Clinical Profiles of Japanese Patients with Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Collected by a Nationwide System from 2006 to 2023.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening severe cutaneous adverse drug reactions. These diseases are rare, and their onset is difficult to predict because of their idiosyncratic reactivity. The Japan Severe Adverse Reactions Research Group, led by the National Institute of Health Sciences, has operated a nationwide to collect clinical information and genomic samples from patients with SJS/TEN since 2006. This study evaluated the associations of clinical symptoms with sequelae and specific causative drugs/drug groups in Japanese patients with SJS/TEN to identify clinical clues for SJS/TEN treatment and prognosis. Acetaminophen, antibiotics, and carbocisteine were linked to high frequencies of severe ocular symptoms and ocular sequelae (p < 0.05). For erythema and erosion areas, antipyretic analgesics had higher rates of skin symptom affecting <10% of the skin than the other drugs, suggesting narrower lesions (p < 0.004). Hepatic dysfunction, was common in both SJS and TEN, and antiepileptic drugs carried higher risks of hepatic dysfunction than the other drug groups (p = 0.0032). This study revealed that the clinical manifestations of SJS/TEN vary according to the causative drugs.

Population/regional differences in efficacy of 3 drug categories (antidiabetic, respiratory and psychotropic agents) among East Asians: A retrospective study based on multiregional clinical trials.

AIMS: This study aimed to identify population/regional differences in drug efficacy and the influencing factors among East Asians to be considered when planning multiregional clinical trials (MRCTs) to facilitate rapid drug approval in Asians. METHODS: A retrospective analysis of efficacy (intergroup difference in endpoint between control and study drug treatment) among East Asian populations for 3 drug categories, antidiabetic, respiratory and psychotropic agents, was conducted in collaboration with pharmaceutical companies using their MRCT data. Common endpoints by drug category were selected; background factors that commonly affected the endpoints among regions were analysed first; then the population/regional differences were evaluated by the interaction term region-by-treatment using an analysis of covariance model after adjusting for background factors. RESULTS: Among 17 endpoints for eight pharmaceutical products from 3 drug categories, no substantial population/regional differences were detected in the 3 drug categories examined (P > .05), except for haemoglobin A1c change between Japan and Korea for an antidiabetic drug, insulin glulisine (P = .0068). However, no such regional differences were evident in patients with clinically important higher haemoglobin A1c baseline values (majority subgroup). Variability in disease severity at baseline and concomitant drugs were determined to be potential influencing factors for regional differences. CONCLUSIONS: This study suggests that the regional variability in efficacy of these 3 drug categories is not large among East Asians, and reveals the importance of considering background factors when planning MRCTs. Further studies are needed to evaluate regional variability in the efficacy of other drug categories and clarify the factors leading to regional differences in East Asians.

Identification of risk factors and development of detection algorithm for denosumab-induced hypocalcaemia.

WHAT IS KNOWN AND OBJECTIVE: This study used electronic medical records to identify risk factors and establish a detection algorithm for denosumab-induced hypocalcaemia. METHODS: We identified 201 patients with cancer who were initially prescribed denosumab. Hypocalcaemia was defined as an adjusted serum calcium level of ≤2.13 mmol/L. A diagnosis of denosumab-induced hypocalcaemia was confirmed by two physicians after reviewing patient medical records. We evaluated patient characteristics as potential screening factors. Moreover, a retrospective cohort study was conducted to identify risk factors for denosumab-induced hypocalcaemia. Odds ratios (ORs) were estimated using logistic regression analysis. RESULTS: We analysed 164 patients with a low risk of hypocalcaemia. Among these, 29 (17.7%) patients were suspected to have denosumab-induced hypocalcaemia. The times to onset of definitive hypocalcaemia were shorter among these patients than among patients with non-denosumab-induced hypocalcaemia. Based on receiver operating characteristic curve analysis, we used time to onset of hypocalcaemia of ≤90 days as a second screening factor. The positive predictive value of this factor was 87.5%. In the retrospective cohort study, a significant difference was observed among patients with serum alkaline phosphatase (ALP) levels of >5.95 µkat/L before initial prescription (P < 0.01). Patients with higher serum ALP levels had a 6.63 times higher risk of developing hypocalcaemia than those without increased serum ALP levels (OR: 6.63, 95% confidence interval [CI]: 1.79-29.31). The same results were observed in a sensitivity analysis using another database. WHAT IS NEW AND CONCLUSION: We developed a detection algorithm for denosumab-induced hypocalcaemia based on calcium levels and time to onset of hypocalcaemia. We also identified elevated ALP levels as a risk factor for hypocalcaemia. Clinicians should carefully monitor initial serum calcium levels and screen for signs of hypocalcaemia in patients receiving denosumab who demonstrate elevated serum ALP levels.

Evaluating the impact of regulatory action on denosumab-induced hypocalcaemia in Japan.

WHAT IS KNOWN AND OBJECTIVE: Since its introduction in April 2012, denosumab has been administered to approximately 7,300 patients as of August 2012, and 32 cases of serious hypocalcaemia after denosumab administration, including two deaths, have been reported in Japan. A Dear Healthcare Professional Letter of Rapid Safety Communication ('Blue letter') was released to warn about the risks of hypocalcaemia associated with denosumab. The goal of this study therefore was to measure the impact of regulatory action on denosumab-induced hypocalcaemia in Japan by using an electronic medical information database (MID). METHODS: We used two different aggregated data sets based on MIDs (data sets one and two). The patients studied were those who were newly prescribed denosumab or zoledronic acid between April 2012 and September 2014. We assessed four indicators: (a) the proportion of patients with calcium supplementation at the initial denosumab treatment, (b) the proportion of patients who underwent a serum calcium test, (c) the average number of serum calcium tests performed and (d) the prevalence of hypocalcaemia. All indices were aggregated by every 3 months. To evaluate the impact of regulatory action, we used difference in difference (DID) analysis. RESULTS AND DISCUSSION: The proportion of patients with calcium supplementation at the initial denosumab treatment increased year by year in both data sets. The average number of serum calcium tests increased year by year in data set two. There was a significant difference in the prevalence of hypocalcaemia in data set two. This suggests that the estimate of impact of the regulatory action may vary according to the database. In DID analysis, however, significant influences of the regulatory action on combination use with a calcium supplement were detected in both data sets. WHAT IS NEW AND CONCLUSION: There was a significant influence on combination use of denosumab with vitamin D and/or calcium supplement in both data sets. That there was no apparent increase in the prevalence of denosumab-induced hypocalcaemia, suggests that the regulatory action had an impact in the clinical setting studied. Such regulatory actions may play an important role in the promotion of drug safety.

Association between dipeptidyl peptidase-4 inhibitors and urinary tract infection in elderly patients: A retrospective cohort study.

PURPOSE: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs. Although they have been reported to increase the risk of infection, the findings are controversial. Given that urinary tract infections (UTIs) are common in the elderly, we conducted a retrospective cohort study by using health care insurance claims data, to elucidate the association between the DPP-4 inhibitors and the incidence of UTI in latter-stage elderly patients. METHODS: We analyzed 25,111 Japanese patients aged 75 years and older between the fiscal years 2011 and 2016. Patients using DPP-4 inhibitors and sulfonylureas (SUs) were matched at a 1:1 ratio using propensity scoring. The Incidence rate ratio (IRR) of UTI was compared between users of SUs and users of DPP-4 inhibitors by Poisson regression. Moreover, subgroup analyses stratified by sex were conducted to evaluate whether the combination of prostatic hyperplasia and DPP-4 inhibitors is associated with the incidence of UTI in male patients. RESULTS: The use of DPP-4 inhibitors was associated with an increased risk of UTI (adjusted IRR 1.23, 95% CI [1.04-1.45]). After propensity score matching, the association remained significant (adjusted IRR 1.28, 95% CI [1.05-1.56]). Moreover, elderly male patients with prostatic hyperplasia who received DPP-4 inhibitors had a higher risk of UTI than SU users without prostatic hyperplasia (Matched: crude IRR 2.90, 95% CI [1.78-4.71]; adjusted IRR 2.32, 95% CI [1.40-3.84]). CONCLUSIONS: The long-term use of DPP-4 inhibitors by elderly patients, particularly male patients with prostatic hyperplasia, may increase the risk of UTI.

Association between infection and severe drug adverse reactions: an analysis using data from the Japanese Adverse Drug Event Report database.

PURPOSE: It has been reported recently that immune reactions are involved in the pathogenesis of certain types of adverse drug reactions (ADRs). We aimed to determine the associations between infections and drug-induced interstitial lung disease (DILD), rhabdomyolysis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), or drug-induced liver injury (DILI) using a spontaneous adverse drug event reporting database in Japan. METHODS: The reported cases were classified into three categories (anti-infectious drug group, concomitant infection group, and non-infection group) based on the presence of anti-infectious drugs (either as primary suspected drug or concomitant drug) and infectious disease. We assessed the association between four severe ADRs and the presence and seriousness of infection using logistic regression analysis. RESULTS: We identified 177,649 cases reported in the study period (2009-2013). Logistic regression analysis showed significant positive associations between infection status and onset of SJS/TEN or DILI (SJS/TEN: anti-infectious drug group: odds ratio (OR) 2.04, 95% CI [1.85-2.24], concomitant infection group: OR 2.44, 95% CI [2.21-2.69], DILI: anti-infectious drug group: OR 1.27, 95% CI [1.09-1.49], concomitant infection group: OR 1.25, 95% CI [1.04-1.49]), compared to the non-infection group. By contrast, there were negative or no associations between infection and DILD or rhabdomyolysis. A significantly positive association between infection and SJS/TEN seriousness (OR 1.48, 95% CI [1.10-1.98]) was observed. CONCLUSIONS: This study suggested that infection plays an important role in the development of SJS/TEN and DILI. For the patients with infection and/ or anti-infectious drugs, careful monitoring for severe ADRs, especially SJS/TEN, might be needed.

Influence of Japanese Regulatory Action on Denosumab-Related Hypocalcemia Using Japanese Adverse Drug Event Report Database.

The anti-receptor activator of nuclear factor kappa-B ligand (RANKL) antibody, Denosumab (DEN), was approved in April 2012 in Japan, but a Dear Healthcare Professional Letter of Rapid Safety Communication was released in September, 2012 by the regulatory authority because of the severe hypocalcemia risks. Currently, the effectiveness of this regulatory action has not been evaluated and, therefore, this study aimed to assess its impact on DEN-induced hypocalcemia using the Japanese Adverse Drug Event Report database (JADER). The case reports from April 2012 to September 2014 were collected from the JADER, which included 151642 adverse events for the primary suspected drugs. The reporting odds ratio (ROR) of hypocalcemia as a signal of the target adverse event was analyzed for DEN and zoledronic acid (ZOL, a reference drug). Changes in RORs were compared between the pre- (Pre, April 2012 to September 2012) and post- (Post 1, October 2012 to September 2013 and Post 2, October 2013 to September 2014) periods of the regulatory action. A decrease in the hypocalcemia ROR was observed for DEN in the post-periods, especially Post 2. Multivariate logistic regression analysis showed a significant decrease in hypocalcemia signal in Post 1 (p=0.0306 vs. Pre) and Post 2 (p=0.0054 vs. Pre). ZOL caused no significant changes in ROR of hypocalcemia, and none of the drugs caused ROR changes in jaw osteonecrosis (a reference adverse event). This study suggests that the regulatory action against hypocalcemia in DEN effectively decreased hypocalcemia signal. Further studies using medical information databases are needed to confirm this result.

Effect of Infectious Diseases on the Pathogenesis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Recent studies have revealed that the prevalence of SJS/TEN is associated with genetic backgrounds, such as polymorphisms in human leukocyte antigens (HLAs). However, non-genetic factors contributing to the etiology of SJS/TEN are largely unknown. This study aimed to assess the involvement of concurrent infection on the pathological states of SJS/TEN, examining the severity of cutaneous symptoms and ocular involvement as well as the time to onset in drug-induced SJS/TEN patients. We recruited 257 Japanese SJS/TEN patients from June 2006 to September 2013 through a nationwide case collection network and participating hospitals and reviewed the clinical information including patient backgrounds, primary disease and medication status. Association between infection and pathological states of SJS/TEN was assessed using univariate and multivariate analyses. The concurrent infectious group of SJS/TEN patients showed a significantly higher rate of exhibiting severer dermatological and ophthalmological phenotypes and an earlier onset of SJS/TEN than the non-infectious group. Our results suggest that the infection could be a risk factor to cause severer symptoms and earlier onset of SJS/TEN.

Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method.

BACKGROUND: Variability in drug response between individual patients is a serious concern in medicine. To identify single-nucleotide polymorphisms (SNPs) related to drug response variability, many genome-wide association studies have been conducted. METHODS: We previously applied a knowledge-based bioinformatic approach to a pharmacogenomics study in which 119 fluoropyrimidine-treated gastric cancer patients were genotyped at 109,365 SNPs using the Illumina Human-1 BeadChip. We identified the SNP rs2293347 in the human epidermal growth factor receptor (EGFR) gene as a novel genetic factor related to chemotherapeutic response. In the present study, we reanalyzed these hypothesis-free genomic data using extended knowledge. RESULTS: We identified rs2867461 in annexin A3 (ANXA3) gene as another candidate. Using logistic regression, we confirmed that the performance of the rs2867461 + rs2293347 model was superior to those of the single factor models. Furthermore, we propose a novel integrated predictive index (iEA) based on these two polymorphisms in EGFR and ANXA3. The p value for iEA was 1.47 × 10(-8) by Fisher's exact test. Recent studies showed that the mutations in EGFR is associated with high expression of dihydropyrimidine dehydrogenase, which is an inactivating and rate-limiting enzyme for fluoropyrimidine, and suggested that the combination of chemotherapy with fluoropyrimidine and EGFR-targeting agents is effective against EGFR-overexpressing gastric tumors, while ANXA3 overexpression confers resistance to tyrosine kinase inhibitors targeting the EGFR pathway. CONCLUSIONS: These results suggest that the iEA index or a combination of polymorphisms in EGFR and ANXA3 may serve as predictive factors of drug response, and therefore could be useful for optimal selection of chemotherapy regimens.

High-temperature calcined fullerene nanowhiskers as well as long needle-like multi-wall carbon nanotubes have abilities to induce NLRP3-mediated IL-1ß secretion.

Because multi-wall carbon nanotubes (MWCNTs) have asbestos-like shape and size, concerns about their pathogenicity have been raised. Contaminated metals of MWCNTs may also be responsible for their toxicity. In this study, we employed high-temperature calcined fullerene nanowhiskers (HTCFNWs), which are needle-like nanofibers composed of amorphous carbon having similar sizes to MWCNTs but neither metal impurities nor tubular structures, and investigated their ability to induce production a major proinflammatory cytokine IL-1ß via the Nod-like receptor pyrin domain containing 3 (NLRP3)-containing flammasome-mediated mechanism. When exposed to THP-1 macrophages, long-HTCFNW exhibited robust IL-1ß production as long and needle-like MWCNTs did, but short-HTCFNW caused very small effect. IL-1ß release induced by long-HTCFNW as well as by long, needle-like MWCNTs was abolished by a caspase-1 inhibitor or siRNA-knockdown of NLRP3, indicating that NLRP3-inflammasome-mediated IL-1ß production by these carbon nanofibers. Our findings indicate that the needle-like shape and length, but neither metal impurities nor tubular structures of MWCNTs were critical to robust NLRP3 activation.

A detection algorithm for drug-induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of Medical Sciences/the Roussel Uclaf Causality Assessment Method scale.

PURPOSE: Drug-induced liver injury (DILI) is one of the primary targets for pharmacovigilance using medical information databases (MIDs). Because of diagnostic complexity, a standardized method for identifying DILI using MIDs has not yet been established. We applied the Digestive Disease Week Japan 2004 (DDW-J) scale, a Japanese clinical diagnostic criteria for DILI, to a DILI detection algorithm, and compared it with the Council for International Organizations of Medical Sciences/the Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) scale to confirm its consistency. Characteristics of DILI cases identified by the DDW-J algorithm were examined in two Japanese MIDs. METHODS: Using an MID from the Hamamatsu University Hospital, we constructed a DILI detection algorithm on the basis of the DDW-J scale. We then compared the findings between the DDW-J and CIOMS/RUCAM scales. We examined the characteristics of DILI after antibiotic treatment in the Hamamatsu population and a second population that included data from 124 hospitals, which was derived from an MID from the Medical Data Vision Co., Ltd. We performed a multivariate logistic regression analysis to assess the possible DILI risk factors. RESULTS: The concordance rate was 79.4% between DILI patients identified by the DDW-J and CIOMS/RUCAM; the Spearman rank correlation coefficient was 0.952 (P < 0.0001). Men showed a significantly higher risk for DILI after antibiotic treatments in both MID populations. CONCLUSIONS: The DDW-J and CIOMS/RUCAM algorithms were equivalent for identifying the DILI cases, confirming the utility of our DILI detection method using MIDs. This study provides evidence supporting the use of MID analyses to improve pharmacovigilance.

Distal promoter regions are responsible for differential regulation of human orosomucoid-1 and -2 gene expression and acute phase responses.

Human orosomucoid (ORM) is a major acute-phase plasma protein, encoded by 2 highly homologous genes, ORM1 and ORM2. Human ORM induction is assumed to be regulated by each proximal promoter region, where putative glucocorticoid responsive elements and CCAAT/enhancer binding protein (C/EBP)ß binding sites are located. However, the details of the differential regulation of these genes remain unknown. To explore this, we assessed the role of the distal promoter region of each ORM in HeLa cells. Luciferase-reporter activities of full constructs, containing approximately 1.1 kbp (FULL), and those of deletion constructs, containing up to 188 bp region (DEL) upstream of the transcription start sites of ORM1 and ORM2 were compared under both basal and inducer-treated conditions. For ORM1 and ORM2 DEL constructs, significantly increased activities after dexamethasone (DEX) treatments (alone and combined with interleukin (IL)-1ß) were observed. Significantly higher FULL construct activities than DEL construct activities were observed for ORM1 after IL-1ß treatment, while those for ORM2 were significantly lower at basal level and after DEX treatments. Upon C/EBPß overexpression, FULL construct activities were significantly higher than those of DEL constructs at basal level and after IL-1ß treatment for ORM1, and at basal level and after inducer-treatments for ORM2. Higher transcription-induction activity in the distal promoter region was evident for ORM1 in the absence of C/EBPß overexpression, and for ORM2 under C/EBPß overexpression conditions. These findings suggest that the ORM distal promoter region differentially regulates expression of ORM genes at basal level and in acute phase responses.

Significant association between hand-foot syndrome and efficacy of capecitabine in patients with metastatic breast cancer.

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is a promising treatment for colorectal, breast and gastric cancers, but often causes hand-foot syndrome (HFS), the most common dose-limiting toxicity. The current study was conducted to investigate the relationship between HFS and efficacy of capecitabine in 98 patients with metastatic breast cancer. Possible associations between HFS and efficacy endpoints, including time-to-treatment failure (TTF), tumor response in metastatic lesions and changes in tumor markers, were investigated retrospectively using electronic medical records. The TTF of group with HFS of grade 1 and ≥2 was significantly longer than that of group with no HFS, respectively (hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.18-0.87 for group with grade 1; HR, 0.42, 95% CI, 0.19-0.90 for group with grade ≥2). Significantly higher disease control rates for the liver metastasis were observed in patients with HFS (grade 1 and greater) than in those without HFS (92.9 vs. 42.9%, p=0.009). Furthermore, prevention of increases in tumor marker levels (carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA15-3) and National Cancer Center-Stomach-439 (NCC-ST439)) was evident in patients with HFS. This study clearly showed a significant correlation between HFS and some efficacy markers of capecitabine therapy in patients with metastatic breast cancer, and suggests that early dose adjustment based on severity of HFS might improve efficacy. Studies are needed to explore predictive biomarkers for HFS/efficacy, so that capecitabine therapy can be further tailored to patient response.

[Trends in drug-induced liver injury based on reports of adverse reactions to PMDA in Japan].

Reports on drug-related adverse reactions from manufacturing/distributing pharmaceutical companies or medical institutions/pharmacies are regulated under the Pharmaceutical Affairs Law of Japan, and this system is important for post-marketing safety measures. Although association between the medicine and the adverse event has not been clearly evaluated, and an incidence may be redundantly reported, this information would be useful to roughly grasp the current status of drug-related adverse reactions. In the present study, we analyzed the incidence of drug-induced liver injury by screening the open-source data publicized by the homepage of Pharmaceutical and Medical Devices Agency from 2005 to 2011 fiscal years. Major drug-classes suspected to cause general drug-induced liver injury were antineoplastics, anti-inflammatory agents/common cold drugs, chemotherapeutics including antituberculous drugs, antidiabetics, antiulcers and antiepileptics. In addition, reported cases for fulminant hepatitis were also summarized. We found that antituberculous isoniazid and antineoplastic tegafur-uracil were the top two suspected drugs. These results might deepen understanding of current situations for the drug-induced liver injury in Japan.

[Questionnaire Survey on Adoption and Prescription of Biosimilars (Antibody and Its-related Products) by Medical Doctors in Japan].

Biosimilars are less expensive than their originators, and Japanese government policies call for their development and promotion. However, the adoption and prescription of some biosimilars, especially antibody/its-related ones, have been delayed for use in Japan, possibly due to concerns on the differences in quality attributes such as glycan structures between the originators and their biosimilars, and that clinical efficacy/safety studies are conducted for usually one disease and its results extrapolated to other indications. We conducted a questionnaire survey among physicians in four disease areas (hematology, medical oncology, rheumatoid arthritis, and inflammatory bowel disease), where biosimilars of antibody/its-related drugs have been approved, regarding their thoughts on the adoption and prescription of biosimilars in Japan from January to April 2020. We received totally 1024 responses. When adopting biosimilars and explaining them to patients, physicians requested specific information including the comparative results of phase III clinical trials and quality characteristics between biosimilars and their originators; the results of clinical studies on switching from originators to their biosimilars; and a comparison of the estimated cost on patients in consideration of the high medical cost payment system. Priority differed depending on the studied disease areas. In terms of post-marketing information, physicians requested a variety of information. When explaining biosimilars to the patients, physicians would like to use general material from government describing the comparability between originators and their biosimilars. These results suggest that physicians sought more comparative information on the quality, efficacy, and patients' cost between originators and their biosimilars when adopting or prescribing biosimilars.

[Current movements of four serious adverse events induced by medicinal drugs based on spontaneous reports in Japan].

Spontaneous reports on suspected serious adverse events caused by medicines from manufacturing/distributing pharmaceutical companies or medical institutions/pharmacies are regulated by the Pharmaceutical Affairs Law of Japan, and this system is important for post-marketing safety features. Although causal relationship between the medicine and the adverse event is not evaluated, and one incidence may be redundantly reported, this information would be useful to roughly grasp the current movements of drug-related serious adverse events, We searched open-source data of the spontaneous reports publicized by Pharmaceutical and Medical Devices Agency for 4 serious adverse events (interstitial lung disease, rhabdomyolysis, anaphylaxis, and Stevens-Johnson syndrome/toxic epidermal necrolysis) from 2004 to 2010 fiscal year (for 2010, from April 1 st to January 31th). Major drug-classes suspected to the adverse events were antineoplastics for interstitial lung disease, hyperlipidemia agents and psychotropics for rhabdomyolysis, antibiotics/chemotherapeutics, antineoplastics and intracorporeal diagnostic agents for anaphylaxis (anaphylactic shock, anaphylactic reactions, anaphylactoid shock and anaphylactoid reactions), and antibiotics/chemotherapeutics, antipyretics and analgesics, anti-inflammatory agents/common cold drugs, and antiepileptics for Stevens-Johnson syndrome/toxic epidermal necrolysis. These results would help understanding of current situations of the 4 drug-related serious adverse events in Japan.

Efficacy Comparison for a Schizophrenia and a Dysuria Drug Among East Asian Populations: A Retrospective Analysis Using Multi-regional Clinical Trial Data.

BACKGROUND AND OBJECTIVES: Multi-regional clinical trials (MRCTs) are an efficient drug development strategy for eliminating drug lag in East Asian countries. In planning MRCTs according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E17 guideline, it is expected that East Asian populations with relatively similar ethnicity can be pooled as one population. However, evidence supporting this assumption is limited. This study aimed to investigate population/regional differences considering influencing factors among East Asian regions using MRCT data as a research model. METHODS: A retrospective analysis was conducted to determine the efficacy of two drugs, asenapine, a schizophrenia drug, and tadalafil, a dysuria drug for benign prostatic hyperplasia, using MRCT data from Japan, Korea, and Taiwan. First, predictive factors and effect modifiers were evaluated. Then, population/regional differences were evaluated using multivariate regression models, with the interaction term Region-by-Treatment group and adjustment for influencing intrinsic/extrinsic factors. RESULTS: Among the 4 outcomes for the two drugs, no significant population/regional differences were detected (P > 0.05) by the adjusted regression models. The effect modifiers, such as pretreatment drug status or concurrent diseases, were common among countries. CONCLUSIONS: No significant population/regional efficacy differences were found for the two drugs among the three regions. This finding supported the possible applicability of the region pooling strategy for MRCTs in East Asia, emphasizing the benefits of exploring ethnic difference/influencing factors at an early stage to design further confirmatory studies. However, further evidence for various drugs should be accumulated.

Real-world evidence of population differences in allopurinol-related severe cutaneous adverse reactions in East Asians: A population-based cohort study.

Allopurinol-related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA-B*58:01, the allele frequency (AF) of which is largely different among East Asians. However, evidence of population differences in SCAR development and relevance of genetic and/or other risk factors in the real-world remain unelucidated. This study aimed to evaluate population differences in allopurinol-related SCAR incidence related to genetic and/or other risk factors among East Asians in the real-world. A population-based cohort study was conducted using claims databases from Taiwan, Korea, and Japan. New users of allopurinol (311,846; 868,221; and 18,052 in Taiwan, Korea, and Japan, respectively) were followed up to 1 year. As control drugs, phenytoin and carbamazepine were used. The crude incidence rate ratios (IRRs) of SCARs for allopurinol against phenytoin or carbamazepine were the highest in Taiwan (IRR, 0.62 and 1.22; 95% confidence interval [CI], 0.54-0.72 and 1.01-1.47, respectively), followed by Korea (IRR, 0.34 and 0.82; 95% CI, 0.29-0.40 and 0.77-0.87), and the lowest in Japan (IRR, 0.04 and 0.16; 95% CI, 0.02-0.08 and 0.09-0.29). This order was accordant with that of AF ratios (AFRs) reported of HLA-B*58:01 against alleles responsible for phenytoin- or carbamazepine-related SCARs. The IRRs were higher in patients with chronic kidney disease, females, and elderly. This study demonstrated population differences in the risk of allopurinol-related SCAR development among East Asians based on genetic and other common risk factors. This finding will help to promote appropriate risk management for allopurinol-related SCARs based on ethnic origins. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC? Allopurinol-related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA-B*58:01, the allele frequency of which is largely different among East Asians. However, there is no direct real-world evidence of population differences in SCAR development and the influence of genetic factors and/or other risk factors. WHAT QUESTION DID THIS STUDY ADDRESS? Do population differences in development of allopurinol-related SCARs, depending on genetic factors and/or other risk factors, exist among three East Asians in the real-world? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The current analysis, based on comparisons of relative risks of SCAR incidence, provides real-world evidence of population differences in allopurinol-related SCAR development risk among East Asians, which was consistent with differences in reported HLA-B*58:01 frequencies, as well as identifying chronic kidney disease, female gender, and old age as common risk factors. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study helps to promote appropriate risk management strategies for allopurinol-related SCARs in the real-world considering risk factors based on the patients' ethnicity. Our approach is useful for evaluating population differences in the real-world.

Modulation of RIP1 ubiquitylation and distribution by MeBS to sensitize cancer cells to tumor necrosis factor α-induced apoptosis.

Overexpression of anti-apoptosis protein cIAP1 due to its genetic amplification is found in certain cancers such as esophageal squamous cell carcinoma, hepatocellular carcinoma, cervical cancer and lung cancer, and plays a significant role in resistance to cancer therapy. We previously reported that a class of small molecules represented by (-)-N-[(2S, 3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-L-leucine methyl ester (MeBS) activates auto-ubiquitylation of cIAP1 for proteasomal degradation, and enhances apoptosis of various cancer cells. However, the molecular mechanism of how MeBS sensitizes cancer cells to apoptosis via downregulation of cIAP1 is not well understood. Here, we show that ubiquitylation and distribution of RIP1, a protein ubiquitylated by cIAP1, is modulated by MeBS. Upon tumor necrosis factor (TNF)α stimulation, ubiquitylated RIP1 associates with the TNF-receptor (TNFR) complex, whereas non-ubiquitylated RIP1 associates with caspase8. MeBS reduces the ubiquitylated RIP1 in the TNFR complex and increases non-ubiquitylated RIP1 bound to caspase8. Downregulation of RIP1 by siRNA reduces apoptosis induced by TNFα plus MeBS treatment. These results indicate an important role of RIP1 in apoptosis induced by combined treatment with TNFα and MeBS, suggesting that MeBS sensitizes cancer cells to apoptosis by modulating RIP1 ubiquitylation and distribution.

CYP3A4*16 and CYP3A4*18 alleles found in East Asians exhibit differential catalytic activities for seven CYP3A4 substrate drugs.

CYP3A4, the major form of cytochrome P450 (P450) expressed in the adult human liver, is involved in the metabolism of approximately 50% of commonly prescribed drugs. Several genetic polymorphisms in CYP3A4 are known to affect its catalytic activity and to contribute in part to interindividual differences in the pharmacokinetics and pharmacodynamics of CYP3A4 substrate drugs. In this study, catalytic activities of the two alleles found in East Asians, CYP3A4*16 (T185S) and CYP3A4*18 (L293P), were assessed using the following seven substrates: midazolam, carbamazepine, atorvastatin, paclitaxel, docetaxel, irinotecan, and terfenadine. The holoprotein levels of CYP3A4.16 and CYP3A4.18 were significantly higher and lower, respectively, than that of CYP3A4.1 when expressed in Sf21 insect cell microsomes together with human NADPH-P450 reductase. CYP3A4.16 exhibited intrinsic clearances (V(max)/K(m)) that were lowered considerably (by 84-60%) for metabolism of midazolam, carbamazepine, atorvastatin, paclitaxel, and irinotecan compared with CYP3A4.1 due to increased K(m) with or without decreased V(max) values, whereas no apparent decrease in intrinsic clearance was observed for docetaxel. On the other hand, K(m) values for CYP3A4.18 were comparable to those for CYP3A4.1 for all substrates except terfenadine; but V(max) values were lower for midazolam, paclitaxel, docetaxel, and irinotecan, resulting in partially reduced intrinsic clearance values (by 34-52%). These results demonstrated that the impacts of both alleles on CYP3A4 catalytic activities depend on the substrates used. Thus, to evaluate the influences of both alleles on the pharmacokinetics of CYP3A4-metabolized drugs and their drug-drug interactions, substrate drug-dependent characteristics should be considered for each drug.