Novel Draft Guideline for Drug Interaction Studies in the Drug Development and Labeling Recommendations

Abstract

Evaluation of drug interactions (DIs) in the drug development is important for reduced incidence of adverse reactions in clinical trials and proper use of drugs in the post-marketing. The current Japanese guidance on DI was issued more than 10 years ago and during which period there were a lot of progress in the research related to DI and the clinical information is accumulated. Novel guideline and draft guidance was also publicized recently from EMA and FDA, respectively. Based on this situation, we started investigation to draft new Japanese guideline from Dec. 2012, constructing a team consisting of experts from industries, academia, and regulatory agencies. Preliminary draft was notified in Dec. 2013 for public comments. After examining comments obtained, the draft guideline was finalized in May 2014, and submitted to and publicized by Japanese Ministry of Health, Labor, and Welfare. In addition to the overall update of existing guidance, the final draft supplemented detailed explanation in every area. Followings are major part of revision. 1) transporter studies on absorption in small intestine, urinally excretion from kidney, and biliary excretion from liver; 2) stepwise examination via metabolizing enzymes and transporters using decision trees; 3) evaluation by modeling and simulation using in vitro and in vivo data; 4) lists of known inhibitors and inducers on major cytochrome P450 isoforms classified in strong-, intermediate- and weak-affecting groups based on the changes of AUC or CL/F, and a table of “drugs susceptible to DIs” and “drugs moderately susceptible to DIs”; 5) Interactions with therapeutic proteins; and 6) labeling recommendations. In this review, we introduce the novel draft guideline focusing on the above important points.