FOOD WITH ORAL CANCER DRUGS?

Are oral oncology drugs being mislabeled? Maybe.
Most oral cancer drugs stipulate that they should be taken in a fasting state, but some actually have better bioavailability when taken with food. This is particularly true for the new prostate cancer drug abiraterone acetate (Zytiga), which has a greater interaction with food than any other marketed drug, yet it is labeled to be taken when fasting.
These points are highlighted in a comment published in the October 20 issue of the Journal of Clinical Oncology by Mark J. Ratain, MD, professor of medicine and director of the Center for Personalized Therapeutics at the University of Chicago, Illinois.
"My major concern is safety," Dr. Ratain told Medscape Medical News. "Very few patients would anticipate that the consequences of taking their medications with food...would be an effective overdose."
In the case of abiraterone acetate, the dose of the drug could be increased 10-fold by eating breakfast half an hour after taking the drug, he writes.
Dr. Ratain notes that food interactions are described in the labeling of many drugs, but are notably absent in the labeling of new oral cancer agents.
Most drugs can be taken either with or without food, he explains, because the effects of food are not clinically significant to drug absorption. There are cases in which absorption is decreased by food; generally, the labeling on those drugs instructs that they be taken on an empty stomach. Similarly, labeling on drugs for which absorption is enhanced by food typically instructs that they be ingested with meals.
"However, a recent study of oral agents approved by the US Food and Drug Administration [FDA] in the last 10 years demonstrated that oral oncology drugs have generally been labeled fasting, despite food effects as large as a 4-fold increase in bioavailability," Dr. Ratain notes.
Bias in Labeling?
This apparent bias for fasting labeling in cancer drugs is exemplified with abiraterone, he notes. Abiraterone, which was approved earlier this year in the United States for the treatment of metastatic prostate cancer, has a greater food interaction than any drug currently on the market. Depending on the fat content, food can increase drug exposure 5- to 10-fold, yet it is labeled to be taken in a fasting state, Dr. Ratain points out.
The effect of a high-fat meal indicates "that absolute bioavailability in the fasting state is no more than 10%," says Dr. Ratain, and is likely due to the low absorption rate under fasting conditions; 77% of the drug is excreted as abiraterone (or its prodrug acetate) in the stool.
"In addition, there is marked interindividual pharmacokinetic variability, with a coefficient of variation in the plasma concentration area under the curve of 59% under labeled conditions," he notes.
It is unclear why this faulty labeling is occurring, or why the FDA has not been more stringent about proper labeling for oral oncology drugs, Dr. Ratain said. He told Medscape Medical Newsthat the FDA has not responded to his inquiries and "essentially stonewalled" him because of the confidentiality of their discussions with sponsors.
"The blame could be assigned to sponsors, the Office of Oncology Drug Products, and/or the Office of Clinical Pharmacology and Biopharmaceutics," he said. "Given that there are multiple sponsors, all of whom who have a different approach to oncology..., the evidence points to an FDA origin."
Oral Drugs Relatively New
Alex Adjei, MD, PhD, who was approached by Medscape Medical News for independent comment, explained that until recently, oncology drugs have generally been given intravenously; for other diseases, oral drugs have been in common use for many years.
Perhaps that is why there has not been that much attention on the food-effect data, Dr. Adjei hypothesized. He is chair of the Department of Medicine at Roswell Park Cancer Institute, in Buffalo, New York.
"In clinical trials, we tend to give the drugs on an empty stomach," he said. "So that was how the drug was tested and that was how it was approved. We don't go back and change the label."
Dr. Adjei pointed out that unlike intravenous drugs, there is considerable variation in the way oral drugs are absorbed. "We try to simplify it by giving them on an empty stomach," he said.
Food-Effect Data Ignored
In a study published last year (Clin Cancer Res. 2010;16:4446-4451), Dr. Ratain and his colleague, Soonmo Peter Kang, MD, also from the University of Chicago, evaluated the effect of food on 99 oral agents that received FDA approval from January 2000 to May 2009. They compared food-labeling patterns between oncology and nononcology drugs using Fisher's exact test.
Food had a significant effect on drug bioavailability in 34 of the 99 drugs evaluated. In cases where food markedly enhanced bioavailability, 8 of 9 nononcology drugs were labeled to be taken with food to take advantage of the food–drug interaction. However, all oncology agents were labeled to be taken in "fasted" states (P = .01).
"The food-labeling pattern of recently approved oral oncology drug products is inconsistent with fundamental principles of oral drug delivery," they write. "The labels of 3 agents (erlotinib, nilotinib, and lapatinib) minimized bioavailability through food restrictions, which is in contrast to the labeling principles used for all other classes of oral agents."
In an editorial that accompanied the study by Drs. Ratain and Kang (Clin Cancer Res. 2010;16:4305-4307), Rajul K. Jain, MD, from the University of Texas M.D. Anderson Cancer Center, Houston, and colleagues explained that the effects of food are complex, and that multiple factors determine final labeling recommendations. "When analyzing the label given to any product or product class, all of the potential influencing factors should be considered," they said.
They also noted that "sponsors are encouraged to conduct food-effect studies early in a product's development so the results can be implemented into larger clinical trials."
In his comment, Dr. Ratain refers back to that editorial, and points out that the agency has "expressed concern about the potential for high intraindividual variability in cancer patients resulting from variability in oral intake secondary to disease or concurrent medications." This appears to indicate a preference for labeling drugs to be used when fasting, even if their bioavailability would be substantially increased when taken with food.
He explains that there isn't any evidence that this concern applies to all oral oncology drugs, and that there is no evidence that intraindividual variability in diet is greater for cancer patients than for those with other life-threatening conditions who also take daily oral drugs.
"If the US Food and Drug Administration were truly concerned about intraindividual variability in diet, why has this never come up in the labeling of nononcology drugs?" he asks.
He notes that the FDA was aware of the food-effect data from early studies of abiraterone and could have required at least 1 randomized study to be conducted to review this, so that it could have been labeled to be taken with food. The FDA has the authority to require such studies as a postmarketing requirement, but chose not to.
With the risk for poor adherence to food-effect labeling, there is a risk for overdose or underdose of a given drug, with the more serious being overdose, Dr. Ratain says.
In addition to this safety issue, there are economic implications, Dr. Ratain notes.
The standard dose of abiraterone for men without liver problems is 1000 mg once daily. But because the bioavailability of the drug is greatly increased when taken with food, it would be interesting to have studies of abiraterone at a dose of 250 mg once daily, administered with a standard breakfast. If this approach is shown to be safe and effective, it could save patients and their payers approximately $3750 per month at current prices.
"It also would send a message to the pharmaceutical industry that flawed drug development has financial consequences," he notes, "along with potential risks of product liability because of defective labeling."
He concludes: "After all, given the high attrition rate for oncology drugs, do we really need to flush our few successful products down the toilet?"
Impracticalities of Dosing and Diet
Lawrence J. Lesko, PhD, FCP, former director of the Office of Clinical Pharmacology at the FDA's Center for Drug Evaluation and Research, and a coauthor of the editorial by Dr. Jain, pointed out that the principal of labeling is consistent safety.
"The most consistent way to take drugs is on an empty stomach," said Dr. Lesko, who is now at the Department of Pharmaceutics at the College of Pharmacy at the University of Florida in Gainesville. "It would be impractical to expect that patients are going to adhere to a specific diet when taking these drugs. And it is often unclear what 'food' may mean to the patient. Is it a glass of juice, breakfast cereal, a cheeseburger?"
The goal is to minimize the variability, he told Medscape Medical News. "Food studies are generally conducted in healthy volunteers and not cancer patients. Labeling can't be done on a theoretical basis; it has to reflect what was done in the study."
Dr. Lesko noted that another problem with tying an oral drug dose to food is that many cancer patients have problems with appetite, nausea and vomiting, and gastrointestinal motility. "Their appetite can change on any given day," he said. "Some days, they may not be able to tolerate a high-fat meal, for example, which raises the bioavailability of abiraterone. It would just be impractical to do this on a day-to-day basis."
The other issue that Dr. Ratain focuses on in his comment is the comparison of oncology and nononcology drugs, Dr. Lesko pointed out. "But you really can't compare them."
For most nononcologic agents, food doesn't matter, so it isn't that important how the product is labeled, he said.
But that is not the case with oral oncologic agents. "Every drug in oncology has a narrow therapeutic index, and taking the drug with food could affect the therapeutic range," he said. "The labels are intended to minimize variability and mimic approval data."

Can it! Soda studies cite stronger link to obesity

As Americans debate what is most to blame for the nation's obesity epidemic, researchers say they have the strongest evidence yet that sugary drinks play a leading role and that eliminating them would, more than any other single step, make a huge difference.
Three studies published Friday in the New England Journal of Medicine represent the most rigorous effort yet to see if there is a link between sugar-sweetened beverages and expanding U.S. waistlines.
"I know of no other category of food whose elimination can produce weight loss in such a short period of time," said Dr. David Ludwig, director of the New Balance Foundation Obesity Prevention Center at Boston Children's Hospital, who led one of the studies. "The most effective single target for an intervention aimed at reducing obesity is sugary beverages."
Previous research on the subject has been mixed, and beverage makers fiercely contest the idea that a single source of daily calories can bear so much responsibility.
"We know, and science supports, that obesity is not uniquely caused by any single food or beverage," said the American Beverage Association (ABA) in a statement. "Studies and opinion pieces that focus solely on sugar-sweetened beverages, or any other single source of calories, do nothing meaningful to help address this serious issue."
The NEJM studies, as well as an editorial and opinion pieces on the topic of sugary drinks and obesity, land as concern about obesity and its impact on public health is rising.
A report released this week projected that at least 44 percent of U.S. adults could be obese by 2030, compared to 35.7 percent today, bringing an extra $66 billion a year in obesity-related medical costs.
Last week, New York City adopted a regulation banning the sale of sugary drinks in containers larger than 16 ounces at restaurants and other outlets regulated by the city health department.
Sugary drinks are in the crosshairs because from 1977 to 2002 the number of calories Americans consumed from them doubled, government data show, making them the largest single source of calories in the diet. Adult obesity rates, 15 percent in the late 1970s, more than doubled in that period. The ABA points out, however, that consumption has since fallen, yet obesity rates keep rising.
Although most observational studies find that people who drink sugary beverages are more likely to be obese than people who do not, no cause-and-effect has been proved. People who drink sugary beverages, especially children, also watch more TV and eat more calorie-dense fast food, raising the possibility that liquid sugar is not the main culprit.
A 2008 analysis of 12 studies, led by a scientist who went on to work for the ABA, concluded that the association between sugary drinks and body-mass index (BMI) "was near zero."
Studies in which children cut their intake of sugary drinks found modest benefits, but "they were considered unconvincing," said Martijn Katan of VU University in Amsterdam: "Most had a small number of subjects and followed them for only a short time." He and his colleagues aimed to do better.
BUILDING A BETTER STUDY
For DRINK (Double-Blind Randomized Intervention in Kids), they gave 641 children aged about 5 to 12 and with a healthy BMI of just under 17 one 8-ounce (250 milliliter) noncarbonated drink per day, sweetened artificially or with sugar. The sugar-free drinks were specially formulated to look and taste like sugary ones so the kids would not know which they had.
About a quarter of the kids stopped drinking the beverages. Among those who stuck it out for 18 months, the sugar-free kids gained less body fat, 2.2 pounds (1 kilogram) less weight, and 0.36 units less BMI than the sugary-drink kids, the researchers report in the NEJM.
Why? There is good evidence that liquid sugar does not produce a feeling of fullness that other calories do. "When children substituted a sugar-free drink, their bodies did not sense the absence of calories, and they did not replace them with other food or drinks," said Katan.
DRINK doesn't answer whether switching to zero-calorie drinks would help obese kids. But another study in the same issue of NEJM suggests it might.
Researchers at Boston Children's had zero-calorie drinks delivered to 110 obese 15-year-olds who had BMIs of about 30 (where obesity starts), counseled them not to drink sugary beverages and offered other support.
After a year the teens had cut their intake of sugary drinks from almost two a day to zero and their daily calorie intake by 454. They had gained an average of 3.5 pounds (1.6 kilograms). By comparison, 114 teens who continued to consume sugar-sweetened beverages gained 7.7 pounds (3.5 kg) on average and ten times the BMI units: 0.63 compared to 0.06.
Once the deliveries stopped the two groups diverged less. After two years, teens who had received the no-cal drink deliveries had gained 9.5 pounds (4.3 kg) and 0.71 unit of BMI, compared to the control group's 11.2 pounds (5.5 kg) and 1.0 unit of BMI.
"It isn't surprising that after the intervention stopped, old behaviors crept back," said Ludwig of the New Balance Center. An "obesogenic" environment that promotes calorie-laden foods "overwhelms individuals' ability to maintain behavioral change" such as avoiding sugary drinks.
Hispanic teens benefited the most: Those receiving no-cal deliveries gained 14 fewer pounds after one year and almost 20 fewer pounds after two. That raised the possibility that genetic factors influence the effect of sugary drinks.
To investigate gene-environment-obesity links, scientists at Harvard School of Public Health looked at 33,097 people from long-term ongoing health studies, such as the Nurses' Health Study, identifying how many sugary drinks they consume and whether they have any of 32 genes linked to obesity.
The effect of genes on the likelihood of becoming obese was twice as large among people who drank one or more sugary drinks per day as among those who had less than one a month, the scientists report in the NEJM. In other words, belting back soda and sugary tea may turbocharge the genetic risk of obesity.
Conversely, eating a healthy diet devoid of sugary drinks keeps fat genes inactive. People with "fat genes" can be thinner if they avoid sugary drinks and other high-calorie foods.

FDA clears first new weight-loss pill in 13 years

The Food and Drug Administration has approved Arena Pharmaceutical's anti-obesity pill Belviq, the first new prescription drug for long-term weight loss to enter the U.S. market in over a decade.

Despite only achieving modest weight loss in clinical studies, the drug appeared safe enough to win the FDA's endorsement, amid calls from doctors for new weight-loss treatments.

The agency cleared the pill Wednesday for adults who are obese or are overweight with at least one medical complication, such as diabetes or high cholesterol. The drug should be used in combination with a healthy diet and exercise.

Obesity Society President Patrick O'Neil said he's encouraged by the drug's approval because it underscores the notion that lifestyle changes alone are not enough to treat obesity.

"This is good news because it tells us that the FDA is indeed treating obesity seriously," said O'Neil, who teaches at Medical University of South Carolina and was the lead researcher on several studies of Belviq. "On the other hand, it's not the answer to the problem — or even a big part of the answer."

Even if the effects of Belviq are subtle, experts say it could be an important first step in developing new treatments that attack the underlying causes of obesity.

"The way these things tend to work is you have some people who do extremely well and other people don't lose any weight at all. But if we had 10 medicines that were all different and worked like this, we would have a real field," said Dr. Louis Aronne, director of the weight loss program at Weill-Cornell Medical College.

The FDA denied approval for Arena's drug in 2010 after scientists raised concerns about tumors that developed in animals studied with the drug. The company resubmitted the drug with additional data earlier this year, and the FDA said there was little risk of tumors in humans.

Arena and its partner Eisai Inc. of Woodcliff Lake, N.J., expect to launch the drug in early 2013.

With U.S. obesity rates nearing 35 percent of the adult population, many doctors have called on the FDA to approve new weight loss treatments.

But a long line of prescription weight loss offerings have been associated with safety problems, most notably the fen-phen combination, which was linked to heart valve damage in 1997. The cocktail of phentermine and fenfluramine was a popular weight loss combination prescribed by doctors, though it was never approved by the FDA.

In a rare move, the FDA explicitly stated in a press release that Belviq "does not appear to activate" a chemical pathway that was linked to the heart problems seen with fen-phen.

The FDA said the drug acts on a different chemical pathway in the brain, which is believed to reduce appetite by boosting feelings of satiety and fullness.

Belviq is one of three experimental weight-loss drugs whose developers have been trying for a second time to win approval, after the FDA shot them all down in 2010 or early 2011 because of serious potential side effects.

Vivus Inc.'s Qnexa is thought to be the most promising of the drugs, achieving the most weight loss. But the FDA has delayed a decision on that pill until July.

Shares of San Diego-based Arena Pharmaceuticals Inc. jumped $2.54, or 28.7 percent, to close at $11.39. Shares of Mountain View, Calif.-based Vivus rose $1.94, or 7.4 percent, to $28.33. Shares of Orexigen Therapeutics Inc., the third drugmaker with an obesity pill before the FDA, rose 20 percent to close at $4.92.

Arena's studies showed that patients taking Belviq, known generically as lorcaserin, had modest weight loss. On average patients lost just 3 to 3.7 percent of their starting body weight over a year. About 47 percent of patients without diabetes lost at least 5 percent of their weight or more, which was enough to meet FDA standards for effectiveness. By comparison, average weight loss with Qnexa is 11 percent, with more than 83 percent of patients losing 5 percent of their weight or more.

The FDA said patients should stop taking Belviq after three months if they fail to lose 5 percent of their body weight. Patients are unlikely to see any significant weight loss by staying with the drug.

Side effects with the drug include depression, migraine and memory lapses.

In May a panel of expert advisers to the FDA voted 18-4 to recommend approval of Arena's drug, concluding that its benefits "outweigh the potential risks when used long term" in overweight and obese people.

Experts say the challenge of weight loss drug development lies in safely turning off one of the body's fundamental directives: to eat enough food to maintain its current weight.

While several drugs are available for short-term weight loss, until Wednesday there was only one FDA-approved prescription drug for long-term weight loss: Xenical from Roche, which is seldom prescribed because of unpleasant digestive side effects and modest weight loss. Belviq is the first new prescription drug approved to treat obesity since Xenical's approval 13 years ago.

Other safety failures for diet pills have continued to pile up in recent years.

Four years ago Sanofi-Aventis SA discontinued studies of its highly anticipated pill Acomplia due to psychiatric side effects, including depression and suicidal thoughts. In 2010, Abbott Laboratories withdrew its drug Meridia after a study showed it increased heart attack and stroke.