当前位置： SCI文献检索 > EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY期刊下所有文献 > Utilizing physiologically based pharmacokinetic modeling to predict theoretically conceivable extreme elevation of serum flecainide concentration in an anuric hemodialysis patient with cirrhosis.

Utilizing physiologically based pharmacokinetic modeling to predict theoretically conceivable extreme elevation of serum flecainide concentration in an anuric hemodialysis patient with cirrhosis.

Abstract：

PURPOSE:Higher drug concentrations in complex clinical scenarios in which multiple factors such as drug-drug interactions (DDIs) and comorbidities are simultaneously present are not necessarily rationalized in prospective clinical studies. Physiologically based pharmacokinetic (PBPK) modeling and simulation of the anti-arrhythmic drug flecainide, as an example, were utilized to quantitatively rationalize the higher flecainide concentration in a complex clinical case involving end-stage renal disease (ESRD), cirrhosis, and the co-administration of mexiletine, a CYP1A2 inhibitor. METHODS:The developed flecainide PBPK model was used to evaluate the DDI effect (as measured by AUC ratio before and after inhibition) of mexiletine and the combined disease effects of ESRD and cirrhosis on flecainide exposure. RESULTS:The predicted DDI effect of mexiletine was negligible or weak in anuric hemodialysis with cirrhosis population (mean [5th/95th percentiles], 1.23 [0.97-1.67]), although it was negligible in healthy volunteers (1.03 [1.02-1.05]). The predicted flecainide concentrations after multiple flecainide doses (50 mg BID) in the anuric hemodialysis with cirrhosis population were comparable with the observed value (3602 ng/mL), which fell between the predicted concentrations in the absence and presence of mexiletine (3043 [718-8499] and 5914 [880-20,624] ng/mL, respectively). CONCLUSIONS:The PBPK simulation proposed a likely explanation that the observed higher flecainide concentration could be attributed to the combined effects of ESRD, cirrhosis, and a potential DDI with mexiletine. This approach provides quantitative insight into theoretically conceivable extremes in drug exposure occurring in complex clinical situations even if uncommon.

journal_name

Eur J Clin Pharmacol

journal_title

European journal of clinical pharmacology

authors

Doki K,Kuga K,Aonuma K,Ieda M,Homma M

doi

10.1007/s00228-020-02861-9

subject

Has Abstract

pub_date

2020-06-01 00:00:00

pages

821-831

issue

eissn

0031-6970

issn

1432-1041

pii

10.1007/s00228-020-02861-9

journal_volume

pub_type

杂志文章

在线工具

Utilizing physiologically based pharmacokinetic modeling to predict theoretically conceivable extreme elevation of serum flecainide concentration in an anuric hemodialysis patient with cirrhosis.