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By Ami Patel

Ami Patel-finalDesign of experiments is a branch of applied statistics, but its concepts resonate beyond this subject. It focuses on planning, conducting, analyzing, and interpreting controlled tests to evaluate factors that control the value of a parameter. There are various factors that affect the ADME of drugs, and understanding the impact of numerous variables on these factors can efficiently deliver quality drug products with minimum overall variation.

My graduate school research topic was to evaluate the gender differences in the renal excretion of drugs and the role of transporters using the isolated perfused rat kidney model. The importance of an appropriate study design and understanding its limitations was stressed throughout the research process. Some key variables were the number of replicates, age and weight of animals, and inclusion of a castrated animals group, among other drug specific considerations such as solubility, stability, non-specific binding, and protein binding. But the choice of concentration was not clinically relevant, which led to repeating some experiments. It seemed unnecessary then, but today I find myself stressing on this key consideration when designing transporter interaction studies.

Sponsors of INDs and NDAs conduct several non-clinical ADME studies to determine potential risks of administering drugs to humans during clinical development. During these studies, principal routes of elimination, contribution by enzymes and transporters to drug disposition, and mechanisms of drug-drug interactions (DDIs) are identified. Ideally, the dose/concentration of the interacting drug(s) used in the DDI studies should demonstrate the maximum potential for an interaction. For this reason, conducting research with a lower, less clinically relevant concentration could lead to a reduced sensitivity for detecting the DDIs and a negative result, which rules out the involvement of the transporter(s) in the drug’s disposition. This false negative can be a significant safety concern when conducting the clinical studies and can impact the cost and timelines of drug development. The FDA and EMA guidances contain recommendations for the in vitro study strategies and design, which highlight the importance of factors such as validated experimental methods, choice of test systems, and the choice of interacting drug, among others.

Students are sometimes limited in their ability to choose the most appropriate study design due to limited resources, while sponsors may be limited due to budget and timeline restrictions. A well-designed experiment can economically maximize the amount of information obtained and ascertain meaningful data generation and interpretation. Experts in this field gather during the upcoming AAPS/ITC Joint Workshop on Drug Transporters to exchange ideas and discuss the hot topics in the translation of transporter data to the clinic. Learn more about the workshop and come join us!

Ami Patel is a Ph.D. candidate at Long Island University with research interests and expertise in study design/protocol development for DDI and complex drug product studies. She works as a scientific account manager at Absorption Systems.