Drug Metab. Pharmacokinet. 25 (1): 3–15 (2010). Review Drug Interaction Studies on New Drug Applications: Current Situations and Regulatory Views in Japan Naomi NAGAI* Office of New Drug IV, Pharmaceuticals and Medical Devices Agency (PMDA), Tokyo, Japan Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: Drug interaction studies on new drug applications (NDAs) for new molecular entities (NMEs) ap- proved in Japan between 1997 and 2008 are examined in the Pharmaceuticals and Medical Devices Agency (PMDA). The situations of drug interaction studies in NDAs have changed over the past 12 years, especially in metabolizing enzyme and transporter-based drug interactions. Materials and approaches to study drug- metabolizing enzyme-based drug interactions have improved, and become more rational based on mechanis- tic theory and new technologies. On the basis of incremental evidence of transporter roles in human phar- macokinetics, transporter-based drug interactions have been increasingly studied during drug development and submitted in recent NDAs. Some recently approved NMEs include transporter-based drug interaction in- formation in their package inserts (PIs). The regulatory document ``Methods of Drug Interaction Studies,'' in addition to recent advances in science and technology, has also contributed to plan and evaluation of drug in- teraction studies in recent new drug development. This review summarizes current situations and further dis- cussionpointsondruginteractionstudiesinNDAsinJapan. Keywords: drug interaction; drug development; new drug application; new molecular entity; phar- macokinetics; metabolism; transport; package insert remarkably significant increase in the concentration of Introduction 5-FU.1–3) Between 1998 and 2001, there has also been Drug interactions change dose-response relationships, early termination of development or withdrawal from and result in low efficacy or high toxicity of drugs, which medical practice of some NMEs, mainly due to metabolic are important considerations especially in medical prac- drug interactions caused by the inhibition of cytochrome tice with multiple-drug therapies. In current clinical set- P450 3A4 (CYP3A4).4) Through these experiences, the tings, multiple-drug therapies are often prescribed, importance of investigating drug interaction potentials resulting in more difficult situations for healthcare for NME during drug development and providing ap- professionals to adequately monitor drug interactions. propriate drug interaction information in PIs has been re- Over the past 20 years, there have been several fatal drug emphasized. Regulatory authorities in Japan and overseas interactions that were only detected by serious adverse therefore issued documents for drug interaction studies reactions occurring after marketing. The life-threatening around 2000.5–8) drug interactions caused by taking sorivudine and tegafur Drug interactions are generally categorized as phar- became a serious problem heavily covered by the media macokinetic (PK)- and pharmacodynamic (PD)- related in Japan in 1993. Further investigations reported that the drug interactions. PK-related drug interactions include mechanism of this interaction could be inhibition of 5- those affecting absorption, distribution, metabolism and fluorourasil (5-FU) metabolism by sorivudine, resulting in excretion. PD-related interactions deal with additive, syn- Received; December 27, 2009, Accepted; January 12, 2010 *To whom correspondence should be addressed: Naomi NAGAI Ph.D., Office of New Drug IV, Pharmaceuticals & Medical devices Agency, Shin- Kasumigaseki Bldg, 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-0013, Japan. Tel. 81-3-3506-9487, Fax. 81-3-3506-9567, E-mail: nagai-naomi＠ pmda.go.jp This review is the author's current thinking on this topic and do not represent the official policy or the requirements of the Pharmaceuticals and Medical Devices Agency and the Ministry of Health, Labour and Welfare. The work was presented in part at the 2009 Annual Meeting and Disposition of the American Association of Pharmaceutical Scientists (AAPS). Table 1 and 3 were based on the regulatory document, ``Methods of Drug Interaction Studies5) and package inserts of HMG-CoA reductase inhibi- tors in Japan. Figure 3 was modified with the figure in the reference book of Clinical Pharmacokinetic Studies of Pharmaceuticals12). 3 4 Naomi NAGAI Fig. 1. Regulatory documents and discussion on drug interaction studies in new drug development JPMA: Japan Pharmaceutical Manufacturer Association, JSSX: the Japanese Society for the Study of Xenobiotics, JSCPT: the Japanese Society of Clinical Pharmacology and Therapeutics, JSPHCT: Japanese Society of Pharmaceutical Health Care and Sciences, CBI: Chem- Bio Informatics Society, ISSX: International Society for the Study of Xenobiotics, AAPS: American Association of Pharmaceutical Scientists. Periods 1, 2 or 3 is a 4-years study period before and after publication of the ``Methods of Drug Interaction Studies''. ergistic and antagonistic action based on the pharmacolo- regulatory documents, related guidelines and informa- gy of both investigational and concomitant drugs. This tion of literatures.12) The United States Food and Drug review refers to only PK-related drug interactions. Administration (U.S. FDA) published a concept paper in 2004 and new draft guidance for drug interaction studies Regulatory Documents and Discussions in 2006, including study design, data analysis and label- on Drug Interaction Studies ing implications.13,14) Many conference meetings and wor- Figure 1 shows regulatory documents and related dis- kshops have also been held in the U.S. to discuss and up- cussion on drug interaction studies in Japan and over- date on this issue over the past 5 years. The European seas. In 1998, the Ministry of Health, Labour and Wel- Medicines Agency (EMEA) announced a concept paper in fare (MHLW) organized the Working Groups for Drug 200815) to recommend revising guidance on investiga- Interactions and Clinical Pharmacokinetic Studies and tions of drug interactions published in 1997. Recently, in started an intensive discussion for drug interaction stu- Japan, there have been many opportunities mainly dies during new drug development. Since then, an in- provided by academia to discuss drug interaction related creasing number of related conference meetings has topics especially on transporter-based drug interactions. been held and related regulatory documents have been Each of the 3 ICH regions (International Conference published in Japan. The regulatory document, ``Methods on Harmonization of Technical Requirements for Regis- of Drug Interaction Studies'' was issued on June 4, 2001 tration of Pharmaceuticals for Human Use) has published and covers fundamental points, in vitro and in vivo study its own regulatory documents for drug interaction stu- approaches concerning drug interactions. ``Clinical Phar- dies. These documents provide similar principles for macokinetic Studies of Pharmaceuticals'' and ``Guideline drug interaction studies in drug development and also on Non-clinical Pharmacokinetic Studies'' describe the reflecte the latest scientific knowledge, technologies and scope and basic principles of pharmacokinetic studies medical practices at the time of their publications, necessary for submitting new drug applications, both of although some differences are found in the scope of in which are useful to plan, conduct and evaluate drug in- vitro and in vivo studies and labeling implications. Figure teraction studies.9–11) In addition to these regulatory 2 shows the contents of ``Methods of Drug Interaction documents, the MHLW Working Groups for Drug Inter- Studies''. The Japanese document includes the following: actions and Clinical Pharmacokinetic Studies published a (1) focusing on not only metabolism-mediated drug inter- reference book in 2003 that includes English versions of actions as the most frequent mechanism for drug interac- Drug Interaction Studies in New Drug Applications in Japan 5 Fig. 2. Methods of drug interaction studies: table of contents tions,16) but also on absorption-, distribution- and ex- mechanisms of drug interactions associated with inves- cretion-mediated drug interactions, therefore including tigationed drugs are identified by basic non-clinical and the points of consideration for all PK process, (2) brief clinical PK studies, non-clinical drug interaction studies labeling implications because official guidelines and and clinical drug interaction studies, (3) the most possible regulatory documents for PIs had been issued,17–20) (3) risk of interactions between investigationed drugs and primarily describing clinical drug interaction studies and other drugs in humans are assessed based on drug inter- in vitro studies using human tissue-derived samples and action studies in early-clinical development phase, (4) expression systems. possible drug interactions in humans are exploratorily Figure 3 shows a typical approach for investigating evaluated in late-clinical development phase, (5) labeling drug interaction potentials during new drug develop- information and drug interaction study data are ap- ment.12) Although the reference book shows a case in propriately provided in PIs and (6) risk reassessment of which a drug candidate may be a metabolic inhibitor and drug interactions, followed by feed back of this informa- developed in oral dosage form,12) basic principles, typical tion to medical practice is periodically conducted