Xuerong Yang, Jingxia Wei, Yong Yang, Yuanyuan He, Lu Guo, Xing He, Lijuan Zhang, Lu Chen
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Additional information related to drug associations was collected to screen factors affecting drug metabolism.</p><p><strong>Results: </strong>The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL-1 and the area under the receiver operating characteristic curve was 0.701 (P = 0.024). The pirfenidone concentration-to-dose ratio (C/D) in CYP1A2*1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL-1; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039). The C/D value of the combined lansoprazole/rabeprazole group was lower than that of the noncombination group (P < 0.05).</p><p><strong>Conclusions: </strong>The ADR incidence was positively correlated with pirfenidone blood concentration. The CYP1A2 (rs762551) AA genotype is associated with lower pirfenidone concentrations and fewer ADRs. Lansoprazole/rabeprazole co-administration reduced pirfenidone concentrations. 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To provide a basis for the precise clinical use of pirfenidone, the authors analyzed the correlation between steady-state pirfenidone trough concentration and adverse drug reactions (ADRs) and examined the impact of CYP1A2*1C (rs2069514) and *1F (rs762551) variants and co-administration on pirfenidone blood concentrations and ADRs.</p><p><strong>Methods: </strong>Forty-four patients were enrolled. The blood concentration of pirfenidone was determined using high-performance liquid chromatography. CYP1A2*1C and *1F genotypes were determined using direct SNP sequencing. Additional information related to drug associations was collected to screen factors affecting drug metabolism.</p><p><strong>Results: </strong>The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL-1 and the area under the receiver operating characteristic curve was 0.701 (P = 0.024). The pirfenidone concentration-to-dose ratio (C/D) in CYP1A2*1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL-1; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039). The C/D value of the combined lansoprazole/rabeprazole group was lower than that of the noncombination group (P < 0.05).</p><p><strong>Conclusions: </strong>The ADR incidence was positively correlated with pirfenidone blood concentration. The CYP1A2 (rs762551) AA genotype is associated with lower pirfenidone concentrations and fewer ADRs. Lansoprazole/rabeprazole co-administration reduced pirfenidone concentrations. 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引用次数: 0
摘要
背景：代谢酶的突变和联合用药可能会影响对肺纤维化有效的吡非尼酮的血药浓度。为了给临床精确使用吡非尼酮提供依据，作者分析了稳态吡非尼酮谷浓度与药物不良反应（ADRs）之间的相关性，并研究了 CYP1A2*1C (rs2069514) 和 *1F (rs762551) 变异以及联合用药对吡非尼酮血药浓度和 ADRs 的影响：方法：共招募了 44 例患者。采用高效液相色谱法测定吡非尼酮的血药浓度。采用直接 SNP 测序法测定 CYP1A2*1C 和 *1F 基因型。还收集了与药物相关的其他信息，以筛选影响药物代谢的因素：当吡非尼酮的稳态谷浓度为 3.18 mcg-mL-1 时，ADR 的预测值最高，接收者操作特征曲线下面积为 0.701（P = 0.024）。CYP1A2*1F同源AA突变体的吡非尼酮浓度剂量比（C/D）低于C携带者（CC+AC）（1.28 ± 0.85 vs. 2.03 ± 1.28 mcg-mL-1；P = 0.036）。同基因 AA 突变体组的药物不良反应（ADR）发生率（28.0%）明显低于 C 基因携带者（CC+AC）（63.2%；P = 0.020），而 A 基因携带者（AC+AA）的药物不良反应发生率大大低于 CC 组（85.7%；P = 0.039）。兰索拉唑/拉贝拉唑联合用药组的 C/D 值低于非联合用药组（P < 0.05）：ADR发生率与吡非尼酮血药浓度呈正相关。CYP1A2（rs762551）AA 基因型与较低的吡非尼酮浓度和较少的 ADR 相关。兰索拉唑/拉贝拉唑联合用药可降低吡非尼酮浓度。随机对照试验应进一步探索吡非尼酮的个性化剂量和联合疗法。
CYP1A2 Polymorphism and Drug Co-administration Affect the Blood Levels and Adverse Effects of Pirfenidone.
Background: Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for the precise clinical use of pirfenidone, the authors analyzed the correlation between steady-state pirfenidone trough concentration and adverse drug reactions (ADRs) and examined the impact of CYP1A2*1C (rs2069514) and *1F (rs762551) variants and co-administration on pirfenidone blood concentrations and ADRs.
Methods: Forty-four patients were enrolled. The blood concentration of pirfenidone was determined using high-performance liquid chromatography. CYP1A2*1C and *1F genotypes were determined using direct SNP sequencing. Additional information related to drug associations was collected to screen factors affecting drug metabolism.
Results: The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL-1 and the area under the receiver operating characteristic curve was 0.701 (P = 0.024). The pirfenidone concentration-to-dose ratio (C/D) in CYP1A2*1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL-1; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039). The C/D value of the combined lansoprazole/rabeprazole group was lower than that of the noncombination group (P < 0.05).
Conclusions: The ADR incidence was positively correlated with pirfenidone blood concentration. The CYP1A2 (rs762551) AA genotype is associated with lower pirfenidone concentrations and fewer ADRs. Lansoprazole/rabeprazole co-administration reduced pirfenidone concentrations. Randomized controlled trials should further explore personalized dosing of pirfenidone and combination therapies.
期刊介绍：
Therapeutic Drug Monitoring is a peer-reviewed, multidisciplinary journal directed to an audience of pharmacologists, clinical chemists, laboratorians, pharmacists, drug researchers and toxicologists. It fosters the exchange of knowledge among the various disciplines–clinical pharmacology, pathology, toxicology, analytical chemistry–that share a common interest in Therapeutic Drug Monitoring. The journal presents studies detailing the various factors that affect the rate and extent drugs are absorbed, metabolized, and excreted. Regular features include review articles on specific classes of drugs, original articles, case reports, technical notes, and continuing education articles.
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