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July 18, 2007 — 利用抗癌药与食物之间的交互作用，可以改善目前的治疗选择吗？根据学者于2007年7月16日临床肿瘤学期刊上的发表，新的研究指出，食物会改变药物的吸收及延缓药品分解，这或许可削减药物花费及增加好处。芝加哥大学肿瘤科医师Mark Ratain及Ezra Cohen表示，标靶治疗抗癌药物每月花费数以万计美元，我们应视药物与药物或药物与食物间的交互作用为机会，以降低花费。
在2007年3月美国临床药物治疗学会年会上发表的研究产生新的评论，主要作者为黎巴嫩新罕布希尔Dartmouth Hitchcock医学中心的Nandi Reddy博士，在第一阶段的小型临床试验中发现，lapatinib与食物并服取代原先标示的空腹使用，增加相对的生体可用率。
Lapatinib (Tykerb, GlaxoSmithKline)是口服的双效酪胺酸磷酸酶抑制剂，它与capecitabine并用可治疗乳癌末期，或因HER2过度表现而曾接受anthracycline及trastuzumab治疗之转移性乳癌患者。
Ratain博士在新闻稿中指出，只要简单的改变给药时间－随餐服用取代空腹投予，我们就可以只用40%，甚至更少的药量，使每位病患从原本每月2,900美金的支出，省下1,740元或是更多。
【食物与饮料影响药物的生体可用率】
作者提出，在lapatinib的仿单也写到，食物搭配一杯葡萄柚汁可能会增加药物血中浓度，可增加药物身体存量至80%，而食物与果汁的花费较低；Ratain博士表示，我们预期250毫克的lapatinib随餐同时以以葡萄柚汁吞咽，可产生相当于空腹时投予5颗药片的药效。
葡萄柚汁影响口服的生体可用率可能与邻酮类有关，作者正在做第一阶段葡萄柚汁与口服sirolimus（Rapamune，惠氏药厂）的前瞻性临床试验；作者建议数十种，未上百种药物皆应进行试验。Cohen博士表示，假如我们了解葡萄柚汁与常见药物之间的关系，例如statins类药物，有数百万人用来预防心脏病，我们可以省下一笔费用，而且病患还能取得一些维他命C。
作者注意到，食物通常会增加药物的生体可用率，这个结果并不令人意外，但是为什么lapatinib仿单与病患用药资讯会指出药物至少在饭前1小时或饭后1小时服用呢？这个答案非常的明显。赞助者正在进行重要的第3阶段临床试验，研究员似乎不知道食物影响此试验的结果。
因此，官方的建议剂量必须与试验相吻合，应在空腹时投予5颗（每颗250 mg）的剂量。
作者指出建议剂量上更有问题的地方，在于与capecitabine并用，其投予方式是一天两次、需与食物并服、且有自己的剂量争议；他们观察到，相较于要病患一套空腹吃，一套随餐吃的复杂处理方式，一次投予所有药量且与食物并服似乎较为简单。
作者附加提到，让lapatinib与食物并服的潜在好处在于使用较低剂量；腹泻是lapatinib 的主要副作用，可能在于无法吸收药物，其投予频次最好以药物血中浓度为依据；与食物并服而使用较低剂量可减少未被吸收之药量，理论上能减少腹泻的频次与严重度。
最后，Ratain 及 Cohen博士表示，药物昂贵的价格会提供研究药理学方式以降低药物花费的动机。
Cut Cancer Drug Costs By Exploring Food Interactions
By Allison Gandey
Medscape Medical News
July 18, 2007 — Could interactions between cancer drugs and food represent a novel approach to improving available treatment options? New studies exploring how certain foods alter absorption or delay the breakdown of drugs may have an interesting flip side — they may eventually cut medication costs and increase benefits, explain researchers in an article published online July 16, 2007 in the Journal of Clinical Oncology. "As we enter an era of targeted anticancer agents with a monthly cost measured in thousands of dollars," University of Chicago oncologists Mark Ratain, MD, and Ezra Cohen, MD, write, "we should view drug-drug or drug-food interactions as opportunities to lower costs."
The new commentary was inspired by a study presented in March at the 2007 annual meeting of the American Society for Clinical Pharmacology and Therapeutics. In the small phase 1 study, lead author Nandi Reddy, MD, from Dartmouth Hitchcock Medical Center, in Lebanon, New Hampshire, showed that taking lapatinib with food, instead of on an empty stomach as suggested by the product label, increases the relative bioavailability.
Lapatinib (Tykerb, GlaxoSmithKline) is an oral dual tyrosine kinase inhibitor. It is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab.
"Simply by changing the timing — taking this medication with a meal instead of on an empty stomach — we could potentially use 40% or even less of the drug," Dr. Ratain said in a news release. "Since lapatinib costs about $2900 a month, this could save each patient $1740 or more a month."
Food and Beverages Affect Drug Bioavailability
Adding a glass of grapefruit juice to a meal, which may also increase plasma concentrations, according to the lapatinib package insert, could increase the savings to 80%, the authors suggest, minus the cost of food and juice. "We expect that a 250-mg lapatinib pill accompanied by food and washed down with a glass of grapefruit juice may yield plasma concentrations comparable to 5 pills on an empty stomach," Dr. Ratain said.
The effect of grapefruit juice on oral bioavailability may be due in part to furanocoumarins. The authors are currently conducting a prospective phase 1 trial of the combination of grapefruit juice and oral sirolimus (Rapamune, Wyeth). Dozens, if not hundreds, of drugs should be studied in this way, the authors suggest. "If we understood the relationship between, say, grapefruit juice and common drugs, such as the statins, which are taken daily by millions of people to prevent heart disease, we could save a fortune in drug costs," Dr. Cohen said in a news release. "And patients would get a little vitamin C to boot."
These results are not surprising given that food often increases a drug’s bioavailability, the authors note. So why does the lapatinib package insert, including the patient information, indicate that lapatinib should be taken at least 1 hour before or at least 1 hour after food? "The answer is fairly straightforward," they write. "This is how the sponsor conducted its pivotal phase 3 trial." Investigators apparently did not know the result of the food effect study. Therefore, the officially recommended dose must match the dose used in the trial, which was 5 tablets (250 mg each) taken while fasting.
The authors point out the recommendation is even more problematic in light of the required colabeling with capecitabine, which is administered twice daily with food and has its own dosing issues. "Obviously, it would be much easier for patients to take all of their pills at 1 time with food, as opposed to having to deal with the complexity of taking one set of pills fasting and one set of pills with food," they note.
There would also be potential clinical benefit to using a lower dose of lapatinib with food, the authors add. Diarrhea is a major adverse effect of lapatinib, and it is suggested that this effect is due to unabsorbed drug, given that its frequency is better correlated with dose than with plasma concentration. Using a lower dose with food would markedly reduce the amount of unabsorbed drug and therefore theoretically also reduce the frequency and severity of diarrhea.
Drs. Ratain and Cohen conclude, "The rapidly escalating price of medications has provided incentives to explore pharmacological approaches to lower the costs of drugs."
J Clin Oncol. 2007. Published online July 16, 2007.