The Value Meal: How to Save $1,700 Per Month or More on Lapatinib (2007)

Drug labels (ie, package inserts) must be approved by national regulatory agencies (eg, US Food and Drug Administration), and are the product of a negotiation between the drug’s sponsor and the regulators. Labels are intended to provide important information for prescribers, pharmacists, and patients regarding the drug’s indication(s) and toxicities, but also include information regarding the drug’s pharmacokinetics, which may not be of interest to most prescribers. However, the label for lapatinib (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 Therapeutics—is that the bioavailability of lapatinib is greatly increased by food, especially a high-fat meal. A randomized, crossover, 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. 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 trial—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 recommendation for 1,250 mg fasting is even more problematic in light of the required colabeling with capecitabine, which is administered bid (approximately 12 hours apart) with food and has its own independent dosing issues. Obviously, it would be much easier for patients to take all of their pills at one 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. The economic implications of this food effect study are particularly remarkable. At the current price of $2,900 per month, a cost savings of 60% or $1,740 per month would be realized if the drug were taken with food. If one were so inclined, there are also opportunities for additional cost savings through dietary modification. The package insert notes that strong CYP3A inhibitors, including grapefruit juice, “may also increase plasma concentrations.” Thus, it is possible that one 250-mg lapatinib pill, accompanied by food and washed down with a glass of grapefruit juice, may yield plasma concentrations comparable to five 250-mg pills on an empty stomach, which would result in a total cost savings of 80% (minus the cost of the food and juice). As a separate issue, the lapatinib label also notes that dividing the daily dose results in a doubling of drug exposure, which would be another approach that may allow a reduction in the number of daily pills (and costs). There would also be potential clinical benefit to using a lower dose of lapatinib with food. Diarrhea is a major toxicity 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. Thus, using a lower dose with food would markedly reduce the amount of unabsorbed drug, and therefore theoretically also reduce the frequency and/or severity of diarrhea. The use of a lower dose with food would also mitigate the potential risk of standard doses of lapatinib with food, which could increase the risk of toxicity. In recent years, there has been an increased enthusiasm for development of oral agents, which is based on both clinical and economic motivations. This includes both completely new agents and analogs of existing parenteral agents, such as capecitabine. The development of oral agents requires a much greater knowledge of a drug’s clinical pharmacology than with parenteral development, because of the multitude of factors that can affect bioavailability (eg, food, dose, and concomitant oral medications). Furthermore, the rapidly escalating price of medications (especially for cancer and other life-threatening diseases) has provided incentives to explore pharmacologic approaches to lower the costs of drugs. Thus, ketoconazole has been combined with cyclosporine, tacrolimus, and sirolimus to decrease the cost of transplant rejection prophylaxis. Grapefruit juice also has the potential to be used to lower drug costs by increasing oral bioavailability, due to the effects of furanocoumarins. In fact, we currently are conducting a prospective phase I trial of the combination of oral sirolimus (rapamycin) and grapefruit juice, with the intention of developing the least expensive approach possible to inhibit the mammalian target of rapamycin. Therefore, as we enter an era of targeted anticancer agents with a monthly cost measured in thousands of dollars, we should JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 25 NUMBER 23 AUGUST 1