Pharmacokinetic model analysis of interaction between phenytoin and capecitabine

Abstract

This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

“…34,35 The study of downregulation of drug-metabolizing enzymes presents a few challenges, some of which include (1) variability in drug response in human hepatocyte experiments partly due to differences in culture conditions; (2) loss of enzymatic activity in hepatocyte cultures over time; (3) lack of positive controls for downregulation; and (4) the facts that observed changes in mRNA may be due to cytotoxicity, and in vitro findings do not always translate into clinical effects. 39 The prolonged change in pharmacokinetics observed in our study is similar to those previously reported in DDIs with warfarin 8,10 and other CYP2C9 substrates, 27,28 and transcriptional changes can take time to disappear. We were unable to find a suitable nonclinical model to study an event that takes this long to manifest.…”

“…Capecitabine coadministration led to increased exposure to celecoxib without major changes in exposure to its major metabolites. Based on (1) our pharmacokinetic findings; (2) reports of increases in drug exposure to the CYP2C9 substrates warfarin, phenytoin, and losartan in the presence of fluoropyrimidines; (3) numerous case reports describing bleeding and/or alteration in coagulation parameters upon coadministration of warfarin and fluoropyrimidines; and (4) the absence of direct CYP2C9 inhibition by 5‐FU, our findings suggest downregulation of CYP2C9 by fluoropyrimidines. Given the widespread use of chemotherapy regimens including a fluoropyrimidine and the fact that several common drugs are CYP2C9 substrates, our work highlights the importance of conducting DDI studies to investigate potential changes in transcriptional regulation along with underlying mechanisms and the potential time course of the interaction for appropriate drug monitoring.…”

“…This is consistent with other pharmacokinetic studies involving fluoropyrimidines and CYP2C9 substrates. For example, a study showed an increase in serum concentrations of phenytoin after initiation of capecitabine therapy that continued throughout the 7‐day rest period between chemotherapy cycles . Physiologically based pharmacokinetic modeling of this interaction predicted that the relative activity of CYP2C9 would progressively decline during coadministration of capecitabine and phenytoin and would not be restored to its baseline levels during the break period.…”

“…For example, a study showed an increase in serum concentrations of phenytoin after initiation of capecitabine therapy that continued throughout the 7-day rest period between chemotherapy cycles. 27 Physiologically based pharmacokinetic modeling of this interaction predicted that the relative activity of CYP2C9 would progressively decline during coadministration of capecitabine and phenytoin and would not be restored to its baseline levels during the break period. These findings are in agreement with our results, as the increases in celecoxib exposure we observed during and after capecitabine treatment suggest that CYP2C9 activity is affected and its recovery rate is slow, a finding explained by the turnover half-life for CYP2C9 activity of 9 days estimated in the aforementioned study.…”

Phenytoin Toxicity During Neoadjuvant Concurrent Capecitabine and Radiation Therapy for Rectal Adenocarcinoma: Case Report of a Drug Interaction

“…Levels should be monitored during and following treatment, especially in response to new neurologic symptoms. Miyazaki and colleagues have published a phenytoin-capecitabine interaction model that can help predict the required phenytoin dose adjustments required to keep levels within the therapeutic range [9].…”