatory effects, is used for the treatment of respiratory diseases. Pulmonary (PC) and hepatic congestion (HC) are secondary to the development of left- and right-sided heart failure (HF), respectively. This study aimed to evaluate the effects of PC and HC on theophylline clearance (CL) by population pharmacokinetic (PPK) analysis with consideration of the severity of HF assessed by the New York Heart Association (NYHA) functional classification. We obtained 710 minimum steady-state concentrations from 201 Japanese bronchial asthma patients with and without HF. PPK analysis was performed by NONMEM. In the analysis, the left ventricular ejection fraction, smoking (SMK), clarithromycin (CAM), sex, and age were also considered as covariates. The final model of apparent theophylline clearance (CL/F) was as follows: CL/F (L/hr/kg) = 0.0465 × 1.40SMK × 0.870CAM × 0.863HC(+)NYHA II × 0.634HC(+)NYHA III × 0.586HC(-)NYHA IV × 0.467HC(+)NYHA IV. SMK is a well-known factor that markedly enhances theophylline clearance through the induction of CYP1A enzymes, while CAM has been reported to inhibit CYP3A4. The final model indicates that HF patients with HC show reduced clearance of theophylline depending on the severity of HF. In this study, no effects of PC were observed.