Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults
Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults
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DOI：
10.1016/j.pupt.2009.03.003
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发表时间：
2009-08-01
影响因子：
3.2
通讯作者：
Loutit, J. S.
中科院分区：
文献类型：
--
作者：
Rubino, C. M.;Bhavnani, S. M.;Loutit, J. S.
吡非尼酮是一种正在研究用于治疗特发性肺纤维化的合成小分子。在一项开放标签、单次给药交叉研究中，在健康成人志愿者中研究了吡非尼酮的药代动力学（PK），伴或不伴食物和抗酸剂。通过液相色谱串联质谱法测定血浆和尿液中吡非尼酮及其代谢产物的浓度，并使用加权非线性回归将候选药代动力学模型拟合至血浆数据。通过使用FDA指南确定“等效性”，评价食物和抗酸剂对吡非尼酮暴露的影响。不良事件由研究中心人员记录，并由研究人员根据严重程度和与研究药物的关系进行分类。使用五室线性模型实现最佳拟合，允许直接转化为主要代谢产物（5-羧基-吡非尼酮）。与食物同时给药降低了吡非尼酮的吸收速率，并在较小程度上降低了吡非尼酮的吸收程度。不良事件分析显示吡非尼酮C-max与胃肠道（GI）不良事件风险之间存在相关性，表明食物可降低吡非尼酮相关的某些不良事件风险。吡非尼酮与食物一起给药对总体暴露量有适度影响，但导致峰浓度较低，这可能改善耐受性。(C)2009爱思唯尔有限公司版权所有。
Pirfenidone is a small, synthetic molecule under investigation for treatment of idiopathic pulmonary fibrosis. In an open-label, single-dose crossover study, the pharmacokinetics; (PK) of pirfenidone were investigated with or without food and antacids in healthy adult volunteers. Concentrations of pirfenidone and its metabolites in plasma and urine were determined by liquid chromatography with tandem mass spectrometry, and candidate pharmacokinetic models were fit to plasma data using weighted, non-linear regression. The effect of food and antacids on pirfenidone exposure was evaluated by determining 'equivalence' using FDA guidelines. Adverse events were recorded by site personnel and classified by investigators on the basis of severity and relationship to study drug.Sixteen subjects yielded 64 pharmacokinetic profiles. The best fit was achieved using a five-compartment, linear model with an allowance for direct conversion to the primary metabolite (5-carboxy-pirfenidone). Coadministration with food decreased the rate and, to a lesser degree, the extent of pirfenidone absorption of absorption. Analysis of adverse events revealed a correlation between pirfenidone C-max and the risk of gastrointestinal (GI) adverse events, suggesting that food may reduce the risk of certain adverse events associated with pirfenidone. Administration of pirfenidone with food has a modest effect on overall exposure but results in lower peak concentrations, which may improve tolerability. (C) 2009 Elsevier Ltd. All rights reserved.