Food and Oral Antineoplastics: More Than Meets the Eye

Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1-7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post-low-fat (n = 6) or high-fat meal (n = 18; days 8-14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration-time curve (AUC) increased ∼5- and ∼10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, abiraterone AUC was ∼2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter abiraterone acetate safety.

Section: Discussionmentioning

confidence: 99%

Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration‐resistant prostate cancer

Spratlin²,

Kollmannsberger

et al. 2015

“…In recent years, there has been considerable interest in understanding the effect of food intake on the oral bioavailability of molecularly targeted oncology therapies, mostly TKIs . On the basis of ceritinib's low solubility, low permeability, and low extent of metabolism based on the amount of unchanged drug recovered in the feces, ceritinib can be classified as a class 4 drug in the Biopharmaceutics Classification System and the Biopharmaceutical Drug Disposition Classification System .…”

Section: Discussionmentioning

confidence: 99%

Effects of meal type on the oral bioavailability of the ALK inhibitor ceritinib in healthy adult subjects

Lau

Lin

et al. 2015

Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK), which has shown acceptable safety and substantial antitumor activity in ALK-positive non-small cell lung cancer (NSCLC) patients. Two food-effect studies were conducted in healthy adults to investigate the influence of food on the oral bioavailability of ceritinib: a study with low- or high-fat meals at 500 mg and a study with a light snack at 750 mg. Compared with the fasted state, AUC0-∞ (90%CI) of ceritinib was increased by 58% (34%, 86%) after the intake of a low-fat meal, by 73% (46%, 105%) after the intake of a high-fat meal, and by 54% (19%, 99%) after the intake of a light snack. Safety assessments also suggested that food may improve gastrointestinal (GI) tolerability after a single ceritinib dose. Based on the pharmacokinetic results, it is essential to avoid any type of meal during dosing of ceritinib because the intake of food may increase the occurrence of exposure-dependent, non-GI toxicities at the labeled dose of 750 mg daily during fasting. A randomized trial is ongoing to determine an alternative way to give ceritinib (450 mg or 600 mg with food) that may enhance GI tolerability in ALK-positive NSCLC patients.

“…There is a wide variability in the composition of meals between regions and patients, and this is the basis for the argument to give oncology drugs in the fasted state. A number of foods modulate the enzymes responsible for metabolizing these drugs, including charcoal‐broiled and smoked foods, grapefruit juice, cruciferous vegetables, watercress, red and black pepper, and excess sodium chloride . The volume and timing of a meal, calorie and liquid content, fat vs carbohydrate content, temperature, and physical composition can also lead to highly unpredictable variability in exposure from dose to dose .…”

Section: Discussionmentioning

confidence: 99%

Food Effect Study Design With Oral Drugs: Lessons Learned From Recently Approved Drugs in Oncology

Farha

Masson

Tomkinson

et al. 2018

Evaluation of the effect of food on the pharmacokinetics of oral oncology drugs is critical to drug development, as food can mitigate or exacerbate toxicities and alter systemic exposure. Our aim is to expand on current US Food and Drug Administration (FDA) guidance and provide data‐driven food‐effect study design recommendations specific to the oncology therapeutic area. Data for recently approved small‐molecule oncology drugs was extracted from the clinical pharmacology review in the sponsor's FDA submission package. Information on subject selection, meal types, timing of the study relative to the pivotal trial, and study outcomes was analyzed. The number of subjects enrolled ranged from 12 to 60, and the majority of studies (19 of 29) were conducted in healthy volunteers. Using AstraZeneca cost data, healthy volunteer studies were estimated to cost 10‐fold less than cancer patient studies. Nine of 29 (31%) studies included meals with multiple levels of fat content. Analysis of a subset of 16 drugs revealed that final results for the food‐effect study were available before the start of the pivotal trial for only 2 drugs. Conducting small food‐effect studies powered to estimate effect, rather than confirm no effect, with only a standardized high‐fat meal according to FDA guidance may eliminate unnecessary studies, reduce cost, and improve efficiency in oncology drug development. Starting food‐effect studies as early as possible is key to inform dosing in pivotal trials.