Drug Interaction Studies on New Drug Applications: Current Situations and Regulatory Views in Japan

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) approved 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 drugmetabolizing enzyme-based drug interactions have improved, and become more rational based on mechanistic theory and new technologies. On the basis of incremental evidence of transporter roles in human pharmacokinetics, 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 information 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 interaction studies in recent new drug development. This review summarizes current situations and further discussion points on drug interaction studies in NDAs in Japan. Keywords: drug interaction; drug development; new drug application; new molecular entity; pharmacokinetics; metabolism; transport; package insert

remarkably significant increase in the concentration of 5-FU.1–3) Between 1998 and 2001, there has also been early termination of development or withdrawal from medical practice of some NMEs, mainly due to metabolic drug interactions caused by the inhibition of cytochrome P450 3A4 (CYP3A4).4) Through these experiences, the importance of investigating drug interaction potentials for NME during drug development and providing appropriate drug interaction information in PIs has been reemphasized. Regulatory authorities in Japan and overseas therefore issued documents for drug interaction studies around 2000.5–8) Drug interactions are generally categorized as pharmacokinetic (PK)- and pharmacodynamic (PD)- related drug interactions. PK-related drug interactions include those affecting absorption, distribution, metabolism and excretion. PD-related interactions deal with additive, syn-

Introduction Drug interactions change dose-response relationships, and result in low efficacy or high toxicity of drugs, which are important considerations especially in medical practice with multiple-drug therapies. In current clinical settings, multiple-drug therapies are often prescribed, resulting in more difficult situations for healthcare professionals to adequately monitor drug interactions. Over the past 20 years, there have been several fatal drug interactions that were only detected by serious adverse reactions occurring after marketing. The life-threatening drug interactions caused by taking sorivudine and tegafur became a serious problem heavily covered by the media in Japan in 1993. Further investigations reported that the mechanism of this interaction could be inhibition of 5fluorourasil (5-FU) metabolism by sorivudine, resulting in

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, ShinKasumigaseki 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 inhibitors in Japan. Figure 3 was modified with the figure in the reference book of Clinical Pharmacokinetic Studies of Pharmaceuticals12).

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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: ChemBio 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 pharmacology of both investigational and concomitant drugs. This review refers to only PK-related drug interactions.

Regulatory Documents and Discussions on Drug Interaction Studies Figure 1 shows regulatory documents and related discussion on drug interaction studies in Japan and overseas. In 1998, the Ministry of Health, Labour and Welfare (MHLW) organized the Working Groups for Drug Interactions and Clinical Pharmacokinetic Studies and started an intensive discussion for drug interaction studies during new drug development. Since then, an increasing number of related conference meetings has been held and related regulatory documents have been published in Japan. The regulatory document, ``Methods of Drug Interaction Studies'' was issued on June 4, 2001 and covers fundamental points, in vitro and in vivo study approaches concerning drug interactions. ``Clinical Pharmacokinetic Studies of Pharmaceuticals'' and ``Guideline on Non-clinical Pharmacokinetic Studies'' describe the scope and basic principles of pharmacokinetic studies necessary for submitting new drug applications, both of which are useful to plan, conduct and evaluate drug interaction studies.9–11) In addition to these regulatory documents, the MHLW Working Groups for Drug Interactions and Clinical Pharmacokinetic Studies published a reference book in 2003 that includes English versions of

regulatory documents, related guidelines and information of literatures.12) The United States Food and Drug Administration (U.S. FDA) published a concept paper in 2004 and new draft guidance for drug interaction studies in 2006, including study design, data analysis and labeling implications.13,14) Many conference meetings and workshops have also been held in the U.S. to discuss and update on this issue over the past 5 years. The European Medicines Agency (EMEA) announced a concept paper in 200815) to recommend revising guidance on investigations of drug interactions published in 1997. Recently, in Japan, there have been many opportunities mainly provided by academia to discuss drug interaction related topics especially on transporter-based drug interactions. Each of the 3 ICH regions (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) has published its own regulatory documents for drug interaction studies. These documents provide similar principles for drug interaction studies in drug development and also reflecte the latest scientific knowledge, technologies and medical practices at the time of their publications, although some differences are found in the scope of in vitro and in vivo studies and labeling implications. Figure 2 shows the contents of ``Methods of Drug Interaction Studies''. The Japanese document includes the following: (1) focusing on not only metabolism-mediated drug interactions as the most frequent mechanism for drug interac-

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Fig. 2. Methods of drug interaction studies: table of contents

tions,16) but also on absorption-, distribution- and excretion-mediated drug interactions, therefore including the points of consideration for all PK process, (2) brief labeling implications because official guidelines and regulatory documents for PIs had been issued,17–20) (3) primarily describing clinical drug interaction studies and in vitro studies using human tissue-derived samples and expression systems. Figure 3 shows a typical approach for investigating drug interaction potentials during new drug development.12) Although the reference book shows a case in which a drug candidate may be a metabolic inhibitor and developed in oral dosage form,12) basic principles, typical approaches and general decision-making to investigate drug interactions in new drug development are common and summarized as follows, (1) sequence of studies are rationally planned from pre-clinical development phase to clinical development phase, (2) possible factors and

mechanisms of drug interactions associated with investigationed drugs are identified by basic non-clinical and clinical PK studies, non-clinical drug interaction studies and clinical drug interaction studies, (3) the most possible risk of interactions between investigationed drugs and other drugs in humans are assessed based on drug interaction studies in early-clinical development phase, (4) possible drug interactions in humans are exploratorily evaluated in late-clinical development phase, (5) labeling information and drug interaction study data are appropriately provided in PIs and (6) risk reassessment of drug interactions, followed by feed back of this information to medical practice is periodically conducted during post-marketing period.

Drug Interaction Studies in Recent NDAs in Japan Purpose and methods: The purpose of this survey is to identify current situations of drug interaction stu-

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Fig. 3. Typical approach for investigating drug interaction potentials in new drug development A case in which an investigationed drug candidate may be a metabolic inhibitor and developed in oral dosage form. CuHi max(appr): an approximation of maximum concentration of the unbound inhibitor in the liver. CP*/CP: extent of increase in plasma concentration (AUC or Css) of the inhibited drug. (modified with the figure in reference 12), in Japanese).

dies conducted and submitted for NDAs in Japan, then consider the impact of ``Methods of Drug Interaction Studies'' and further discussion points. The 300 NDAs of NMEs (Shin-yukoseibun ganyuiyakuhin, both chemical and biological NMEs) approved in Japan between 1997 and 2008 were examined. The information sources used for analysis are mainly the review reports prepared by the PMDA and Pharmaceuticals and Medical Devices Evaluation Center of the National Institute of Health Sciences (PMDEC, predecessor organization of PMDA), and summaries of data submitted by applicants. Both review reports and summaries of data are open to the public, and are mostly available on the Web site.21–22) For comparing situations before and after publication of ``Methods of Drug Interaction Studies'' as well as considering effects of recent trends in science and technology, NDAs were divided into three groups, NDAs approved between 1997 and 2001 (Period 1, included 113), NDAs between 2001 and 2004 (Period 2, included 77) and NDAs between 2005 and 2008 (Period 3, included 110) (Figs. 1 and 4). The following information regarding non-clinical and clinical drug interaction studies was collected by six reviewers of the Office of New Drugs in the PMDA and PMDEC, Non-clinical drug interaction study: mechanism of PK-related drug interactions (plasma protein binding, transport proteins, drug-metabolic enzyme-inhibition or induction), study systems and materials (human biologi-

cal materials, cDNA expression systems, animals) and marker drugs (substrates, inhibitors, inducers) Clinical drug interaction study: study design, concomitant drugs, labeling information. Current situation of drug interaction studies: The trends of drug interaction studies for NMEs approved between 1997 and 2008 are shown in Figure 4. The number of approved NMEs were more than 100 in periods 1 and 3, although temporarily decreased in period 2 when PMDEC was reorganized to the present PMDA in 2004 (Fig. 4A). In period 1, 82% of the NDAs (93/113 NDAs) were found to have at least one non-clinical drug interaction study, which has decreased to 71% (55/77 NDAs) and 72% (79/110 NDAs) in periods 2 and 3 (Fig. 4B), respectively. Those containing at least one clinical drug interaction study have slightly increased from 54% (61/113 NDAs) in period 1 to 56% (43/77 NDAs) and 58% (64/110 NDAs) in periods 2 and 3, respectively (Fig. 4C). Figure 5 shows trends in administration routes of 300 NMEs approved between 1997 and 2008. Among the approved NMEs, 54% (163/300 NDAs) have been developed in oral dosage form, 28% (83/300 NDAs) in systemic injection dosage form (intravenous or intra-arterial) and about 9% (26/300 NDAs) in local injection dosage form (subcutaneous or intramuscular) (Fig. 5A). NDAs containing at least one drug interaction study were different in oral and other dosage forms (Fig. 5B).

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Fig. 4. Drug Interaction studies in new drug applications (NDAs) for new molecular entities (NMEs) approved in Japan between 1997 and 2008 A: Numbers of approved NMEs. B: NDAs containing non-clinical drug interaction studies, C: NDAs containing clinical drug interaction studies.

Fig. 5. Relationships between drug interaction studies in NDAs and administration routes (A and B) for new molecular entities (NMEs) approved between 1997 and 2008 Open column: numbers of approved NDAs between 1997 and 2008, light grey column: NDAs containing non-clinical drug interaction studies, solid column: NDAs containing clinical drug interaction studies. * one NMEs was developed as both oral and intravenous injection dosage forms.

Regarding orally administered NMEs, most NDAs contained non-clinical drug interaction studies and four fifths of NDAs contained clinical drug interaction studies, while less drug interaction studies were submitted for injection and other routes of administration. Drug interactions after oral administration could pre-systemically and systemically occur so that more drug interaction studies were conducted in the development of the oral dosage form. Figure 6 shows trends in therapeutic areas

of 300 NMEs approved between 1997 and 2008. Therapeutic areas were classified into 10 disease groups: gastrointestinal disease, cardiorenal disease, neuropharmacologic disease, endocrinologic disease, infectious disease, HIV, urologic and gynecologic diseases, allergic and immunologic diseases, cancer and others (medical diagnosis, radiopharmacology and biological products other than recombinant NMEs), according to the new drug review teams of the Office of New Drugs in the PMDA as of

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Fig. 6. Relationships between drug interaction studies in NDAs and therapeutic areas (A and B) for new molecular entities (NMEs) approved between 1997 and 2008 Open column: numbers of approved NDAs between 1997 and 2008, light grey column: NDAs containing non-clinical drug interaction studies, solid column: NDAs containing clinical drug interaction studies.

2008. NDAs that contained at lease one drug interaction study were not consistent in different therapeutic areas (Fig. 6B). Drug interactions were the most frequently studied in the development of anti-HIV, cardiorenal and anti-infective drugs, followed by neuropharmacologic drugs. Cardiorenal and neuropharmacologic drugs are usually administered in oral dosage form and prescribed as multiple and/or long-term drug therapies. During longterm drug therapies, drug accumulation and enzyme induction may occur and the number and frequency of concomitant drugs may be increased. Compared to these therapeutic areas, NDAs of hormones (therapeutic area, mainly endocrinologic disease and cancer) and anti-cancer drugs contained fewer drug interaction studies, since in part anti-cancer drugs and hormones are usually developed in injection dosage form. Almost all NDAs of HIV drugs contained various and many drug interaction studies, probably due to their oral dosage form and the style of medical practice (multiple-drug therapy). No drug interaction studies have been submitted for NDAs of diagnostic drugs and radiopharmaceuticals and fewer drug interaction studies have been submitted for biological NMEs. This analysis thus shows that drug interaction studies conducted in new drug development and submitted for NDAs reflect both PK profiles of each NME, dosege form and current medical practice in each therapeutic area. In this analysis, the number of NDAs for biological NMEs including recombinant NMEs has been incremen-

tally increased from 4% of total NDAs in the period 1 to 15% and 25% in the periods 2 and 3, respectively. The ``Methods of Drug Interaction Studies'' describes that it is difficult to uniformly apply points to consideration of this document in drug interaction studies on biological NMEs, because of different PK profiles between chemical and biological NMEs. This analysis shows that drug interaction information about biological NMEs is limited at present, probably because drug interaction studies have not been conducted during current drug development. Therefore, a case-by-case discussion is currently needed to study and evaluate drug interaction potentials for biological NMEs. Non-clinical drug interaction studies: Trends in non-clinical drug interaction studies (plasma protein binding-, transporter- and drug-metabolizing enzymebased drug interaction studies) are shown in Figures 7 and 8. 1) Plasma protein binding-based drug interaction studies (Fig. 7A) The percentage of NDAs containing plasma protein binding-based drug interaction studies (displacement studies) decreased from 40% in period 1 to about 20% in period 3. According to the ``Methods of Drug Interaction Studies'', displacement studies between NME and other drugs should be conducted primarily based on the extent of plasma protein binding ability of NME, with consideration to volume of distribution, elimination pathways and rapeutic range. This analysis shows that displacement stu-

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Fig. 7. Classification of targeted mechanism of drug interactions in non-clinical drug interaction studies A: plasma protein binding-based drug interaction studies, B: transporter-based drug interaction studies, C: drug-metabolic enzyme-based drug interaction studies (metabolic inhibition), D: drug-metabolic enzyme-based drug interaction studies (enzyme induction).

Fig. 8. Study systems using metabolic inhibition (A) and enzyme induction (B) studies A: Open column: numbers of approved NDAs containing metabolic inhibition studies, light grey column: microsome, solid column: human hepatocyte, dark grey column: cDNA expression system, B: Open column: numbers of approved NDAs containing enzyme induction studies, solid column: human hepatocyte, dark grey column: in vivo animals.

dies have recently tended to be conducted and submitted in NDAs only for NMEs that have more than 90% of in vitro plasma protein binding, 2) Transporter-based drug interaction studies (Fig. 7B) Transporter-based drug interactions have been increasingly studied in vitro from about 6% in period 1, to about 12% and about 19% in periods 2 and 3, respectively. NDAs containing transporter-based drug interaction studies in period 3 have tripled in number, compared to

period 1. ``Methods of Drug Interaction Studies'' mention that it may be useful to examine in vitro inhibition using human tissue-derived samples, cells, membrane vesicles and transport protein expression systems and study the extent of transporter's contribution to absorption, distribution and excretion process of NMEs, when active transport is greatly suspected. In this analysis, the target transport proteins in the pre-clinical development phase were primarily P-glycoprotein (P-gp), followed by

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organic anion transporting polypeptide (OATP), organic anion transporter (OAT), organic cation transporter (OCT), multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP). 3) Drug-metabolic enzyme-based drug interaction studies (Figs. 7C and 7D, 8A and 8B) The percentage of NDAs containing metabolic inhibition studies has increased throughout the 3 periods, reaching a maximum of 60% in period 3. On the other bend, the percentage of NDAs containing enzyme induction studies has decreased from about 75% in period 1 to about 53% in period 3. To predict clinically significant drug-metabolic enzyme-based drug interactions caused by NME, the importance of in vitro studies using human tissue-derived samples and enzyme expression systems is emphasized in ``Methods of Drug Interaction Studies''. Although the study systems using human liver microsomes were the most common over the 3 periods, there was a recent trend toward increase in the number and variety of study systems such as human hepatocytes in period 3 (Fig. 8A). ``Methods of Drug Interaction Studies'' describes that the case and points regarding the induction study system using experimental animals, which is at present, in vivo animal studies where levels of P450 isoforms are monitored following the repeated dosing of NME, may be useful for screening in the early stage of drug development. The document also points out that prediction of human outcomes with animal data must be carefully made, because of species differences. Cultured human hepatocytes can be useful. This analysis proves that study systems for examining CYP induction have remarkably changed over the past 12 years, showing increase in the use of human hepatocytes, while the use of in vivo animals has been reduced (Fig. 8B). 4) Interpretation of pre-clinical findings to clinical development phase Although understanding mechanisms of drug interactions at molecular levels helps designing appropriate clinical drug interaction studies, quantitative interpretation from in vitro results is still one of the most important considerations.23–28) The choice of probe inhibitors, inducers and marker substrates for early in vitro studies is the first important process to examine drug interaction potentials in new drug development. ``Methods of Drug Interaction Studies'' provides detailed information on typical substrates, inhibitors and inducers for investigating drug interactions for in vitro and in vivo studies, calculation methods for decision making of whether an investigationed drug candidate should be further developed or not, and designs of clinical drug interaction studies (Table 1 and Fig. 3). Based on this analysis, materials and methods for in vitro drug-metabolic enzyme, especially CYP-based drug interaction studies including probe substrates, other reagents and study systems have been common in recent NDAs. Therefore, the standardization

of methodologies and the common understanding of the mechanistic theory to examine in vitro CYP-based drug interaction studies has been achieved in recent new drug development. Because in vitro studies for transporterbased drug interaction have been increasingly conducted in recent new drug development, standardization of materials and general methodologies including decision criteria and prediction from in vitro data to clinical studies needs to be discussed. Non-CYP enzymes, interaction potentials of quantitatively important metabolites in humans, and co or multiple-interactions between metabolism and transport such as CYP3A4 and P-gp-mediated interactions or between inhibition and induction such as CYP3A4-mediated interaction also need to be discussed. Clinical drug interaction studies: Drug interaction studies in the early clinical development phase are usually conducted as clinical pharmacology studies using marker drugs which can assess most expected drug interactions in clinical situations. ``Methods of Drug Interaction Studies'' recommends that clinical studies must be ethically and scientifically conducted. Therefore, it is desirable to reduce the number of clinical studies in the drug development. To successfully understand clinical drug interaction profiles for investigationed drugs, appropriate choices of concomitant drugs for early clinical pharmacology studies, results of in vitro studies and basic human PK data are essential. Table 2 shows the top 5 drugs used in clinical drug interaction studies. Although digoxin, warfarin and cimetidine have been the most frequently used drugs, the number of clinical drug interaction studies with cimetidine which inhibits both P450 nonspecifically and renal tubular secretions, has been decreasing. Clinical drug interaction studies with ketoconazole, one of the potent CYP3A4 inhibitors, have increasingly been submitted for recent NDAs. The rationale for choice of ketoconazole as the marker drug in clinical drug interaction studies has been noted in regulatory documents in Japan and overseas.5,13–14) The FDA draft guidance suggests that if an investigationed drug is shown to be metabolized by CYP3A4 and contribution of this enzyme to the overall elimination pathway is either substantial (À25% of the clearance pathway) or unknown, the choice of inhibitor and inducer may be ketoconazole and rifampin, respectively.14) In this analysis, a wide range of drugs was selected for clinical drug interaction studies, mainly since the choice of drugs was determined based on possible co-prescription or combination therapy in current medical practice, in addition to PK based considerations. ``Methods of Drug Interaction Studies'' also points out that population PK (PPK) approach may be useful when data from many patients are available, depending on the target disease. PPK is used to evaluate a large number drugs in clinical phases 2 and 3, allowing more scientifi-

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Table 1. Subsrates, inhibitors, inducers and reference compounds of major CYP enzymes for in vitro and in vivo drug interaction studies (in ``Methods of Drug Interaction Studies'') P450s

Substrates

Clopidogrel Flutamide CYP1A2 Caffeine (Phenacetin) Theophylline

Inhibitors (in vitro)

Inhibitors (in vivo)

Furafylline a-Naphthofravone Ellipticine Methoxsalen

Fluvoxamine Furafylline Ciprofloxacin Methoxsalen

Methoxsalen Ketoconazole

Inducers

Marker drugs (in vitro)

Charcoal-grilled beef Cigarette smoke Cruciferous vegetables Caffeine Omeprazole Griseofulvin

Marker drugs (in vivo)

Phenacetin Ethoxyresorufin

CYP2A6

(Coumarin) Tegafur Nicotine SM-12502

R-(－)-Menthofuran Tranylcypromine Pilocarpine Ellipticine

CYP2C8

Paclitaxel Diclofenac (5-OH) Rosiglitazone Fluvastatin

Paclitaxel Diclofenac Retinoic acid

CYP2C9

NSAID drugs Phenytoin Tolbutamide S-Warfarin

Sulfaphenazole Dicoumarol

Sulfaphenazole Sulfinpyrazone

Rifampicin Barbiturates

S-Warfarin Tolbutamide

S-Warfarin Tolbutamide Indomethacin Diclofenac (4?-OH)

(S-Mephenytoin) Diazepam Hexobarbital CYP2C19 Imipramine Omeprazole Proguanil Propranolol

Omeprazole S-Mephenytoin Tranylcypromine Mephobarbital Paraverine

Omeprazole

Rifampicin Phenobarbital

(Mephenytoin) Omeprazole Proguanil Diazepam

Mephenytoin Omeprazole

Antidepressants Neuroleptics b-blockers Antiarrhythmics CYP2D6 Codeine Dextromethorphan Ethylmorphine Nicotine

Haloperidol Quinidine Ritonavir

Ajimaline Fluoxetine Paroxetine Quinidine Ritonavir

(Debrisoquine) Dextromethorphan Metoprolol

Debrisoquine Dextromethorphan Bufuralol

1,1,1-Trichloroethane

Diethyldithiocarbamate Ethanol Dimethyl sulfoxide Isoniazid Disulfiram

(Chlorzoxazone)

p-Nitrophenol Chlorzoxazone

Ketoconazole Metyrapone

Clotrimazole Ritonavir (Ketoconazole) Troleandomycin Clarithromycin Glibenclamide Itraconazole Grapefruit juice

Felodipine Midazolam Simvastatin Dextromethorphan Triazolam [Cortisol-6OH excretion]

Felodipine Midazolam Simvastatin Dextromethorphan Testosterone Dapsone Diazepam Triazolam

CYP2E1

(Chlorzoxazone) Alcohols Enflurane Dapsone

Midazolam Erythromycin Cyclosporin Saquinavir Carbamazepine Felodipine CYP3A4 Nifedipine Triazolam Simvastatin Terfenadine Dextromethorphan Verapamil Warfarin

SM-12502 Nicotine

SM-12502 Coumarin

Paclitaxel (6a-OH)

Dexamethasone Phenytoin Rifampicin Troleandomycin Carbamazepine Phenobarbital

There are cases where other enzymes or isoforms, not indicated in the table, are main metabolic enzymes. SM-12502: not approved for sale ( ): therapeutic indications are different from overseas [ ]: endogenous substances used as index of metabolic activity

cally based screening of drug interaction potentials of NMEs.12) Recent new drug development uses the PPK approach for that purpose. If precise sample collection and data analysis are successfully achieved the PPK approach probably can minimize the number of clinical drug interaction studies during drug development, as well as obtain useful information for post marketing phase. Approximately 90% of clinical drug interaction studies

in NDAs are conducted overseas. Foreign clinical trials may be applicable for Japanese regulatory submission.29–31) When foreign clinical drug interaction studies are extrapolated to the patient population and medical practice in Japan, intrinsic and extrinsic ethnic factors should be carefully considered based on ICH E5 guidelines, ``Ethnic Factors in the Acceptability of Foreign Clinical Data''.

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Table 2. Concomitant drugs used in clinical drug interaction studies 2005–2008 (Period 3, 110NDAs)

2001–2004 (Period 2, 77 NDAs)

1997–2000 (Period 1, 113NDAs)

1992–1997 (US, 193 NDAs)*

1

Warfarin

Warfarin

Cimetidine

Cimetidine

2

Digoxin

Antacids

Warfarin

Digoxin

3

Ketoconazole

Digoxin

Digoxin

Warfarin

4

Oral Contraceptive

Ketoconazole

Zidovudine

Theophylline

5

Antacids/Cimetidine

Cimetidine

Antacids

Antacids

Top 5 drugs in all clinical drug interaction studies in NDAs * reference 44)

Table 3. Drug interaction information in PIs: HMG-CoA reductase inhibitors-ciclosporin or digoxin Drug interaction information Name of HMG-CoA reductase inhibitors

Approval year

with ciclosporin

Metabolic enzyme Transport protein Status

with digoxin

Changes in PK

Possible mechanism

Status

Changes in PK

Possible mechanism

Pravastatin

1989

(not metabolized by CYP3A4)

precausion

—

—

—

—

—

Simvastatin

1991

CYP3A4

precausion

—

inhibition (CYP3A4)

—

—

—

Fluvastatin

1998

CYP2C9 (mainly)

precausion

—

—

precausion

Cmax: increase AUC: no change (digoxin)

not clearly determined

Atorvastatin

2000

CYP3A4, P-gp

precausion

—

inhibition (metabolism and biliary excretion)

precausion

Cmax: 1.10–1.20 AUC: 1.04–1.15 (digoxin)

inhibition (P-gp)

Pitavastatin

2003

OATP1B1 (OATP-C/OATP2), (not metabolized by CYP3A4), CYP2C9 (slightly)

contraindication

increase Cmax 6.6 fold AUC 4.6 fold

inhibition (hepatic uptake)

—

—

—

Rosuvastatin

2005

OATP-C (OATP-2), CYP2C9, 2C19 (slightly)

contraindication

increase AUC 7 fold no chanage (ciclosporin)

inhibition (hepatic uptake)

—

no change (digoxin)

—

This table is based on information from PIs of HMG-CoA reductase inhibitors in Japan, —: not informed in PIs

``Methods of Drug Interaction Studies'' also recommends the followings, (1) If significant individual differences in PK due to genetic polymorphism are expected, it is desirable to conduct a study including or excluding subjects with specific genotypes. (2) If a polymorphically expressed enzyme is largely responsible for the metabolism of an investigational drug, it is necessary to discuss the possibility of drug interactions considering the phenotype and/or genotype of each patient. Most clinical drug interaction studies are generally conducted on healthy volunteers. Therefore, for example, if PK study is conducted in poor metabolizers of a polymorphic enzyme, it can be useful instead of drug interaction information with potent inhibitors. The official discussion opportunity for pharmacogenomic issue between sponsor and regulatory agency is now available as formal consultation in PMDA.32) The appropriate use of PPK, global sharing of drug in-

teraction studies based on the ICH E5 guideline and recent advances in pharmacogenomics contribute to rational planning of the number and kinds of clinical drug interaction studies for approval. Considerations of labeling: This analysis shows that drug interaction information has been increasingly and systemically provided on PIs of recently approved NMEs. When outcomes of clinical drug interaction studies conducted in drug development gave significant impact, they were submitted for NDAs and informed as a labeling implication in the drug interaction section and data of clinical drug interaction study were usually presented in either the drug interaction section or PK section. Among NMEs in the same pharmacology class, more recently approved NMEs tend to obtain detailed and increasing amounts of drug interaction information during drug development. Approved labeling tend to include both mechanism and quantitative information of

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Table 4. Transporter-based drug interaction information in PIs in Japan Transport proteins

Nonproprietary Name of NMEs approved between 1997 and 2008

P-glycoprotein

Atorvastatin calcium1, Clarithromycin1, Etaravirine1&2, Everolimus1, Fexofenadine hydrochroride1&2, Ivelmectine2, Lanatocide1, Maraviroc2, Raltegravir pottassium2,*, Rosuvastatin calcium2,*, Saquinavir mesylate1

Organic anion transporter

Adefovir pivoxil1

Organic anion transporting polypeptide

Rosuvastatin calcium2, Pitavastatin calcium2

Peptide transporter

Valaciclovir hydrochloride2, Valganciclovir hydrochrolide2

Others (documented as active renal secretion etc)

Bosentan hydrate2, Doripenem hydrate2, Emtricitabine2, Entecavir hydrate1&2, Tenofovir disoproxil fumarate1&2

Section of statement: 1 Interaction, 2 Pharmacokinetics * no interaction suggested

drug interactions. For example, Table 3 shows drug interaction information on PIs of HMG-CoA reductase inhibitors approved in Japan. In the NDAs of atorvastatin, pitavastatin and rosuvastatin been approved in Japan after 2000, information from many various drug interaction studies including the studies with ciclosporin and/or digoxin were submitted. Ciclosporin is a substrate of CYP3A4 and an inhibitor of OATP.33,34) Some transport proteins including OATP and/or CYP enzymes have important roles in PK of HMG-CoA reductase inhibitors.35–38) Several molecular based studies suggest that inhibition of hepatic uptake of HMG-CoA reductase inhibitors may be a mechanism of drug interactions between HMG-CoA reductase inhibitors and ciclosporin.39) In PIs of pitavastatin and rosuvastatin, possible mechanisms of drug interactions with ciclosporin and quantitative effects on the pharmacokinetics of pitavastatin and rosuvastatin have been shown based on clinical and nonclinical drug interaction studies. PIs of other HMG-CoA reductase inhibitors provide no information on either possible mechanisms or PK change. The drug interaction possibility with digoxin was provided in the PI of atorvastatin and fluvastatin. For atorvastatin, the mechanism would be inhibition of P-gp and digoxin PK change was marginal and for fluvastatin, the mechanism was not clearly determined. According to the literature and Japanese PIs,40–43) Japanese PIs tend to include not enough quantitative information or description about drug interactions. Differences in drug interaction information in PIs among HMG-CoA reductase inhibitors may be time differences between drug development and publication of regulatory documents.40,41) Some recently approved NMEs in Japan include transporter-based drug interaction information in the approved PIs (Table 4). Of the various transport proteins, drug interactions with P-gp are the most well understood and investigated in new drug development; they are listed in either the drug interaction section or PK section in PIs of 11 NMEs approved between 1997 and 2008. The transport proteins currently documented in PIs other

than or in addition to P-gp were OATP and peptide transporter (PEPT1). As the mechanism of drug interactions, descriptions such as active renal secretion were also found in PIs of some NMEs, although no information of the target transport proteins and quantitative impact on the PK was provided. The primary objectives of drug interaction studies during new drug development is to obtain information about whether dose adjustment of the drug itself or concomitant drugs is needed. Although there are many NMEs approved before the publication of ``Methods of Drug Interaction Studies'', clinically important drug interactions for these drugs have been studied and reported in the literature after approval. Some studies are information sources for drug interaction labeling in PIs, depending on the quality of studies. Therefore, drug interaction information helpful for dose adjustment considerations should be periodically reflected in PIs even after approval. Furthermore, how to appropriately provide drug interaction information and give adequate recommendations including dose adjustment in PIs should be carefully considered based on non-clinical and clinical drug interaction studies.

Conclusions and Further Discussion Points Drug interaction studies in new drug development were analyzed using NDAs of NMEs in Japan between 1997 and 2008. The situation of drug interaction studies conducted during new drug development has recently changed, compared to situations when the present regulatory document was issued. The quality of drug interaction studies has improved and become more rational, resulting in more informative labeling in PIs of recently approved NMEs. Thus, the Japanese regulatory document, ``Methods of Drug Interaction Studies,'' in addition to recent advances in science and technology, has contributed to plans and evaluation of drug interaction studies in recent new drug development as well as understanding of drug interaction studies by pharmaceutical companies and a regulatory agency. Based on this analy-

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sis, the following areas described as general points to consideration in the ``Methods of Drug Interaction Studies'', therefore need to be further discussed and updated, (1) Standardization of materials and general methodologies for transporter-based drug interactions to provide more clear instructions for choosing the timing and types of drug interaction studies to be conducted during new drug development. (2) More reliable interpretation of pre-clinical data to design clinical drug interaction studies. (3) Points of consideration to evaluate co or multiple interactions such as multiple CYP inhibitions, inhibition and induction, interactions of both CYP and transporter, non-CYP enzyme mediated drug interactions and drug interaction potentials of quantitatively important metabolites. (4) Basic principles and general approaches for examining drug interaction potentials of biological NMEs during new drug development. (5) More adequate description and reassessment system for drug interaction information on PIs

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Acknowledgements: I thank co-investigators of this survey, T. Arato, F. Kobayashi, S. Hidaka and H. Makimoto and T. Ito. I also thank M. Saito, D. Iwata, M. Hirano, K. Chikazawa, M. Yamada, K. Mori, H. Akagawa and S. Toyoshima for their comments on this work.

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