The Value Meal

I'm sure I'm not just imagining it, that these threads are seeing an influx of younger, intelligent and vociferous newcomers - you know who you are :-) Quite a few here are given to doing a spot or two of research and we can constitute a significant lobby if we all keep asking the medical authorities the right questions and pressing for the most rapid progress possible in the advancement of knowledge and treatment in this field. Accordingly, for the more academically inclined members here, I'd like to raise a topic of huge prospective value for us all.

The witty name of a recent article on drug administration and food (in the Journal of Clinical Oncology in 2007) is

"The Value Meal: How to Save $1,700 Per Month or More on Lapatinib" by Mark J. Ratain and Ezra E. Cohen.

Now, Lapatinib is a drug used primarily for breast cancer but there is a principle involved here which obviously has a much wider application. The simple point is that the instructions for taking that drug are that it should be in a semi-fasting condition - i.e. not within an hour or so either side of a meal but it is known that the drug is vastly more effective when taken with (esp. high-fat) food.

This is well-explained in the following passage:

"However, the label for lapatinib1 (approved by the US Food and Drug Administration on March 13, 2007) includes a number of pharmacokinetic details of high interest to both prescribers and patients. A most notable finding—also presented at the 2007 meeting of the American Society for Clinical Pharmacology and Therapeutics2—is that the bioavailability of lapatinib is greatly increased by food, especially a high-fat meal. A randomized, cross-over, food-effect study demonstrated that both peak concentration and area under the concentration–time curve were increased markedly when a single 1,500-mg dose of lapatinib was taken with food as opposed to when fasting, and was increased further by a high-fat meal. The (geometric) mean increase for the area under the concentration–time curve was 167% for low-fat meals and 325% for high-fat meals. These results are not surprising, given that food often increases a drug's bioavailability.3,4

So why does the lapatinib package insert, including the patient information, indicate, “TYKERB should be taken at least one hour before, or at least one hour after, food”? The answer is fairly straightforward: this is how the sponsor conducted its pivotal phase III trial5—the sponsor apparently did not know the result of the food effect study. Thus, the officially recommended dose must match the dose used in the pivotal trial, which was five 250-mg tablets taken fasting."

The ramifications of this are pretty obvious and late in the article we have the following insightful commentary:

"So where do we go from here? The one thing that should not be anticipated is an efficacy study conducted by the sponsor of lapatinib (GlaxoSmithKline, Philadelphia, PA) comparing two 250-mg tablets with food to five 250-mg tablets fasting. However, such a study could be mounted by a number of other entities, including the federal government, other payors, or advocacy groups. Alternatively, physicians could simply extrapolate from the existing pharmacokinetic and clinical data and prescribe 500 mg (two 250-mg tablets) daily with food, at 40% of the current cost for the drug.

It is important, however, to emphasize that we strongly recommend study of a lower dose with food, rather than routine prescribing without a formal pharmacokinetic study. Given that lapatinib may have nonlinear pharmacokinetics (as illustrated by the equivocal relationship between dose and exposure,8 and higher exposure with divided doses), the magnitude of the effect of food at a lower dose may differ from that observed at 1,500 mg. It is also possible that the degree of interpatient variability (coefficient of variation in oral clearance of 48%)19 may be affected by food, although this was not demonstrated in the food effect study."

My feeling is that the more of us who are aware of such facts, the more chance we have of informed discussion and increasing the accountability of Big Pharma. Of course, we all depend on having a thriving pharmaceutical industry, ever pushing the frontiers of drug R & D and bringing us new life-savers/extenders/improvers. We don't want to kill the goose that we hope will keep laying golden eggs. On the other hand, we want to see drugs available that are not so extortionately priced as to preclude those who desperately need them from being able to afford them.

One problem is that the R & D costs have to be recoverable and they are huge. With too big a disincentive, drugs that could be crucial might wither on the vine if the producers can't make sufficient sales to keep their R & D adequate to fill the pipeline with new, prospective revenue-earning product.

To be fair to Big Pharma, and to produce a balanced view of the issue, I would like to draw attention to a brilliantly written and cogently argued riposte from GSK scientists, explaining the theoretical and practical strictures within which they are constrained to work. I found this of considerable interest and relevance to a better understanding of the nature of this debate. Like "The Value Meal", the letter "In Reply" appears in the Journal of Clinical Oncology and was published online on Dec 10 2008 and contains the following passage outlining some of the problems:

"The letter states that emerging data have contributed to confusion about how to dose lapatinib, and repeats the misinterpretations of Ratain et al5 that administering lapatinib with food would improve bioavailability, reduce toxicity, and lower the cost of treatment by requiring fewer tablets (a lower dose). These assertions ignore data showing that administering lapatinib with food increases variability and does not reduce toxicity.3,6 As for cost savings, drug pricing is not simply determined by the cost of a drug substance, but also by the cost of development, and most importantly, by the value to patients. However, concern about the cost of drugs is not confined to lapatinib, which is not the most expensive agent in this class.

We agree with Ciccarese et al that studies assessing targeted agents should not follow the cytotoxic paradigm equating maximum tolerated dose (MTD) with optimal therapeutic dose (OTD). The OTD should be defined using objective, quantitative measures. However, such measures are often elusive for novel agents, because valid surrogate markers are rarely developed in parallel with the drug. Biomarkers that reflect the biologic or clinical activity of a drug are sometimes available; however, in many cases, they do not exist or are not technically or ethically feasible. Agents with intracellular targets encounter additional barriers. Serial biopsies are difficult for patients to endure, imaging techniques (if applicable) are inconvenient and expensive, and the technical requirements of sample processing and handling are unwelcome additions to the demands on clinic staff involved in patient care. Defining the OTD can then default to demonstrating clinical activity or efficacy later in development, adding expense and risk. The development of lapatinib included several studies that attempted to obtain intracellular phosphorylation biomarkers and circulating human epidermal growth factor receptor 2 extracellular domain, but for a number of reasons, including those cited in this letter, none provided sufficient data to define the OTD. As a result, quantitative dose selection has proved elusive, and emerging data may indeed seem confusing. In this context, pharmacokinetic data alone cannot provide sufficient rationale for dose selection."

The fact remains that the effects of food in general (and some particular foods such as grapefruit especially) on the efficacy of important drugs must be researched more intensively to ensure optimal dose administration and reduction in the cost of the drugs, consonant with permitting Big Pharma to stay in business.