To Take or Not to Take With Meals? Unraveling Issues Related to Food Effects Labeling for Oral Antineoplastic Drugs

Abstract

There has been controversy regarding whether bioavailability of certain oral oncology drugs should be maximized by taking these medications with food, irrespective of label instructions in the dosing and administration section. To provide insight into this controversy, we conducted an in-depth analysis for oral antineoplastic drugs approved by the Food and Drug Administration in 2000-2016 and identified important issues influencing food labeling decisions. Furthermore, a case study involving sonidegib, a drug approved for locally advanced basal cell carcinoma with a significant food effect on exposure, was used to demonstrate the consequences of failure to adhere to food label recommendations using drug-specific population pharmacokinetic and exposure-toxicity models. In 2000-2009, 80% (4 out of 5) of all approved oral antineoplastics with increased bioavailability in the fed state were labeled as "take on empty stomach." In contrast, we found that in 2010-2016 there is a greater diversity in food recommendations for drugs with increased bioavailability in the fed state. Currently, many oral oncology drugs are given with food to maximize their bioavailability; however, as seen from our case study of sonidegib, failure to fully adhere to label recommendations to either take with food or not could lead to adverse consequences in terms of safety and efficacy.

Effect of Food on the Pharmacokinetics of Quizartinib

“…Exposure to several oral tyrosine kinase inhibitors is affected by the presence of food, necessitating guidance regarding whether to dose these medications with or without food. 24 Consistent practices are important in evaluating the effects of food on absorption of anticancer medication. The effect of food on the PK of midostaurin was evaluated in an open-label, randomized, parallelgroup study following a single 50-mg dose of a final market image formulation in healthy subjects (n = 48); exposure to midostaurin increases 1.2-fold when it is administered with a standard meal (450 calories, 25% fat content) and 1.6-fold when it is administered with a high-fat meal (900-1000 calories, 50% fat content).…”

“…23 For oral anticancer therapies, adherence to administration recommendations with regard to food can be critical to ensure that target drug concentrations are being achieved and to avoid toxicity. 24 Consistent practices are important in evaluating the effects of food on absorption of anticancer medication. Food effect studies ideally are conducted early in the drug development process under well-defined conditions.…”

“…Blood samples for measurement of plasma quizartinib and AC886 concentrations were collected from all subjects before quizartinib dosing on day 1 and at 0.25, 0.5, 1, 2, 3,4,5,6,8,12,24,36,48,72,96,120,144,168,192,216,288,360,432, and 504 hours after quizartinib administration. The choice of the sampling duration (504 hours) was based on the t 1/2 of quizartinib being approximately 100 hours (5-fold).…”

Food for thought: formulating away the food effect – a PEARRL review

“…While the case for taking these medicines with food in an off‐label manner seems to stand to reason, other factors are important and warrant consideration, not least of which is conditions under which the drug product is licensed. While food effect studies are most often carried out as single‐dose studies in healthy subjects, the pivotal phase 3 clinical studies, which establish safety and efficacy in patients, may have been initiated in different prandial conditions, leading to a licensed dosing recommendation which reflects that of the relevant clinical study . Dosing in differing prandial conditions to that recommended in the drug product label constitutes off‐label administration, and risks administration under conditions which have not been demonstrated as safe and effective in clinical trials .…”

The Effect of a High‐Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

“…Of 35 orally administered cancer drugs that were approved by the US Food and Drug Administration (FDA) between January 2011 and April 2017, all but 1 had conducted a food effect study and had included food effects data in their initial submissions . A landscape analysis of the food effects and labeling recommendations for 30 oral antineoplastic drugs approved between 2010 and 2016 reported greater diversity in food recommendations for drugs that have increased bioavailability in the fed state as compared with 11 drugs approved in 2000 to 2009, when the drugs were almost always labeled as “taken on empty stomach.” Food effects on drug bioavailability and clearance are highly variable among small‐molecule kinase inhibitors . Although food does not meaningfully affect crizotinib exposure, food increases exposure to ceritinib, and ingestion of a high‐fat meal increases combined exposure to alectinib and its major active metabolite M4 …”