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医药导报, 2019, 38(6): 796-799
doi: 10.3870/j.issn.1004-0781.2019.06.025
食物对小分子靶向药物生物利用度的影响
赵德华1,, 楚明明2, 陈静1, 贾霖1, 韩建军1, 何霞1, 龙小庆1, 王继生1,

摘要:

目的 探讨食物对小分子靶向药物体内生物利用度的影响。 方法 检索并整理食物影响小分子靶向药物生物利用度的相关文献,检索Pubmed、EMbase、Cochrane Library、中国知网、维普数据库、万方数据库。结果 食物可影响一部分小分子靶向药物的生物利用度,受到影响较为显著且具有临床意义的药物主要包括厄洛替尼、埃克替尼、拉帕替尼、尼洛替尼、凡德他尼、阿法替尼、依维莫司、索拉非尼、瑞戈非尼、色瑞替尼以及帕唑替尼 。结论 应重视食物与小分子靶向药物之间的相互作用,选择合理的服药时间,以避免增加药物不良反应或降低药物疗效。

关键词: 食物 ; 小分子靶向药物 ; 生物利用度 ; 药物不良反应

Abstract:

小分子靶向药物多为酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI),与传统化疗药物比较,具有疗效确切、毒副反应小及使用方便等优点,已经成肿瘤内科治疗的重要手段之一。目前,已有多种小分子靶向药物成功应用于临床[1],该类药物显示出显著的疗效和良好的耐受性,提高肿瘤患者的无疾病进展生存期(progression free survival,PFS)和总生存期(overall survival,OS)。由于小分子靶向药物多为口服制剂,而口服制剂的生物利用度容易受到食物的影响[2,3],为探讨食物与小分子靶向药物生物利用度之间的关系,笔者对相关文献进行检索并整理,以期为临床用药提供参考,促进合理用药。

1 小分子靶向药物分类

按照作用信号通路,可将小分子靶向药物分为7类[1,4]:①EGFR-TKI通路,相关药物有埃克替尼、吉非替尼、厄洛替尼、奥希替尼;②ALK-TKI通路,相关药物有克唑替尼、色瑞替尼;③VEGFR-TKI通路,相关药物有阿昔替尼、阿帕替尼;④EGFR/ HER2-TKI通路,相关药物有拉帕替尼、阿法替尼、达克替尼;⑤BCR- ABL-TKI通路,相关药物有伊马替尼、 达沙替尼、尼洛替尼;⑥mTOR激酶抑制剂,如依维莫司;⑦多靶点(VEGFR,PDGFR,FLT3)TKI,相关药物有索拉非尼、舒尼替尼、凡德他尼、瑞戈非尼、乐伐替尼、帕唑替尼。

2 食物与小分子靶向药物之间的相互作用关系

食物可通过影响胃肠血流、胃排空、肠蠕动、胃肠 pH值以及P-蛋白来影响小分子靶向药物的吸收,进而影响药物的口服生物利用度。然而影响程度却不尽相同,部分药物受到影响较小,或受到一定的影响却无临床意义,而另一部分药物受到的影响较为显著,且具有临床意义。

2.1 食物影响较少或无临床意义的小分子靶向药物

2.1.1 达沙替尼 食物可提高达沙替尼的口服生物利用度,一项来自于健康受试者的研究结果表明[5,6],在服用达沙替尼前30 min食用高脂饮食,达沙替尼的血药浓度-时间曲线下面积(AUC)可增加14%,而低脂饮食可使达沙替尼的AUC增加21%,虽然食物可增加达沙替尼的生物利用度,但却对其临床疗效和毒副反应无影响,即无临床意义,故服用达沙替尼时可不用考虑进餐的影响,即空腹服用或与食物同用均可。

2.1.2 伊马替尼 高脂饮食可轻微降低伊马替尼的吸收,使药物的AUC和血药浓度峰值(Cmax)分别降低7.4%和11%,但差异无统计学意义(P>0.05),提示伊马替尼的服用时间不受进餐影响[7,8]

2.1.3 吉非替尼 健康人体试验结果表明,食物可影响吉非替尼的吸收与生物利用度[9],与食物同服,吉非替尼的AUC和Cmax分别增加32%和37%,但其临床疗效与毒副反应却未受到影响,即无临床意义。因此,吉非替尼的服用时间不受进餐影响。

2.1.4 奥希替尼 高脂饮食可增加奥希替尼的生物利用度[10],与食物同服,奥希替尼的AUC和Cmax分别增加19%和14%,但却无临床意义,提示奥希替尼的服用时间不受进餐影响。

2.1.5 克唑替尼 相关文献报道[11]高脂肪食可使克唑替尼的AUC和Cmax 均降低约14%,但对临床疗效却无影响,提示服用克唑替尼时,可不考虑进餐因素,即空腹服用或与食物同服均可。

2.1.6 阿昔替尼 食物可影响阿昔替尼的生物利用度[12],但不同热量的食物,其影响程度也不同,如中度脂肪饮食可使其AUC降低10%,而高脂肪饮食可使其AUC增加19%,但两者均对阿昔替尼的临床疗效和毒副反应无显著影响,提示阿昔替尼的服用时间不受进餐影响。

2.1.7 阿帕替尼 相关研究在转移性实体瘤患者中考察食物对阿帕替尼吸收的影响[13],结果表明,食物对阿帕替尼的生物利用度影响不显著,差异无统计学意义,提示阿帕替尼的服用时间不受进餐影响。

2.1.8 舒尼替尼 食物可影响舒尼替尼的Cmax,但不影响其AUC,一项以健康受试者为研究对象的Ⅰ期临床试验结果表明,食物可使舒尼替尼的Cmax降低23%,但其AUC变化不明显[14],提示舒尼替尼的服用时间不受进餐影响。

2.1.9 乐伐替尼 食物对乐伐替尼生物利用度的影响较小,高脂食物可使乐伐替尼的AUC增加6%,使Cmax下降5%,但影响均无临床意义[15],提示乐伐替尼的服用时间不受进餐影响。

2.1.10 达克替尼 一项来自健康受试者的临床研究表明[16],食物可增加达克替尼的生物利用度,使AUC和Cmax分别增加14%和24%,但这种影响无临床意义,提示达克替尼可以空腹服用也可以与食物同服。

2.2 食物影响具有临床意义的小分子靶向药物

2.2.1 尼洛替尼 食物可增加尼洛替尼的口服生物利用度,与空腹相比,低脂饮食后2 h服用尼洛替尼,则尼洛替尼的AUC和Cmax分别增加15%和33%,而餐后30 min服药,则尼洛替尼的AUC和Cmax分别增加29%和55%[17];而高脂饮食后30 min服药,则尼洛替尼的AUC和Cmax分别增加82%和112%[17]。但随着尼洛替尼生物利用度的增加,其毒副反应如皮疹、腹泻以及肺毒性等的发生率和严重程度也随之增加。故为避免增加药物的毒副反应,应在餐前1 h或餐后2 h服用尼洛替尼。

2.2.2 厄洛替尼 相关研究表明[16],食物可增加厄洛替尼的生物利用度,可使其AUC和Cmax分别增加40%和34%,但其毒副反应也随之增加。故为了用药安全性,推荐在餐前1 h或餐后2 h服用厄洛替尼[18,19]

2.2.3 埃克替尼 高能量食物能显著影响埃克替尼的吸收,可使其AUC和Cmax分别增加79%和59%。此外,食物还影响埃克替尼的表观分布容积和血浆清除率,空腹服药和餐后服药,其平均分布容积分别为355和113 L,而血浆清除率分别为46和22 L·h-1[20]。为避免食物对埃克替尼的药动学造成的影响,应避免将埃克替尼与食物同服。

2.2.4 凡德他尼 食物可降低凡德他尼的生物利用度,高脂肪饮食可使凡德他尼AUC和Cmax分别降低10%和17%,提示应避免将凡德他尼与食物同用[21]

2.2.5 拉帕替尼 食物可增加拉帕替尼的生物利用度[22],低脂饮食(5%脂肪,约2095 J)和高脂饮食(50%脂肪,约4190 J)分别使拉帕替尼的AUC增加3和4倍;Cmax增加2.5和3倍[23]。随着暴露量的增加,其不良反应的发生率和严重程度也显著增加,如皮疹和腹泻[20,21]。故为避免出现严重毒副反应,应避免将拉帕替尼与食物同服,适宜给药时间应为餐前1 h[23]

2.2.6 阿法替尼 食物可降低阿法替尼的生物利用度,与高脂肪食物同服,阿法替尼的AUC和Cmax分别降低39%和51%[24],提示应避免将阿法替尼与食物同服,适宜的服用时间应为餐前1 h或餐后2 h[24]

2.2.7 依维莫司 食物可降低依维莫司的暴露量,根据一项健康受试者的研究表明,高脂肪饮食可使依维莫司的AUC和Cmax分别降低22%和54%;而低脂肪饮食可使依维莫司的AUC和Cmax分别降低32%和42%[25]。为避免降低药物疗效,故推荐依维莫司宜在餐前1 h或餐后2 h服用,不宜与食物同服。

2.2.8 索拉非尼 食物可降低索拉非尼的生物利用度[26],高脂肪饮食(50%脂肪,约3771 J)可使索拉非尼的AUC和Cmax分别降低29%和38%,而中度脂肪饮食(30%脂肪,约2933 J)可使索拉非尼的AUC和Cmax分别降低14%和17%。为避免降低药物疗效,故推荐索拉非尼的服用时间应在餐前1 h或餐后2 h[26,27]

2.2.9 瑞戈非尼 不同热量的食物对瑞戈非尼的生物利用度有着不同的影响,高脂饮食可使瑞戈非尼的AUC增加48%,但同时也可降低其代谢产物(M-2,M-5)的AUC,分别降低20%和51%;而低脂饮食可使瑞戈非尼、M-2和M-3的AUC分别增加36%,40%和23%,同时未观察到显著的毒副反应[28],故推荐将瑞戈非尼与低脂饮食同时服用。

2.2.10 色瑞替尼 食物对色瑞替尼的生物利用度有显著影响[29],且不同食物的影响也不同,高脂饮食可使色瑞替尼的AUC和Cmax分别增加58%和43%;低脂饮食可使色瑞替尼的AUC和Cmax分别增加73%和41%;零食可使色瑞替尼的AUC和Cmax分别增加54%和45%,而随着生物利用度的增加,色瑞替尼的毒副反应也随之增加,如丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)显著上升。故推荐应在空腹服用色瑞替尼。

2.2.11 帕唑替尼 食物对帕唑替尼的生物利用度影响较为明显[30],药动学研究表明食物可使帕唑替尼的AUC和Cmax均增加200%[31],故推荐应将帕唑替尼与食物相间隔服用,即餐前1 h或餐后2 h。

3 结束语

由上述的临床研究可知,食物可影响一部分小分子靶向药物的生物利用度,具体表现为增加或降低其AUC和Cmax,其中受到影响较为显著且具有临床意义的药物主要包括厄洛替尼、埃克替尼、拉帕替尼、尼洛替尼、凡德他尼、阿法替尼、依维莫司、索拉非尼、瑞戈非尼、色瑞替尼以及帕唑替尼。当药物的生物利用度增加时,其毒副反应的发生率和严重程度也可能随之增加;当药物的生物利用度降低时,则其疗效可能会下降,故在服用上述小分子靶向药物时,应注意服用时间,以避免降低药物疗效或增加药物毒副反应。

The authors have declared that no competing interests exist.

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Abstract PURPOSE: Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy. PATIENTS AND METHODS: Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state. RESULTS: Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non-small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting > or = 6 months. CONCLUSION: Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.
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关键词(key words)
食物
小分子靶向药物
生物利用度
药物不良反应


作者
赵德华
楚明明
陈静
贾霖
韩建军
何霞
龙小庆
王继生