Proposal Description:

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Oral anticancer drugs have revolutionized cancer therapy. Patients are no longer infused with toxic drugs that non-discriminately attack any rapidly dividing cells in the body and cause considerable adverse effects such as neurotoxicity, alopecia, emesis, and neutropenia. The considerably higher efficacy and safety of the newer classes of anticancer drugs have transformed cancer from a death sentence to a chronic disease. However, many of these agents still have black box warnings. The majority of oral anticancer drugs experience positive food effect, wherein coadministration with a meal results in increased Cmax and area under the curve. This is well documented with protein kinase inhibitors. Nilotinib represents the extreme example wherein high plasma levels can induce fatal QTc prolongation. It is unclear at the present moment to what magnitude food effect will play in newer classes of anticancer agents such as histone deacetylase inhibitors and small molecule immune checkpoint inhibitors. Anticancer agents are unique in that they are typically labeled to be taken on an empty stomach; whereas, the opposite is true for drugs in other therapeutic areas. Oral anticancer drugs are formulated and administered at high dosage strengths to account for poor and variable bioavailability. This approach leads to considerable drug waste. A patient taking the labeled dose with food may suffer from adverse events such as QTc prolongation from being exposed to supra-therapeutic drug levels. Administration of a lower dose with food has been proposed as a solution. These two situations represent cases in which poor adherence to food labeling may lead to either overdose or underdose. The case for overdose is far more compelling. There are numerous reasons why bioavailability of certain molecules is affected by food. The most likely reasons are improved solubilization in the gastrointestinal tract and slower gastrointestinal motility.

There are studies demonstrating that food effect can be predicted based on physicochemical information. Poor aqueous solubility and Biopharmaceutics Classification System class are a couple of good determinants. Consideration of food effect during lead optimization can result in a molecule design with a better pharmacokinetic profile. Bioavailability enhanced formulations can minimize the reliance on dietary fats for solubilization and absorption. These enhanced formulations can minimize complications of coadministration, improve patient adherence, and potentially accelerate speed to market. This clinical challenge can be addressed at various stages of pre-clinical and clinical drug development.

During this short course, medicinal chemists, formulators, regulators, and clinicians gather to identify times when food effect can be addressed and propose solutions and future studies to that can be applied industry-wide. Investigators will benefit from a standardized toolkit to predict and study food effect, design development pathways based on results of food effect studies, and optimize clinical administration regimens.

Learning Objectives:
•Be able to identify new classes of anticancer compounds in development, their targets, and potential formulation and clinical issues
•Explain the role of food in affecting the bioavailability of oral anticancer drugs and current approaches
•Propose new approaches to address and minimize pharmacokinetic variability and food effects seen in patients taking oral anticancer drugs