Reduced theophylline clearance due to hepatic congestion secondary to right heart failure - A population pharmacokinetic study. (December 2021)

• Record Type: Journal Article
• Authors: Kurata, Yasuo; Muraki, Shota; Hirota, Takeshi; Araki, Hiroshi; Ieiri, Ichiro
• Is Part Of: Drug metabolism and pharmacokinetics. Volume 41(2021)
• Publication Date: 2021-12
• Subjects: Population pharmacokinetics -- Theophylline clearance -- Heart failure -- Hepatic congestion -- New York heart association functional classification; Drugs -- Metabolism -- Periodicals; Pharmacokinetics -- Periodicals; 615.7
• DOI: 10.1016/j.dmpk.2021.100403
• Languages: English
• ISSNs: 1347-4367

Abstract

Abstract: 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 × 1.40 SMK × 0.870 CAM × 0.863 HC(+)NYHA II × 0.634 HC(+)NYHA III × 0.586 HC(−)NYHA IV × 0.467 HC(+)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.