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。
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。
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。
2.1.1 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(
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
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
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
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
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
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
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
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
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
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
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;
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
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
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
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
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
The authors have declared that no competing interests exist.
[1] |
|
[2] |
目的:了解靶向抗肿瘤药物的药动学相互作用研究进展。方法:查阅近年来国内外相关文献,对靶向抗肿瘤药物酪氨酸激酶抑制剂(TKI)和哺乳动物雷帕霉素靶蛋白(m TOR)抑制剂与其他药物的药动学相互作用进行归纳和总结。结果:吉非替尼、厄洛替尼、拉帕替尼、索拉非尼、舒尼替尼、伊马替尼等TKI和坦西莫司、依维莫司等m TOR抑制剂,吸收均较迅速,血浆蛋白结合率较高,主要由细胞色素P450(CYP)3A4参与代谢,药物受CYP3A4抑制剂或诱导剂影响明显(索拉菲尼除外),均为外排转运体P-糖蛋白和乳腺癌耐药蛋白的底物(坦西莫司除外)。为抵抗胃食管反流疾病,吉非替尼、厄洛替尼常与酸抑制剂联用。拉帕替尼、舒尼替尼与药物联用产生的肝毒性可能与药物代谢活化生成活性中间体而与生物大分子结合有关。结论:靶向抗肿瘤药物药动学及药物相互作用的研究已成为抗肿瘤药物治疗过程的重要研究课题,可为临床合理使用靶向抗肿瘤药物提供参考,更可为抗肿瘤药物治疗提供新的研究方向。
[本文引用:1]
|
[3] |
|
[4] |
|
[5] |
The 4-anilinoquinazolines (gefitinib, erlotinib and lapatinib) are members of a class of potent and selective inhibitors of the human epidermal growth factor receptor (HER) family of tyrosine kinases...
[本文引用:1]
|
[6] |
|
[7] |
|
[8] |
|
[9] |
|
[10] |
|
[11] |
|
[12] |
DOI:10.1002/psp4.v6.6
URL
[本文引用:1]
|
[13] |
|
[14] |
|
[15] |
DOI:10.5414/CP201937
URL
[本文引用:1]
|
[16] |
|
[17] |
Abstract The objectives of this study were to determine (1) the accuracy with which individual patient level exposure can be determined and (2) whether a known food effect can be identified in a trial simulation of a typical population pharmacokinetic trial. Clinical trial simulations were undertaken using NONMEM VII to assess a typical oncology pharmacokinetic trial design. Nine virtual trials for each compound were performed for combinations of different levels of between-occasion variability, number of patients in the trial, and magnitude of a food covariate on oral clearance. Less than 5% and 20% bias and precision were obtained in individual clearance estimated for both abiraterone and nilotinib using this design. This design resulted in biased and imprecise population clearance estimates for abiraterone. The between-occasion variability in most trials was captured with less than 30% of percent bias and precision. The food effect was detectable as a statistically significant covariate on oral clearance for abiraterone and nilotinib with percent bias and precision of the food covariate less than 20%. These results demonstrate that clinical trial simulation can be used to explore the ability of specific trial designs to evaluate the power to identify individual and population level exposures, covariate, and variability effects.
[本文引用:2]
|
[18] |
|
[19] |
|
[20] |
|
[21] |
|
[22] |
|
[23] |
|
[24] |
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.
[本文引用:2]
|
[25] |
|
[26] |
|
[27] |
|
[28] |
|
[29] |
DOI:10.1002/jcph.619
URL
[本文引用:1]
|
[30] |
Intake of oral targeted anticancer agents with food or acid-reducing agents can majorly affect drug absorption and thereby potentially treatment benefit or the severity of toxicities.
[本文引用:1]
|
[31] |
|