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Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information
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Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information Q4,1
Akihiro Ishiguro*, Reiko Sato, Naomi Nagai 1 Pharmaceuticals and Medical Devices Agency, Shin-Kasumigaseki Bldg. 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 August 2019 Received in revised form 12 November 2019 Accepted 13 November 2019 Available online xxx
Drug interactions, in particular with concomitant drugs having a narrow therapeutic range, sometimes cause serious adverse drug reactions or attenuation of the therapeutic effect. Therefore, evaluation of the characteristics and severities of possible drug interactions in drug develoment is essential to understand such interactions to help prevent any potential risk for patients. In Japan, a regulatory document which was notified in 2001 to outline the basic principles of drug interaction studies during drug development was revised as a new guideline after 17 years to present general procedures that are currently considered scientifically valid. This article aims to present an overview of development process of the new Japanese guideline for investigating drug interactions and show the impact of implementating this guideline on drug interaction evaluations, thereby providing future perspectives of regulatory activities on drug interactions.
Keywords: Drug interaction Cytochrome P450 Transporter Package insert Guideline Drug development Japan
© 2019 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
1. Background Drug interactions are the phenomena that occur between concomitant drugs, or drugs and food that may affect drug responses such as pharmacokinetic (PK) profile, efficacy or safety of drug. Knowledge of how to prevent serious adverse drug reactions or attenuation of therapeutic effect due to drug interactions can lead to more efficient drug development. In addition, reflecting drug interaction data in drug package inserts including information on mechanisms and the degree of interactions which were determined during the drug development process is essential for ensuring proper use of drugs in clinical settings. In Japan, the regulatory document notified by the Ministry of Health, Labour and Welfare (MHLW) in June 2001 was referenced to investigate drug interactions during drug development and review drug interactions during the regulatory approval review [1]. Based
* Corresponding author. Planning and Coordination Division, Advanced Science and Technology Division, Office of Research Promotion, Center for Regulatory Science, Pharmaceuticals and Medical Devices Agency, Shin-Kasumigaseki Bldg. 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan. E-mail address: [email protected] (A. Ishiguro). 1 Current address; Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202e8585, Japan.
on accumulated scientific knowledge and technology advancement in the area of PK or clinical pharmacology after the notification was published in 2001, and the recent revisions of regulatory documents on drug interaction studies in the EU and US, the Japanese regulatory document was revised [2,3]. The Japanese guideline revisions were undertaken by a research group that consisted of academics affiliated with relevant academic societies, such as the Japanese Society for the Study of Xenobiotics and the Japanese Society of Clinical Pharmacology and Therapeutics, personnel engaged in preclinical and clinical development at pharmaceutical companies, and regulators of regulatory authorities (Fig. 1). Until the notification of the new Japanese guideline in 2018, a final draft of the guideline was published, and public consultations occurred twice around the time of the final draft publication [4,5]. Responses to major comments obtained during the public consultation or guideline descriptions requiring appropriate commentary with relevant referenced literature are included in a document on questions and answers that was published along with the new Japanese guideline [5]. This article aims to present the highlights of the new Japanese guideline and address the background underlying investigations by the research group as needed. Hereafter, the Japanese regulatory document notified in 2001 is referred to as “the old notification” and the Japanese guideline notified in 2018 is referred to as “the new guideline” [1,5].
https://doi.org/10.1016/j.dmpk.2019.11.009 1347-4367/© 2019 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
Please cite this article as: Ishiguro A et al., Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.11.009
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Fig. 1. Overview of the development of regulatory documents on drug interaction studies in the EU, US and Japan. An overview when the old notification was released was also reported by the author [6]. Abbreviations; ICH, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; FY, Japanese fiscal year.
In a previous study [6], the author collected information on characteristics of drug interaction studies shown in review reports or new drug applications (NDAs) that were approved around the time when the old notification was published in 2001. Additionally, the previous study clarified future issues requiring further consideration such as methods for investigating transporter-mediated drug interactions or more reliable interpretations of non-clinical data to decide whether a clinical drug interaction study is necessary. In this article, we searched the PMDA website, which is publicly available, to present the results of a follow-up survey on drug interaction studies in NDAs for new drugs that were approved until fiscal 2018, which is when the new guideline was published. Based on the available regulatory review data, impacts of the new guideline implementation on new drug development will also be discussed. 2. New guideline contents The basic policy for developing the new guideline was to provide a comprehensive guide of methods for investigating drug interactions from drug development to post-marketing stages, including in vitro drug interaction assessments, judgment on the necessity of a clinical drug interaction study, study design to evaluate the presence or absence of drug interactions and levels of impacts of the interactions in clinical settings, and a general guide for interpretations and provision of information obtained from the study data. Moreover, consistency with regulatory documents published by the European Medicines Agency and US Food and Drug Administration was taken into account to the extent possible to finalize the new guideline. As in the old notification, descriptions in the new guideline focused on methodologies for investigating PK drug interactions following oral administration. Methodologies for evaluating pharmacodynamic drug interactions were outside the scope of this guideline as there are no universal indicators, such as blood drug concentration for evaluating PK drug interactions. Similar to the old notification, the new guideline consists of chapters on drug absorption, tissue distribution, drug metabolism, excretion, and planning and conducting clinical drug interaction studies (Table 1). In addition to these chapters, the new guideline includes new sections on drug interactions mediated by transporters (Chapter 6)
and general principles for reflection of information and alerts on drug interactions in package inserts (Chapter 8). The appendices provides decision trees for investigating the possibility that an investigational drug could be a substrate, inhibitor, or inducer of a drug metabolizing enzyme (DME), or a transporter, which can be used as reference for determining the necessity of a clinical drug interaction study based on data obtained from in vitro drug interaction studies or a PK study in an early clinical development stage. 2.1. Clarification of procedures from non-clinical through clinical development In the old notification, the involvement of transporters in drug absorption and excretion was described, however, transporter isoforms targeted for drug interaction studies to be conducted during drug development were not identified. In contrast, the new guideline referred to not only major DMEs, such as CYP1A2, CYP2B6, or CYP3A, but also specific transporter isoforms for the first time. The new guideline also included some specific methods for investigating drug interactions mediated by transporters involved in absorption (P-gp and BCRP), uptake into liver (OATP1B and OATP1B3), and renal excretion (OAT1, OAT3, OCT2, MATE1, and MATE2-K). In the new guideline, decision trees were drawn to facilitate determination of the need for a clinical study of drug interactions mediated by DMEs, so as to investigate whether an investigational drug can be a substrate of a specific DME and can inhibit or induce any DMEs. The need for such a clinical drug interaction study is decided based on the in vivo contribution ratio (CR) of the major elimination pathway estimated from fraction metabolized (fm) obtained from an in vitro metabolism study using human liver microsomes in general and data available from PK studies conducted in early clinical development, e.g., mass balance studies, intravenous administration studies. If the in vivo CR values for major isoenzymes of DMEs of investigational drugs are estimated to be small, an in vitro metabolism study should be considered for the other isoenzymes, such as CYP2A6, or CYP2E1, or phase I enzyme other than P450, such as monoamine oxidase, flavin monooxygenase, xanthine oxidase, aldehyde oxidase, alcohol dehydrogenase, or aldehyde dehydrogenase [7e12]. The necessity of a clinical interaction study to investigate whether the investigational
Please cite this article as: Ishiguro A et al., Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.11.009
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Table 1 Table of contents for “Guideline on drug interaction for drug development and appropriate provision of information” [5]. Table of Contents 1. Introduction 1.1 Background and objectives 1.2 Scope 1.3 Principles of drug interaction studies 2. Drug interactions in absorption 2.1 Effects on gastrointestinal pH, complex/chelate formation, and solubility 2.1.1 Effects of concomitant drugs on the investigational drug 2.1.2 Effects of the investigational drug on concomitant drugs 2.2 Effects on gastrointestinal motility 2.2.1 Effects of concomitant drugs on the investigational drug 2.2.2 Effects of the investigational drug on concomitant drugs 2.3 Drug interactions mediated by transporters in the gastrointestinal tract 2.4 Drug interactions mediated by drug metabolizing enzymes in the gastrointestinal tract 3. Drug interactions in tissue distribution 3.1 Plasma protein binding 3.2 Tissue distribution 3.2.1 Binding to specific tissue components 3.2.2 Involvement of transporters in uptake and efflux in tissue 4. Drug interactions in drug metabolism 4.1 Evaluation of the possibility of the investigational drug as an affected drug 4.2 Evaluation of the possibility of the investigational drug inhibiting drug metabolizing enzymes 4.3 Evaluation of the possibility of the investigational drug inducing drug metabolizing enzymes 4.4 Drug interaction studies mediated by enzymes other than cytochrome P450 4.5 Drug interactions with biotechnological/biological products (Therapeutic proteins) 5. Drug interactions in excretion 5.1 Drug interactions in urinary excretion 5.2 Drug interactions in hepatobiliary transport 6. Drug interactions mediated by transporters 6.1 General considerations in in vitro studies 6.2 Studies to examine drug interactions mediated by transporters involved in absorption 6.3 Studies to examine drug interactions mediated by transporters in the liver 6.4 Studies to examine drug interactions mediated by transporters in the kidney 7. Evaluation by clinical drug interaction studies 7.1 Need for and timing of clinical drug interaction studies 7.2 Relevant indices of drug interactions and pharmacokinetic parameters to be evaluated 7.3 Study design 7.4 Dose and route of administration 7.5 Duration and timing of administration 7.6 Selection of inhibitors for drug metabolizing enzymes and transporters 7.6.1 Clinical drug interaction studies using inhibitors of cytochrome P450 7.6.2 Clinical drug interaction studies using inhibitors of drug metabolizing enzymes other than cytochrome P450 and transporters 7.7 Selection of inducers for drug metabolizing enzymes 7.8 Selection of substrates for drug metabolizing enzymes and transporters 7.9 Other considerations for evaluation by clinical drug interaction studies 7.9.1 Drugs metabolized by a single enzyme and multiple enzymes 7.9.2 Drug interactions involving both drug metabolizing enzymes and transporters 7.9.3 Cocktail substrate studies 7.9.4 Evaluation by population pharmacokinetic analysis 7.9.5 Considerations for subjects with special background 7.9.5.1 Evaluation of drug interactions in consideration of genetic polymorphism 7.9.5.2 Investigational drugs mainly applied to special population or patient populations with specific diseases 7.9.5.3 Studies in patients 8. General principles for reflection of information and alerts on drug interaction in package inserts 8.1 Description in Precautions in drug package inserts 8.2 Description in “Drugs” in the section of “INTERACTIONS” 8.3 Description in the section of “PHARMACOKINETICS” 9. Relevant guidelines etc. 10. Glossary 11. Appendices 11.1 List of figures and tables 11.2 Decision trees 11.3 Examples of substrates, inhibitors, and inducers
drug can inhibit or induce DMEs should be judged by non-clinical data, e.g., the ratio of intrinsic clearance value of a sensitive substrate under the presence and absence of the investigational drug for a specific enzyme reaction (R value) and the range of change in the mRNA expression level of the target gene using primarycultured liver cells among investigational drug-exposed, vehicle control and positive control groups.
The new guideline also described the availability of a modeling and simulation (M&S) at each phase of drug development, which is used to predict possible DME-mediated drug interactions so that the advisability of a proposed clinical drug interaction study can be decided, or a better information for designing the clinical study can be obtained. In the decision trees to investigate DME-mediated interactions, analyses with the use of mechanistic static pharmacokinetics (MSPK) model or physiologically based
Please cite this article as: Ishiguro A et al., Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.11.009
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pharmacokinetics (PBPK) model were covered as one of predictors of clinical drug interaction as well as the non-clinical data as mentioned earlier. Decision trees were also offered as references for considering the need for a clinical study to investigate whether an investigational drug is a substrate of transporters or inhibits transporters. The need for a clinical study to investigate transporter-mediated drug interactions could be decided based on the criteria in the decision trees by comparing the results from proper in vitro study systems, i.e., the transport activities to be evaluated were confirmed in advance.
new guideline requires that drug interactions data included in package inserts should be in principle clinical PK information to ensure that the data are easily understood for healthcare professionals in clinical settings. Information on drug interactions provided in package inserts may include the results of in vitro drug interaction studies for transporters or estimates given by M&S approaches, therefore, the new guideline also requires that there should be clear distinctions among data from clinical studies or in vitro studies, and from actual measured values or estimate values.
2.2. Basic guide for conducting a clinical drug interaction study and for appropriately providing information related to drug interactions The new guideline specified representative substrates as concomitant drug candidates for assessing the possibility that an investigational drug inhibits or induces DMEs as a reference for developing clinical drug interaction study protocols. These substrates, referred to as “clinical index substrates” in the new guideline, are sensitive to PK drug interactions with high specificity for the DME that were previously verified by the results of multiple clinical studies (e.g., the representative substrates of CYP3A are midazolam and triazolam). Likewise, the new guideline also specified representative inhibitors or inducers, referred to as “clinical index inhibitors” or “clinical index inducers” that facilitate assessment of inhibitory or inducing effects to the maximum extent when investigating whether the investigational drug is a substrate of a DME as a concomitant drug candidate. Inhibitors have been classified into three levels based on clinical inhibitory effect as follows; when an inhibitor increases the plasma AUC of a sensitive substrate by 5-fold, 2- to < 5-fold, and 1.25to < 2-fold increases, the drug is considered a strong, moderate, and weak inhibitor, respectively (e.g., representatives of the strong inhibitor to CYP3A are clarithromycin and itraconazole). Likewise, inducers are classified according to the degree of induction as follows; when an inducer reduces the plasma AUC of a sensitive substrate to 1/5 or less, 1/2 but >1/5, and <1/1.25 but >1/2, the drug is considered a strong, moderate, and weak inducer, respectively (e.g., representatives of the strong inducer to CYP3A are phenytoin and rifampicin). The new guideline has also offered a summary of typical in vivo substrates and inhibitors for transporters based on publicly available findings. In the final draft of the guideline released in 2014 [4], exhaustive lists were drawn to show examples of substrates, inhibitors, and inducers of DMEs of interest for investigating interactions based on the strength classification, i.e., strong, moderate, or weak, classified earlier. Because frequent list updates would be warranted in light of the newly accumulated scientific knowledge, these lists were not included in the new guideline or the associated document on questions and answers, but will be published in an academic journal as review data along with background information and references from the research group [13]. In parallel with activities of the research group, revision activities had been made to the notifications on instructions for package inserts of prescription drugs released by the MHLW in 1997; then, the new instructions for package inserts were notified in June 2017 [14,15]. The new instructions included a requirement that package inserts should include descriptions of specific DMEs that would be associated with the mechanism of PK drug interactions. The new guideline also requires to give careful consideration to the needs of specifying the strength classification for interactions, i.e., strong, moderate, and weak, in addition to the names of DMEs and transporters contributing to drug interactions when reviewing the contents of the precautionary statement based on drug interactions data obtained during the drug development process. Moreover, the
3. Status of drug interaction evaluation in NDA dossiers submitted to PMDA The major purpose of the new guideline was to clarify suitable investigation procedures throughout the drug development process from non-clinical to clinical stages, where it provides some approaches for investigating drug interactions of specific isoenzymes of DMEs and transporters. To examine the possible impacts of the new guideline implementation on evaluation of PK drug interactions in new drug development, the status of conducting in vitro drug interaction studies was surveyed for new active ingredients of oral formulations based on the relevant review reports and synopses of NDA dossiers on the PMDA website [16]. In accordance with the decision trees in the new guideline, the survey covered the following isoenzymes or isoforms, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, and/or UGT2B7 for DMEs; and P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K for transporters. We identified 103 NDAs for new active ingredients that were approved during the previous five years from fiscal 2014 to 2018, which is the time when the final draft and the new guideline were published. The survey found that in vitro metabolism studies for investigating DME-mediated interactions were conducted in most of NDAs, excluding in vitro enzyme inhibition studies for UGT1A1 and UGT2B7 (Fig. 2a). The absence of a standardized approach to estimate the CR values for UGT isoenzymes may have resulted in a lower percentage of in vitro enzyme inhibition studies compared with other DMEs, however, it is recommended to conduct multifaceted analyses while referring to latest published literatures, such as by using a combination of approaches with expression systems of major UGT isoenzymes and inhibition studies using human liver microsomes and available substrates (e.g., b-estradiol for UGT1A1, morphine or zidovudine for UGT2B7) [17]. In vitro studies for investigating transporter-mediated drug interactions were conducted in approximately more than half of NDAs, except in vitro studies of drugs as substrates of OAT1, OAT3, OCT2, MATE1 and MATE2-K (Fig. 2b). There is a report that the plasma AUC of HMG-CoA reductase inhibitor, a substrate of OATP that is involved in hepatic uptake of drugs, increased by more than five-fold when used with inhibitors of OATP such as cyclosporine or gemfibrozil [18]. Consequently, proper investigations of transporter-mediated drug interactions will lead to a better understanding of safety profiles for investigational drugs. Although the percentages of in vitro studies of drugs as substrates of OAT1, OAT3, OCT2, MATE1 and MATE2-K, which contribute to urinary excretion of drugs by the kidney, were about 10e20% and lower than the percentage of study conducted on other transporter molecules (Fig. 2b), it is recommended to conduct in vitro studies using cell lines known to express kidney transporters for investigational drugs that are known to be mainly excreted into urine.
Please cite this article as: Ishiguro A et al., Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.11.009
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Fig. 2. Characteristics of in vitro drug interaction studies in NDAs for new active ingredients of oral formulation that were approved between 2014 and 2018 in Japan. Percentage of studies of in vitro drug interactions mediated by drug metabolizing enzymes (a), and transporters (b) described in decision trees of the new guideline [5]. Closed, open, and gray bars indicate percentages of the NDAs (n ¼ 103) that included data on in vitro drug interaction studies to investigate whether new active ingredients can be substrates, inhibitors and/or inducers, respectively.
4. Discussions 4.1. New guideline implementation effects and limitations The new guideline provided scientifically validated and updated methodologies to encourage strategic and systematic investigations of drug interactions and information provision from the non-clinical through post-marketing stages based on the latest trends in new drug development as presented in Section 2. We expect that distribution of package inserts containing information on the mechanisms of drug interactions, strength of the interactions, or CR of the major elimination pathway as newly described in the new guideline will promote better understanding of information related to drug interactions and, subsequently, proper use of drugs in clinical settings. The survey in Section 3 indicated that there was no cause for concern regarding the feasibility of using methodologies described in the new guideline, because in vitro drug interaction studies for numerous products have already been performed on isoenzymes of DMEs and transporters, which are recommended for investigating during the drug development in the new guideline. The range of transporter isoforms that were recommended to be assessed by the new guideline was overall consistent with the views expressed by the International Transporter Consortium (ITC) [19]; thus, it appears that the new guideline reflects the latest scientific findings and provides appropriate contents, despite the trend for a lower percentage of investigations on transporter-mediated drug interactions compared with those on DMEs. The ITC article also extends to other isoforms that may aid drug developers in predicting characteristics of drug interactions under specific conditions or for special populations (e.g., OATP2B1 and vitamin-drug interactions, THTR2 and populations susceptible to drug-induced thiamine deficiency), which makes continued discussion warranted for validating the range of the transporter isoforms to be evaluated during clinical development. Although the new guideline has proposed cutoff values based on data from in vitro studies with the use of transcellular transport systems as benchmarks for judging the need for a clinical study to evaluate drug interaction medicated by transporters, it was reported that there are differences in the cutoff values among regulatory agencies [20]. There are multiple known cases in which drugs that are eliminated via drug metabolism can be a substrate of a transporter, but no quantitative risk assessment approaches have been established for complex drug interactions between DMEs and
transporters [21]. Some approaches for investigating transportermediated interactions, including cutoff values, could be changed based on initiatives by international harmonisation relating to approaches for investigating drug interactions, which will be discussed later in Section 4-2.
4.2. Future perspectives The new guideline includes M&S approaches such as PBPK model analysis, for the first time. Only 17/150 NDAs (11.3%) of new molecular entities submitted to the PMDA from 2014 to 2016 included data with PBPK model analysis; however, more than half of the PBPK analyses (10/17 NDAs), were carried out to evaluate drug interactions of investigational drugs [22]. The application of M&S approaches to investigate drug interactions during clinical development is expected to become widely available as additional scientific knowledge such as physiology parameters is gained and confidence in the use of model analysis increases. When M&S approaches are used to investigate drug interaction during clinical development, sufficient explanations have to be provided regarding the appropriateness of the constructed model including evaluation of predictive performance in view of statistical, physiological, medical, and pharmaceutical aspects, which depends on the intended use of M&S data for the approval application filing (e.g., as a reference for developing clinical drug interaction study protocols, supplementing clinical PK data, or substituting for an actual clinical drug interaction study). In recent years, countries and regions have released their own regulatory documents on approaches for investigating drug interactions [23e25]. New drug development that follows these regulatory documents will help accumulate knowledge on drug interactions based on updated, scientifically validated approaches, which will encourage evidence-based scientific discussions. Meanwhile, the limitations of scientific knowledge may raise concerns about differences in the acceptance criteria among regulatory agencies, such as the aforementioned example of different cutoff values for investigating transporter-mediated drug interactions based on in vitro studies. A report noted that there were differences in precautionary statements regarding drug interactions when package inserts for new drugs approved in recent years are compared among countries including the US, UK, and Japan [26]. At the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), a new topic relating to drug interaction studies, the ICH M12 informal working
Please cite this article as: Ishiguro A et al., Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.11.009
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group, initiated its activities in June 2019 [27]. Multi-regional drug development is in an increasing trend that has continually underscored the importance of international harmonisation on guideline for investigating drug interactions, and is raising expectations for early development and publication of the ICH M12 guidelines. Author Contributions A.I. surveyed the data in NDAs, and wrote the original manuscript draft. All authors contributed to the writing, reviewing and editing of the document. Declaration of competing Interest The authors declare no conflict of interest. The views presented in this article are those of authors and do not necessarily reflect the official position of the Pharmaceuticals and Medical Devices Agency. Acknowledgements This research was supported by research grants from the Ministry of Health and Labour Welfare (MHLW) (H24-tokubetsu-sitei034, H25-iyaku-sitei-011) and the Japan Agency for Medical Research and Development (AMED) (15mk0101060h0101, 16mk0101040h0002, 17mk0101040h0003). We thank all researchers who joined the MHLW Drug Interaction Research/ Working Group, and the research group that continued as the Research on Regulatory Science of Pharmaceuticals and Medical Devices, AMED. References [1] Ministry of Labor and Welfare. Methods of drug interaction studies, notification No.813, evaluation and licensing division. Japan: Pharmaceuticals Medical Safety Bureau; June 4, 2001. [2] European Medicines Agency. Guideline on the investigation of drug interactions, draft, CPMP/EWP/560/95/Rev.1, committee for human medical products, EU. April 22, 2010. https://www.ema.europa.eu/en/documents/ scientific-guideline/draft-guideline-investigation-drug-interactions_en.pdf. [Accessed 14 August 2019]. [3] Food and Drug Administration. Guidance for industry, drug interaction studies e study design, data analysis, implications for dosing, and labeling recommendations, DRAFT. Center for Drug Evaluation and Research, U.S. Department of Health and Human Services; February 2012. [4] Ministry of Labor and Welfare. Guideline on drug interaction for drug development and appropriate provision of information (final draft), office communication. Japan: Pharmaceutical Evaluation Division, Pharmaceuticals Safety and Environmental Health Bureau; July 8, 2014. [5] Ministry of Labor and Welfare. Guideline on drug interaction for drug development and appropriate provision of information, notification No.07234, pharmaceutical evaluation division, pharmaceuticals safety and environmental Health bureau, Japan. July 17, 2018. https://www.pmda.go.jp/files/ 000228122.pdf. [Accessed 14 August 2019]. [6] Nagai N. Drug interaction studies on new drug applications: current situations and regulation views in Japan. Drug Metab Pharmacokinet 2010;25:3e15. [7] Miners JO, Mackenzie PI, Knights KM. The prediction of drug-glucuronidation parameters in humans: UDP-glucuronosyltransferase enzymeselective substrate and inhibitor probes for reaction phenotyping and in vitroein vivo extrapolation of drug clearance and drug-drug interaction potential. Drug Metab Rev 2010;42:196e208.
[8] Yuan R, Madani S, Wei X, Reynolds K, Huang S-M. Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metab Dispos 2002;30:1311e9. [9] Walsky RL, Obach RS. Validated assays for human cytochrome P450 activities. Drug Metab Dispos 2004;32:647e60. [10] Grimm SW, Einolf HJ, Hall SD, He K, Lim H-K, Ling KJ, et al. The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the Pharmaceutical Research and Manufacturers of America. Drug Metab Dispos 2009;37:1355e70. [11] Fontana E, Dansette PM, Poli SM. Cytochrome P450 enzymes mechanism based inhibitors: common sub-structures and reactivity. Curr Drug Metabol 2005;6:413e54. [12] Guengerich FP, Kim DH, Iwasaki M. Role of human cytochrome P-450 IIEl in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol 1991;4:168e79. [13] Maeda K, Hisaka A, Ito K, Ohno Y, Ishiguro A, Sato R, et al. Classification of drugs for evaluating drug interaction in drug development and clinical management. Drug Metab Pharmacokinet; in preparation. Q3 [14] Ministry of Labor and Welfare. Instructions for package inserts of prescription drugs. Notification No.0608-1. Japan: Pharmaceuticals Safety and Environmental Health Bureau; June 8, 2017. [15] Ministry of Labor and Welfare. Points to consider for the instructions for package inserts of prescription drugs. Notification No.0608-1. Japan: Pharmaceutical Safety Division, Pharmaceuticals Safety and Environmental Health Bureau; June 8, 2017. [16] (Japanese-language website) Pharmaceuticals, Medical Devises Agency, Search for Drug Information http://www.pmda.go.jp/PmdaSearch/ iyakuSearch/. [Accessed 20 May 2019]. [17] Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, et al. The conduct of in vitro and in vivo drug-drug interaction studies, A PhRMA perspective. J Clin Pharmacol 2003;43:443e69. [18] Yoshida K, Maeda K, Sugiyama Y. Hepatic and intestinal drug transporters: prediction of pharmacokinetic effects caused by drug-drug interactions and genetic polymorphisms. Annu Rev Pharmacol Toxicol 2013;53:581e612. [19] Zamek-Gliszczynski MJ, Taub ME, Chothe PP, Chu X, Giacomini KM, Kim RB, et al. Transporters in drug development: 2018 ITC recommendations for transporters of emerging clinical importance. Clin Pharmacol Ther 2018;104: 890e9. [20] Vaidyanathan J, Yoshida K, Arya V, Zhang L. Comparing various in vitro prediction criteria to assess the potential of a new molecular entity to inhibit organic anion transporting polypeptide 1B1. J Clin Pharmacol 2016;56(Suppl 7):S59e72. [21] Zhang L, Zhang Y, Huang S-M. Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions challenges in predicting drug interaction. Mol Pharm 2009;6:1766e74. [22] Sato M, Ochiai Y, Kijima S, Nagai N, Ando Y, Shikano M, et al. Quantitative modeling and simulation in PMDA: a Japanese regulatory perspective. CPT Pharmacometrics Syst Pharmacol 2017;6:413e5. [23] European Medicines Agency. Guideline on the investigation of drug interactions, CPMP/EWP/560/95/Rev.1 Corr.2, committee for human medical products, EU. June 21, 2012. https://www.ema.europa.eu/en/documents/ scientific-guideline/guideline-investigation-drug-interactions_en.pdf. [Accessed 14 August 2019]. [24] Food and Drug Administration. Guidance for industry, clinical drug interaction studies e study design, data analysis and clinical implications, DRAFT. Center for Drug Evaluation and Research, U.S. Department of Health and Human Services; October 2017. https://www.fda.gov/media/82734/download. [Accessed 14 August 2019]. [25] Food and Drug Administration. Guidance for industry. Vitro metabolism- and transporter- mediated drug-drug interaction studies, DRAFT. Center for Drug Evaluation and Research, U.S. Department of Health and Human Services; October 2017. https://www.fda.gov/media/108130/download. [Accessed 14 August 2019]. [26] Jeong S, Kam G, Li J, Lee S, Lee H, Noh Y, et al. Assessment of consistency of drug interaction information in drug labels among the United States, the United Kingdom, China, Japan, and korea. Clin Pharmacol Ther 2019;105: 505e14. [27] The ICH official website. https://www.ich.org/home.html. [Accessed 27 June 2019].
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Review
Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information Q4,1
Akihiro Ishiguro*, Reiko Sato, Naomi Nagai 1 Pharmaceuticals and Medical Devices Agency, Shin-Kasumigaseki Bldg. 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 August 2019 Received in revised form 12 November 2019 Accepted 13 November 2019 Available online xxx
Drug interactions, in particular with concomitant drugs having a narrow therapeutic range, sometimes cause serious adverse drug reactions or attenuation of the therapeutic effect. Therefore, evaluation of the characteristics and severities of possible drug interactions in drug develoment is essential to understand such interactions to help prevent any potential risk for patients. In Japan, a regulatory document which was notified in 2001 to outline the basic principles of drug interaction studies during drug development was revised as a new guideline after 17 years to present general procedures that are currently considered scientifically valid. This article aims to present an overview of development process of the new Japanese guideline for investigating drug interactions and show the impact of implementating this guideline on drug interaction evaluations, thereby providing future perspectives of regulatory activities on drug interactions.
Keywords: Drug interaction Cytochrome P450 Transporter Package insert Guideline Drug development Japan
© 2019 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
1. Background Drug interactions are the phenomena that occur between concomitant drugs, or drugs and food that may affect drug responses such as pharmacokinetic (PK) profile, efficacy or safety of drug. Knowledge of how to prevent serious adverse drug reactions or attenuation of therapeutic effect due to drug interactions can lead to more efficient drug development. In addition, reflecting drug interaction data in drug package inserts including information on mechanisms and the degree of interactions which were determined during the drug development process is essential for ensuring proper use of drugs in clinical settings. In Japan, the regulatory document notified by the Ministry of Health, Labour and Welfare (MHLW) in June 2001 was referenced to investigate drug interactions during drug development and review drug interactions during the regulatory approval review [1]. Based
* Corresponding author. Planning and Coordination Division, Advanced Science and Technology Division, Office of Research Promotion, Center for Regulatory Science, Pharmaceuticals and Medical Devices Agency, Shin-Kasumigaseki Bldg. 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan. E-mail address: [email protected] (A. Ishiguro). 1 Current address; Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202e8585, Japan.
on accumulated scientific knowledge and technology advancement in the area of PK or clinical pharmacology after the notification was published in 2001, and the recent revisions of regulatory documents on drug interaction studies in the EU and US, the Japanese regulatory document was revised [2,3]. The Japanese guideline revisions were undertaken by a research group that consisted of academics affiliated with relevant academic societies, such as the Japanese Society for the Study of Xenobiotics and the Japanese Society of Clinical Pharmacology and Therapeutics, personnel engaged in preclinical and clinical development at pharmaceutical companies, and regulators of regulatory authorities (Fig. 1). Until the notification of the new Japanese guideline in 2018, a final draft of the guideline was published, and public consultations occurred twice around the time of the final draft publication [4,5]. Responses to major comments obtained during the public consultation or guideline descriptions requiring appropriate commentary with relevant referenced literature are included in a document on questions and answers that was published along with the new Japanese guideline [5]. This article aims to present the highlights of the new Japanese guideline and address the background underlying investigations by the research group as needed. Hereafter, the Japanese regulatory document notified in 2001 is referred to as “the old notification” and the Japanese guideline notified in 2018 is referred to as “the new guideline” [1,5].
https://doi.org/10.1016/j.dmpk.2019.11.009 1347-4367/© 2019 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.
Please cite this article as: Ishiguro A et al., Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.11.009
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Fig. 1. Overview of the development of regulatory documents on drug interaction studies in the EU, US and Japan. An overview when the old notification was released was also reported by the author [6]. Abbreviations; ICH, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; FY, Japanese fiscal year.
In a previous study [6], the author collected information on characteristics of drug interaction studies shown in review reports or new drug applications (NDAs) that were approved around the time when the old notification was published in 2001. Additionally, the previous study clarified future issues requiring further consideration such as methods for investigating transporter-mediated drug interactions or more reliable interpretations of non-clinical data to decide whether a clinical drug interaction study is necessary. In this article, we searched the PMDA website, which is publicly available, to present the results of a follow-up survey on drug interaction studies in NDAs for new drugs that were approved until fiscal 2018, which is when the new guideline was published. Based on the available regulatory review data, impacts of the new guideline implementation on new drug development will also be discussed. 2. New guideline contents The basic policy for developing the new guideline was to provide a comprehensive guide of methods for investigating drug interactions from drug development to post-marketing stages, including in vitro drug interaction assessments, judgment on the necessity of a clinical drug interaction study, study design to evaluate the presence or absence of drug interactions and levels of impacts of the interactions in clinical settings, and a general guide for interpretations and provision of information obtained from the study data. Moreover, consistency with regulatory documents published by the European Medicines Agency and US Food and Drug Administration was taken into account to the extent possible to finalize the new guideline. As in the old notification, descriptions in the new guideline focused on methodologies for investigating PK drug interactions following oral administration. Methodologies for evaluating pharmacodynamic drug interactions were outside the scope of this guideline as there are no universal indicators, such as blood drug concentration for evaluating PK drug interactions. Similar to the old notification, the new guideline consists of chapters on drug absorption, tissue distribution, drug metabolism, excretion, and planning and conducting clinical drug interaction studies (Table 1). In addition to these chapters, the new guideline includes new sections on drug interactions mediated by transporters (Chapter 6)
and general principles for reflection of information and alerts on drug interactions in package inserts (Chapter 8). The appendices provides decision trees for investigating the possibility that an investigational drug could be a substrate, inhibitor, or inducer of a drug metabolizing enzyme (DME), or a transporter, which can be used as reference for determining the necessity of a clinical drug interaction study based on data obtained from in vitro drug interaction studies or a PK study in an early clinical development stage. 2.1. Clarification of procedures from non-clinical through clinical development In the old notification, the involvement of transporters in drug absorption and excretion was described, however, transporter isoforms targeted for drug interaction studies to be conducted during drug development were not identified. In contrast, the new guideline referred to not only major DMEs, such as CYP1A2, CYP2B6, or CYP3A, but also specific transporter isoforms for the first time. The new guideline also included some specific methods for investigating drug interactions mediated by transporters involved in absorption (P-gp and BCRP), uptake into liver (OATP1B and OATP1B3), and renal excretion (OAT1, OAT3, OCT2, MATE1, and MATE2-K). In the new guideline, decision trees were drawn to facilitate determination of the need for a clinical study of drug interactions mediated by DMEs, so as to investigate whether an investigational drug can be a substrate of a specific DME and can inhibit or induce any DMEs. The need for such a clinical drug interaction study is decided based on the in vivo contribution ratio (CR) of the major elimination pathway estimated from fraction metabolized (fm) obtained from an in vitro metabolism study using human liver microsomes in general and data available from PK studies conducted in early clinical development, e.g., mass balance studies, intravenous administration studies. If the in vivo CR values for major isoenzymes of DMEs of investigational drugs are estimated to be small, an in vitro metabolism study should be considered for the other isoenzymes, such as CYP2A6, or CYP2E1, or phase I enzyme other than P450, such as monoamine oxidase, flavin monooxygenase, xanthine oxidase, aldehyde oxidase, alcohol dehydrogenase, or aldehyde dehydrogenase [7e12]. The necessity of a clinical interaction study to investigate whether the investigational
Please cite this article as: Ishiguro A et al., Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.11.009
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Table 1 Table of contents for “Guideline on drug interaction for drug development and appropriate provision of information” [5]. Table of Contents 1. Introduction 1.1 Background and objectives 1.2 Scope 1.3 Principles of drug interaction studies 2. Drug interactions in absorption 2.1 Effects on gastrointestinal pH, complex/chelate formation, and solubility 2.1.1 Effects of concomitant drugs on the investigational drug 2.1.2 Effects of the investigational drug on concomitant drugs 2.2 Effects on gastrointestinal motility 2.2.1 Effects of concomitant drugs on the investigational drug 2.2.2 Effects of the investigational drug on concomitant drugs 2.3 Drug interactions mediated by transporters in the gastrointestinal tract 2.4 Drug interactions mediated by drug metabolizing enzymes in the gastrointestinal tract 3. Drug interactions in tissue distribution 3.1 Plasma protein binding 3.2 Tissue distribution 3.2.1 Binding to specific tissue components 3.2.2 Involvement of transporters in uptake and efflux in tissue 4. Drug interactions in drug metabolism 4.1 Evaluation of the possibility of the investigational drug as an affected drug 4.2 Evaluation of the possibility of the investigational drug inhibiting drug metabolizing enzymes 4.3 Evaluation of the possibility of the investigational drug inducing drug metabolizing enzymes 4.4 Drug interaction studies mediated by enzymes other than cytochrome P450 4.5 Drug interactions with biotechnological/biological products (Therapeutic proteins) 5. Drug interactions in excretion 5.1 Drug interactions in urinary excretion 5.2 Drug interactions in hepatobiliary transport 6. Drug interactions mediated by transporters 6.1 General considerations in in vitro studies 6.2 Studies to examine drug interactions mediated by transporters involved in absorption 6.3 Studies to examine drug interactions mediated by transporters in the liver 6.4 Studies to examine drug interactions mediated by transporters in the kidney 7. Evaluation by clinical drug interaction studies 7.1 Need for and timing of clinical drug interaction studies 7.2 Relevant indices of drug interactions and pharmacokinetic parameters to be evaluated 7.3 Study design 7.4 Dose and route of administration 7.5 Duration and timing of administration 7.6 Selection of inhibitors for drug metabolizing enzymes and transporters 7.6.1 Clinical drug interaction studies using inhibitors of cytochrome P450 7.6.2 Clinical drug interaction studies using inhibitors of drug metabolizing enzymes other than cytochrome P450 and transporters 7.7 Selection of inducers for drug metabolizing enzymes 7.8 Selection of substrates for drug metabolizing enzymes and transporters 7.9 Other considerations for evaluation by clinical drug interaction studies 7.9.1 Drugs metabolized by a single enzyme and multiple enzymes 7.9.2 Drug interactions involving both drug metabolizing enzymes and transporters 7.9.3 Cocktail substrate studies 7.9.4 Evaluation by population pharmacokinetic analysis 7.9.5 Considerations for subjects with special background 7.9.5.1 Evaluation of drug interactions in consideration of genetic polymorphism 7.9.5.2 Investigational drugs mainly applied to special population or patient populations with specific diseases 7.9.5.3 Studies in patients 8. General principles for reflection of information and alerts on drug interaction in package inserts 8.1 Description in Precautions in drug package inserts 8.2 Description in “Drugs” in the section of “INTERACTIONS” 8.3 Description in the section of “PHARMACOKINETICS” 9. Relevant guidelines etc. 10. Glossary 11. Appendices 11.1 List of figures and tables 11.2 Decision trees 11.3 Examples of substrates, inhibitors, and inducers
drug can inhibit or induce DMEs should be judged by non-clinical data, e.g., the ratio of intrinsic clearance value of a sensitive substrate under the presence and absence of the investigational drug for a specific enzyme reaction (R value) and the range of change in the mRNA expression level of the target gene using primarycultured liver cells among investigational drug-exposed, vehicle control and positive control groups.
The new guideline also described the availability of a modeling and simulation (M&S) at each phase of drug development, which is used to predict possible DME-mediated drug interactions so that the advisability of a proposed clinical drug interaction study can be decided, or a better information for designing the clinical study can be obtained. In the decision trees to investigate DME-mediated interactions, analyses with the use of mechanistic static pharmacokinetics (MSPK) model or physiologically based
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pharmacokinetics (PBPK) model were covered as one of predictors of clinical drug interaction as well as the non-clinical data as mentioned earlier. Decision trees were also offered as references for considering the need for a clinical study to investigate whether an investigational drug is a substrate of transporters or inhibits transporters. The need for a clinical study to investigate transporter-mediated drug interactions could be decided based on the criteria in the decision trees by comparing the results from proper in vitro study systems, i.e., the transport activities to be evaluated were confirmed in advance.
new guideline requires that drug interactions data included in package inserts should be in principle clinical PK information to ensure that the data are easily understood for healthcare professionals in clinical settings. Information on drug interactions provided in package inserts may include the results of in vitro drug interaction studies for transporters or estimates given by M&S approaches, therefore, the new guideline also requires that there should be clear distinctions among data from clinical studies or in vitro studies, and from actual measured values or estimate values.
2.2. Basic guide for conducting a clinical drug interaction study and for appropriately providing information related to drug interactions The new guideline specified representative substrates as concomitant drug candidates for assessing the possibility that an investigational drug inhibits or induces DMEs as a reference for developing clinical drug interaction study protocols. These substrates, referred to as “clinical index substrates” in the new guideline, are sensitive to PK drug interactions with high specificity for the DME that were previously verified by the results of multiple clinical studies (e.g., the representative substrates of CYP3A are midazolam and triazolam). Likewise, the new guideline also specified representative inhibitors or inducers, referred to as “clinical index inhibitors” or “clinical index inducers” that facilitate assessment of inhibitory or inducing effects to the maximum extent when investigating whether the investigational drug is a substrate of a DME as a concomitant drug candidate. Inhibitors have been classified into three levels based on clinical inhibitory effect as follows; when an inhibitor increases the plasma AUC of a sensitive substrate by 5-fold, 2- to < 5-fold, and 1.25to < 2-fold increases, the drug is considered a strong, moderate, and weak inhibitor, respectively (e.g., representatives of the strong inhibitor to CYP3A are clarithromycin and itraconazole). Likewise, inducers are classified according to the degree of induction as follows; when an inducer reduces the plasma AUC of a sensitive substrate to 1/5 or less, 1/2 but >1/5, and <1/1.25 but >1/2, the drug is considered a strong, moderate, and weak inducer, respectively (e.g., representatives of the strong inducer to CYP3A are phenytoin and rifampicin). The new guideline has also offered a summary of typical in vivo substrates and inhibitors for transporters based on publicly available findings. In the final draft of the guideline released in 2014 [4], exhaustive lists were drawn to show examples of substrates, inhibitors, and inducers of DMEs of interest for investigating interactions based on the strength classification, i.e., strong, moderate, or weak, classified earlier. Because frequent list updates would be warranted in light of the newly accumulated scientific knowledge, these lists were not included in the new guideline or the associated document on questions and answers, but will be published in an academic journal as review data along with background information and references from the research group [13]. In parallel with activities of the research group, revision activities had been made to the notifications on instructions for package inserts of prescription drugs released by the MHLW in 1997; then, the new instructions for package inserts were notified in June 2017 [14,15]. The new instructions included a requirement that package inserts should include descriptions of specific DMEs that would be associated with the mechanism of PK drug interactions. The new guideline also requires to give careful consideration to the needs of specifying the strength classification for interactions, i.e., strong, moderate, and weak, in addition to the names of DMEs and transporters contributing to drug interactions when reviewing the contents of the precautionary statement based on drug interactions data obtained during the drug development process. Moreover, the
3. Status of drug interaction evaluation in NDA dossiers submitted to PMDA The major purpose of the new guideline was to clarify suitable investigation procedures throughout the drug development process from non-clinical to clinical stages, where it provides some approaches for investigating drug interactions of specific isoenzymes of DMEs and transporters. To examine the possible impacts of the new guideline implementation on evaluation of PK drug interactions in new drug development, the status of conducting in vitro drug interaction studies was surveyed for new active ingredients of oral formulations based on the relevant review reports and synopses of NDA dossiers on the PMDA website [16]. In accordance with the decision trees in the new guideline, the survey covered the following isoenzymes or isoforms, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, and/or UGT2B7 for DMEs; and P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K for transporters. We identified 103 NDAs for new active ingredients that were approved during the previous five years from fiscal 2014 to 2018, which is the time when the final draft and the new guideline were published. The survey found that in vitro metabolism studies for investigating DME-mediated interactions were conducted in most of NDAs, excluding in vitro enzyme inhibition studies for UGT1A1 and UGT2B7 (Fig. 2a). The absence of a standardized approach to estimate the CR values for UGT isoenzymes may have resulted in a lower percentage of in vitro enzyme inhibition studies compared with other DMEs, however, it is recommended to conduct multifaceted analyses while referring to latest published literatures, such as by using a combination of approaches with expression systems of major UGT isoenzymes and inhibition studies using human liver microsomes and available substrates (e.g., b-estradiol for UGT1A1, morphine or zidovudine for UGT2B7) [17]. In vitro studies for investigating transporter-mediated drug interactions were conducted in approximately more than half of NDAs, except in vitro studies of drugs as substrates of OAT1, OAT3, OCT2, MATE1 and MATE2-K (Fig. 2b). There is a report that the plasma AUC of HMG-CoA reductase inhibitor, a substrate of OATP that is involved in hepatic uptake of drugs, increased by more than five-fold when used with inhibitors of OATP such as cyclosporine or gemfibrozil [18]. Consequently, proper investigations of transporter-mediated drug interactions will lead to a better understanding of safety profiles for investigational drugs. Although the percentages of in vitro studies of drugs as substrates of OAT1, OAT3, OCT2, MATE1 and MATE2-K, which contribute to urinary excretion of drugs by the kidney, were about 10e20% and lower than the percentage of study conducted on other transporter molecules (Fig. 2b), it is recommended to conduct in vitro studies using cell lines known to express kidney transporters for investigational drugs that are known to be mainly excreted into urine.
Please cite this article as: Ishiguro A et al., Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.11.009
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Fig. 2. Characteristics of in vitro drug interaction studies in NDAs for new active ingredients of oral formulation that were approved between 2014 and 2018 in Japan. Percentage of studies of in vitro drug interactions mediated by drug metabolizing enzymes (a), and transporters (b) described in decision trees of the new guideline [5]. Closed, open, and gray bars indicate percentages of the NDAs (n ¼ 103) that included data on in vitro drug interaction studies to investigate whether new active ingredients can be substrates, inhibitors and/or inducers, respectively.
4. Discussions 4.1. New guideline implementation effects and limitations The new guideline provided scientifically validated and updated methodologies to encourage strategic and systematic investigations of drug interactions and information provision from the non-clinical through post-marketing stages based on the latest trends in new drug development as presented in Section 2. We expect that distribution of package inserts containing information on the mechanisms of drug interactions, strength of the interactions, or CR of the major elimination pathway as newly described in the new guideline will promote better understanding of information related to drug interactions and, subsequently, proper use of drugs in clinical settings. The survey in Section 3 indicated that there was no cause for concern regarding the feasibility of using methodologies described in the new guideline, because in vitro drug interaction studies for numerous products have already been performed on isoenzymes of DMEs and transporters, which are recommended for investigating during the drug development in the new guideline. The range of transporter isoforms that were recommended to be assessed by the new guideline was overall consistent with the views expressed by the International Transporter Consortium (ITC) [19]; thus, it appears that the new guideline reflects the latest scientific findings and provides appropriate contents, despite the trend for a lower percentage of investigations on transporter-mediated drug interactions compared with those on DMEs. The ITC article also extends to other isoforms that may aid drug developers in predicting characteristics of drug interactions under specific conditions or for special populations (e.g., OATP2B1 and vitamin-drug interactions, THTR2 and populations susceptible to drug-induced thiamine deficiency), which makes continued discussion warranted for validating the range of the transporter isoforms to be evaluated during clinical development. Although the new guideline has proposed cutoff values based on data from in vitro studies with the use of transcellular transport systems as benchmarks for judging the need for a clinical study to evaluate drug interaction medicated by transporters, it was reported that there are differences in the cutoff values among regulatory agencies [20]. There are multiple known cases in which drugs that are eliminated via drug metabolism can be a substrate of a transporter, but no quantitative risk assessment approaches have been established for complex drug interactions between DMEs and
transporters [21]. Some approaches for investigating transportermediated interactions, including cutoff values, could be changed based on initiatives by international harmonisation relating to approaches for investigating drug interactions, which will be discussed later in Section 4-2.
4.2. Future perspectives The new guideline includes M&S approaches such as PBPK model analysis, for the first time. Only 17/150 NDAs (11.3%) of new molecular entities submitted to the PMDA from 2014 to 2016 included data with PBPK model analysis; however, more than half of the PBPK analyses (10/17 NDAs), were carried out to evaluate drug interactions of investigational drugs [22]. The application of M&S approaches to investigate drug interactions during clinical development is expected to become widely available as additional scientific knowledge such as physiology parameters is gained and confidence in the use of model analysis increases. When M&S approaches are used to investigate drug interaction during clinical development, sufficient explanations have to be provided regarding the appropriateness of the constructed model including evaluation of predictive performance in view of statistical, physiological, medical, and pharmaceutical aspects, which depends on the intended use of M&S data for the approval application filing (e.g., as a reference for developing clinical drug interaction study protocols, supplementing clinical PK data, or substituting for an actual clinical drug interaction study). In recent years, countries and regions have released their own regulatory documents on approaches for investigating drug interactions [23e25]. New drug development that follows these regulatory documents will help accumulate knowledge on drug interactions based on updated, scientifically validated approaches, which will encourage evidence-based scientific discussions. Meanwhile, the limitations of scientific knowledge may raise concerns about differences in the acceptance criteria among regulatory agencies, such as the aforementioned example of different cutoff values for investigating transporter-mediated drug interactions based on in vitro studies. A report noted that there were differences in precautionary statements regarding drug interactions when package inserts for new drugs approved in recent years are compared among countries including the US, UK, and Japan [26]. At the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), a new topic relating to drug interaction studies, the ICH M12 informal working
Please cite this article as: Ishiguro A et al., Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.11.009
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group, initiated its activities in June 2019 [27]. Multi-regional drug development is in an increasing trend that has continually underscored the importance of international harmonisation on guideline for investigating drug interactions, and is raising expectations for early development and publication of the ICH M12 guidelines. Author Contributions A.I. surveyed the data in NDAs, and wrote the original manuscript draft. All authors contributed to the writing, reviewing and editing of the document. Declaration of competing Interest The authors declare no conflict of interest. The views presented in this article are those of authors and do not necessarily reflect the official position of the Pharmaceuticals and Medical Devices Agency. Acknowledgements This research was supported by research grants from the Ministry of Health and Labour Welfare (MHLW) (H24-tokubetsu-sitei034, H25-iyaku-sitei-011) and the Japan Agency for Medical Research and Development (AMED) (15mk0101060h0101, 16mk0101040h0002, 17mk0101040h0003). We thank all researchers who joined the MHLW Drug Interaction Research/ Working Group, and the research group that continued as the Research on Regulatory Science of Pharmaceuticals and Medical Devices, AMED. References [1] Ministry of Labor and Welfare. Methods of drug interaction studies, notification No.813, evaluation and licensing division. Japan: Pharmaceuticals Medical Safety Bureau; June 4, 2001. [2] European Medicines Agency. Guideline on the investigation of drug interactions, draft, CPMP/EWP/560/95/Rev.1, committee for human medical products, EU. April 22, 2010. https://www.ema.europa.eu/en/documents/ scientific-guideline/draft-guideline-investigation-drug-interactions_en.pdf. [Accessed 14 August 2019]. [3] Food and Drug Administration. Guidance for industry, drug interaction studies e study design, data analysis, implications for dosing, and labeling recommendations, DRAFT. Center for Drug Evaluation and Research, U.S. Department of Health and Human Services; February 2012. [4] Ministry of Labor and Welfare. Guideline on drug interaction for drug development and appropriate provision of information (final draft), office communication. Japan: Pharmaceutical Evaluation Division, Pharmaceuticals Safety and Environmental Health Bureau; July 8, 2014. [5] Ministry of Labor and Welfare. Guideline on drug interaction for drug development and appropriate provision of information, notification No.07234, pharmaceutical evaluation division, pharmaceuticals safety and environmental Health bureau, Japan. July 17, 2018. https://www.pmda.go.jp/files/ 000228122.pdf. [Accessed 14 August 2019]. [6] Nagai N. Drug interaction studies on new drug applications: current situations and regulation views in Japan. Drug Metab Pharmacokinet 2010;25:3e15. [7] Miners JO, Mackenzie PI, Knights KM. The prediction of drug-glucuronidation parameters in humans: UDP-glucuronosyltransferase enzymeselective substrate and inhibitor probes for reaction phenotyping and in vitroein vivo extrapolation of drug clearance and drug-drug interaction potential. Drug Metab Rev 2010;42:196e208.
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Please cite this article as: Ishiguro A et al., Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information, Drug Metabolism and Pharmacokinetics, https://doi.org/10.1016/j.dmpk.2019.11.009
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