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Volume 41, Issue 1
Displaying 1-11 of 11 articles from this issue
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Feature Articles : Microdose Clinical Trials
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Yuji KUMAGAI2009 Volume 41 Issue 1 Pages 1
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSDownload PDF (75K) -
Hiroshi MAYAHARA2009 Volume 41 Issue 1 Pages 2-8
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSMicrodose clinical trials are defined as trials conducted in humans to determine the most appropriate compound(s) among candidate compounds with doses ≤100th the calculated human clinical dose and/or ≤100 μg. In the past 6 years, microdose clinical trials have been adopted by authorities of EU, USA and Japan as a new type of clinical trial conducted at the exploratory stage of drug development to facilitate new drug development. All of the guidelines for microdose clinical trials released by the authorities recommend “extended single dose toxicity studies” to support the conduct of microdose clinical trials, however, the reasons for this are not stated in these guidelines. This is because the concept of “extended single dose toxicity studies” was first introduced by FDA in 1996 to support the conduct of “screening clinical trials”, and the rationale for this type of toxicity study are well established. In that context, a microdose clinical trial is considered to be one of the various types of “screening clinical trials”. In the present paper, the history of microdose clinical trials is retraced including “screening clinical trials”, which was approved initially by FDA in 1996, screening-IND studies approved by FDA in 2001, microdose clinical trials approved by EU/EMEA in 1993, by USA/FDA in 2006 and by Japan/MHRW in 2008, exploratory-IND studies approved by FDA in 2006 and exploratory clinical trials adopted in the ICH-M3 (R2) guideline in 2009.View full abstractDownload PDF (399K) -
Yasuo OHNO2009 Volume 41 Issue 1 Pages 9-16
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSMicrodose clinical study was introduced to Japan in June 2008 for the purpose of promoting new drug development. However, the upper dose of the study is below 100 μg and the application of findings to drug development is limited. On the other hand, the ICH-M3 guidance “Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals” was revised in June 2009, which introduces other approaches to exploratory clinical studies. The guidance describes five approaches (two microdose approaches, one sub-therapeutic single dose approach, and two up to therapeutic dose range repeated-dose approaches). Because the highest doses of these studies are limited to within the anticipated non-toxic dose ranges, requirement of toxicity tests is decreased compared to the classic phase 1 study. The rationales for the reduction of toxicity tests are explained.View full abstractDownload PDF (316K) -
Yasuhiko IKEDA2009 Volume 41 Issue 1 Pages 17-20
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSFollowing the publication of the guidance information for clinical studies, it is increasingly important to create an environment conductive to the implementation of microdosing clinical trials. It is known that the accelerator mass spectrometry method using radiolabeled compounds is advantageous over liquid chromatograph/mass spectrometry/mass spectrometry method in detecting and determining Japanese-specific metabolites. However to date, no pharmacokinetic study using radiolabeled compounds has been conducted for drug development in Japan probably due to a resistance in the use of radioactive substances. It is important to demonstrate the safety of the administration of a small dose of radiolabeled compound. When a microdosing clinical trial is conducted as a first in a human trial in drug development, the principal investigator and the deliberators in the Institutional Review Board (Ethics Committee) should be cautious from both the scientific and ethical viewpoints.View full abstractDownload PDF (232K) -
Michio SENDA2009 Volume 41 Issue 1 Pages 21-26
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSThe PET microdose technique is a pharmacokinetic study, in which the subject is administered with a drug candidate compound labeled with a positron emitter (11C or 18F) and the distribution and time course of radioactivity is measured with a PET camera. The labeled compound can also be given in a therapeutic dose. Together with blood sampling and metabolite analysis, the pharmacokinetics of the entire body can be examined. It is the only way to directly measure organ pharmacokinetics in human subjects and it is useful to measure the intracerebral concentration of a compound, which often has a large species variation. However, there are some limitations. Because 11C is too short-lived (half life=20 min), the compound should contain fluorine that can be labeled with 18F (half life=110 min) efficiently. Although formulation is an important factor for absorption, the labeled compound is usually given in a water solution in the case of oral administration, which may result in different absorption kinetics from that of capsules and tablets. Also radiation exposure to the alimentary tract cannot be ignored if a radioactive compound is orally administered. Considering those limitations, more researchers and drug companies are developing PET probes to image specific transporters and drug targets, which can be used to evaluate specific drug transport systems, to select subjects, or to measure receptor occupancy and other pharmacological effects of a candidate compound given in a therapeutic dose. Because of small mass dose, eIND and other microdose approaches are available for the clinical development of such PET probes to be used as diagnostics.View full abstractDownload PDF (347K) -
Kazuya MAEDA, Yuichi SUGIYAMA2009 Volume 41 Issue 1 Pages 27-34
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSThough many types of in vitro high-throughput screening systems have been developed, the number of new drug applications has not increased. One of the reasons is that the time profiles of plasma and tissue concentrations in humans are not desirable for pharmacological actions. Thus, the pharmacokinetics of drug candidates in humans are needed in order to select the most appropriate drugs for further clinical development. The microdosing (MD) study is a powerful approach to directly obtain pharmacokinetic data in humans without extensive toxicology studies. This approach can yield quantitative profiling of drug metabolites by accelerator mass spectrometer (AMS), comparison of plasma and urine profiles of drug candidates simultaneously by cocktail MD administration and measurement by high-spec LC/MS/MS, and real-time monitoring of tissue concentration by positron emission tomography (PET). Therefore, human MD study prior to a clinical study should be very helpful for theoretical drug selection. On the other hand, the concern about the linearity of pharmacokinetics between administration of MD and therapeutic dose is often an issue. In this article, we discuss how to obtain the human pharmacokinetic data of drug candidates by MD study and predict the pharmacokinetics of the clinical dose of specific drugs based on the results of MD and in vitro studies.View full abstractDownload PDF (396K)
Original
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Kazuhiro HARADA, Tomoko HASUNUMA, Tsutomu KOTEGAWA, Eiji UCHIDA, Tomon ...2009 Volume 41 Issue 1 Pages 35-42
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSPreexisting chronic renal failure is a major risk factor of disopyramide-induced hypoglycemia because renal excretion plays a major role in the elimination of disopyramide from systemic circulation. We evaluated the effect of renal failure on the pharmacokinetics of disopyramide, and examined the relationship between plasma disopyramide concentration and serum level of glucose or insulin.
Seventeen subjects with mild to severe chronic renal impairment estimated by the Cockcroft-Gault method and without arrhythmia were enrolled and administered a single oral dose of 100 mg disopyramide after overnight fasting. Four and 24-hour creatinine clearance correlated significantly with AUC (r=0.620 and 0.554 for 4-hour and 24-hour methods, respectively), CL/F (r=0.553 and 0.520) and t1/2 (r=0.584 and 0.616) of disopyramide, as well as AUC (r=0.625 and 0.532) and t1/2 (r=0.611 and 0.670) of monoisopropyl disopyramide, the major metabolite, but did not correlate with Cmax of disopyramide or its metabolite. Serum concentration of alpha-1 acid glycoprotein (AAG) correlated significantly with the pharmacokinetic parameters of disopyramide. Both serum glucose and insulin levels decreased significantly 4 hours after disopyramide administration compared to before dosing, and a weak but significant correlation was observed between plasma disopyramide concentration and the change in serum insulin level (r=0.373), but not the change in serum glucose level.
In conclusion, disopyramide pharmacokinetics is affected not only by renal function impairment, but also by serum AAG concentration. In addition to severe renal function impairment, higher serum AAG concentration may be a risk factor that elevates plasma disopyramide concentration and induces toxic effects.View full abstractDownload PDF (87K)
Forum
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Tomomi FUJINO, Yoshihiko ITO, Yuko TAKI, Nozomi KAKIZAWA, Satomi ONOUE ...2009 Volume 41 Issue 1 Pages 43-52
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSThe so-called health foods, such as functional foods and dietary supplements (vitamins and minerals), are increasingly being used worldwide. With the widespread use of health foods, the chance of their concomitant use with medications is also increasing. However, there is a paucity of practical and useful information on drug-nutrient interactions for medical professionals. The goal of this study was to construct a comprehensive database on clinical interactions between medications and essential nutrients such as vitamins and minerals, which is practical and useful for medical professionals. We conducted an intensive search for literature concerning clinical interaction between warfarin and vitamin K using the PubMed database. Thirty-two articles on the adverse effects associated with their concomitant use were identified. The majority of these articles reported disturbances of the anticoagulation effect of warfarin by the interaction of dietary supplements and vitamin K-containing foods (such as vegetables, chlorella, and fermented soybean called natto) with warfarin. The disturbances including significant falls or rises in international normalized ratio (INR), were caused by the sudden initiation or cessation of consumption of multi-vitamins or foods containing vitamin K. To avoid this potential interference with the efficacy of warfarin, patients are often given instructions to maintain a constant dietary intake of vitamin K. However, in patients with low vitamin K status, even a slight increase in vitamin K intake may lead to a significant reduction in sensitivity to warfarin. In conclusion, to avoid serious adverse effects, the upper limit of vitamin K intake to maintain an optimal anticoagulation level should be appropriately estimated in patients on warfarin treatment, taking into consideration the baseline vitamin K status.View full abstractDownload PDF (412K) -
Kazumi MIURA, Taichi HATTA, Toshinori MURAYAMA, Haruhiko AKIYAMA, Koji ...2009 Volume 41 Issue 1 Pages 53-57
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSBackground: While many previous studies have examined the satisfaction of participants in clinical trials sponsored by pharmaceutical companies for the development of new drugs, few studies of subject satisfaction have been conducted on investigator-initiated clinical trials. The present study surveyed the participants' satisfaction with an investigator-initiated clinical trial and their appraisal of clinical research coordinators (CRCs).
Methods: A questionnaire was sent by post to 32 middle-aged patients who participated in a phase II trial related to an orthopaedic disease. The questionnaire consisted of a total of 16 items. The participants were asked to fill out the questionnaires anonymously and return them by post.
Results: The response rate of the questionnaire was 91%. The contribution of CRCs to the trial was highly rated and they were considered indispensable to the clinical trial. Particularly, CRC's knowledge about the healthcare and insurance systems was given a high score, and their assistance at medical examinations during the trial was also highly rated.
Conclusion: The present study revealed the needs and potential contribution of CRCs in an investigator-initiated clinical trial for an orthopedic disease. Further studies are required to determine whether the results obtained from the present study can be generalized to clinical trials in other clinical areas.View full abstractDownload PDF (392K) -
Takayuki ANZAI, Tetsuo SATOH2009 Volume 41 Issue 1 Pages 59-65
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSThe sensitivity and detection limit of chemical analysis have improved remarkably since the 1980's, and pharmaceuticals are frequently detected in the environment. Many substances including pharmaceuticals, cosmetics, body care products, disinfectants, fire retardants, industrial additives and gasoline additives have been referred to generally as emerging contaminants. The EU and US have already established regulations concerning environmental risk assessment (ERA) of pharmaceuticals. In Japan, a group closely related to the Ministry of Health, Labour and Welfare has begun to study similar regulations. The adoption of these regulations has been welcome in the EU and US, and ERA guidelines will also be established in Japan in the near future. On the other hand, health professions such as doctors, nurses and pharmacists in Japan appear to be unaware of ERA of pharmaceuticals as emerging contaminants. This article provides a general overview of ERA of pharmaceuticals in the EU and USA, especially targeting health professions in Japan.View full abstractDownload PDF (352K)
Lecture Series : An Example of How to Deal with Claimants
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Ryouji MIWA2009 Volume 41 Issue 1 Pages 75-78
Published: 2009
Released on J-STAGE: April 02, 2010
JOURNAL FREE ACCESSDownload PDF (286K)
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