Increased risk of hypocalcemia with decreased kidney function in patients prescribed bisphosphonates based on real-world data from the MID-NET® in Japan: a new-user cohort study.

BACKGROUND: In the post-marketing stage, cases of hypocalcemia associated with bisphosphonate preparations (BPs) have been reported in patients with decreased kidney function, despite warning against use of BPs in such patients in the package insert (PI) of Japan. The purpose of this study was to investigate the safety of BPs in patients with decreased kidney function. METHODS: The cohort study was conducted in patients with osteoporosis and newly prescribed bisphosphonate utilizing real-world data from MID-NET® in Japan. The adjusted hazard ratios (aHRs) for hypocalcemia (a corrected serum Ca level < 8.00 mg/dL) relative to the normal group were calculated in each decreased kidney function group (mild, moderate or severe group). RESULTS: A total of 14,551 patients were included in the analysis, comprising 2,601 (17.88%) with normal (eGFR ≥ 90 mL/min/1.73m2), 7,613 (52.32%) with mild (60 ≤ eGFR < 90 mL/min/1.73m2), 3,919 (26.93%) with moderate (30 ≤ eGFR < 60 mL/min/1.73m2), and 418 (2.87%) with severe kidney function (eGFR < 30 mL/min/1.73m2). The aHRs (95% confidence interval) for hypocalcemia were 1.85 (0.75-4.57), 2.30 (0.86-6.21), and 22.74 (8.37-61.78) in the mild, moderate, and severe groups, respectively. The increased risk of hypocalcemia depending on kidney function was also observed even when calculating the aHR for each specific BP such as alendronate sodium hydrate, minodronic acid hydrate, and sodium risedronate hydrate. Furthermore, similar results were obtained in the sensitivity analysis by altering the outcome definition to a 20% or more reduction in corrected serum Ca level from the baseline, as well as when focusing on patients with more than one laboratory test result per 30 days during the follow-up period. CONCLUSIONS: These findings suggest that the risk of hypocalcemia during BP prescription is higher in patients with decreased kidney function, particularly those with severely decreased kidney function. The quantitative real-world evidence on the safety risk of BPs obtained in this study has led to the PI revision describing a relationship between hypocalcemia risk and decreased kidney function as a regulatory action in Japan and will contribute to promoting the proper use of BPs with appropriate risk management in clinical practice.

Cardiovascular risk of urate-lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

In the present study, we aimed to investigate the association between urate-lowering drugs and cardiovascular events, primarily focusing on the risk of febuxostat and topiroxostat when compared with allopurinol in Japan. We conducted an observational study with a cohort design using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, including new urate-lowering drugs users between August 1, 2010, and March 31, 2018. Exposure and control groups were defined based on the first prescription of urate-lowering drugs as follows: febuxostat or topiroxostat for exposure groups, allopurinol for the control group, and benzbromarone for the secondary control group. The primary outcome was cardiovascular events, defined as a composite of acute coronary syndrome, cerebral infarction, and cerebral hemorrhage. Hazard ratios were estimated using a Cox proportional hazards model. The number of patients in each exposure and control group was 1,357,671 in the febuxostat group, 83,683 in the topiroxostat group, 1,273,211 in the allopurinol group, and 258,786 in the benzbromarone group. The adjusted hazard ratios for the cardiovascular risk were 0.97 (95% confidence interval [CI]: 0.95-0.98) for febuxostat and 0.84 (95% CI: 0.78-0.90) for topiroxostat groups. The benzbromarone group exhibited similar results. No increased cardiovascular risk was observed with febuxostat or topiroxostat when compared with allopurinol in patients with hyperuricemia in Japan. These results provide real-world evidence regarding the cardiovascular risk associated with urate-lowering drugs, indicating that no additional safety-related regulatory actions are warranted in Japan.

Assessing the Risk of Decrease in Kidney Function in Patients Prescribed Direct-Acting Antivirals for Hepatitis C Utilizing the MID-NET® Medical Information Database Network in Japan.

An association between kidney disease and direct-acting antivirals against hepatitis C (DAAs) has been suggested, however the warning on the package insert (PI) of the drug varies among DAAs. In this study, the risk of decreased kidney function associated with DAAs marketed in Japan was investigated to determine whether the risk of kidney disease is a common adverse event and class effect of DAAs. Data for patients who were new users of DAAs marketed in Japan, with eGFR ≥ 45 mL/min/1.73 m2 and without specific risk factors, were extracted from the MID-NET® medical information database network in Japan. Changes from the baseline on estimated glomerular filtration rate (eGFR) categories (eGFR ≥ 90, 90 > eGFR ≥ 60, 60 > eGFR ≥ 45, 45 > eGFR ≥ 30, 30 > eGFR ≥ 15, 15 > eGFR; unit: mL/min/1.73 m2) were used for evaluating the risk of decreased kidney function. Exposure groups for DAAs and relevant concomitant drugs were categorized into 10 patterns based on the PI. Among the 10 patterns, a significant increase in the incidence rate ratio (P < 0.01) was observed in the prescription patterns of concomitant use of telaprevir with peginterferon alpha and ribavirin, concomitant use of daclatasvir hydrochloride with asunaprevir, and ombitasvir hydrate combined with paritaprevir hydrate and ritonavir, which were concomitantly used with ribavirin; such an increase was not observed in the other prescription patterns. The effects of DAAs on kidney function may differ among drugs, suggesting the possibility that the risk of kidney disease is not a class effect of DAAs and should be evaluated individually for each DAA.

Potential Future Drug Development Lag in Japan Based on an Analysis of Multiregional Clinical Trials in the US, Europe, and East Asia.

Although the "drug lag"-namely, the delay in drug approval time in Japan relative to the United States and/or European Union (US/EU)-has been shortened for drugs approved in Japan, there remain many new drugs that have been approved in the US/EU, but not in Japan. To assess the possibility of a future drug lag, this study has examined the current lag in drug development in Japan based on "ClinicalTrials.gov" data from multiregional clinical trials (MRCTs) conducted in the US/EU and East Asia. Among 828 MRCTs registered as of April 5th, 2021, the percentage of MRCTs in which Japan participated (jMRCTs) was 57.1%. jMRCTs were common for some diseases such as "nervous system" and "visual system" disorders, but less common for "neoplasm," infection," "mental," and "circulatory" disorders. Regarding the investigational drugs in non-jMRCTs (i.e., MRCTs without Japanese participation) in the latter four therapeutic areas (i.e., neoplasm, infection, mental and circulatory disorders), approximately 80% (313/399) of drugs were not being developed in Japan. Furthermore, many of these drugs were being developed by the top 50 pharmaceutical companies by sales, and the majority would be recognized as a new active ingredient with a new mode of action in Japan. This study has highlighted the possibility of a future drug lag in Japan, especially in the therapeutic areas of neoplasm, infection, mental, and circulatory disorders. Such a lag may arise not only between Japan and the US/EU, but also between Japan and other countries in the East Asian region.

Factors Influencing Classifications of Safety Specifications in a Risk Management Plan for Antineoplastic Agents Approved in Japan: A Review and Descriptive Analysis.

A risk management plan (RMP) has an important role in assuring the optimal benefit-risk balance of a drug throughout its life cycle. However, no clear standards have been established for differentiating risk classification between "important identified risks" and "important potential risks". This study was a review and descriptive analysis for Japanese RMPs with a focus on antineoplastic agents to identify effective factors to discriminate an important identified risk from an important potential risk. Analysis based on 51 RMPs, reporting 310 important identified risks and 72 important potential risks, revealed significant associations between selection of the risk classification and several factors, including severe cases, actual cases in the Japanese population, availability of confirmatory trial data, and incidence of adverse events. Trend of the association was also found for discontinuation cases and immune-oncology agents [IO (drug type)]. These results suggest that consideration of these factors may be useful for coherent risk classification in creating a RMP.

Nested Case-Control Study Utilizing MID-NET® on Thrombocytopenia Associated With Pegfilgrastim in Patients Treated With Antineoplastic Agents.

Although several spontaneous case reports on the occurrence of thrombocytopenia in patients treated with human granulocyte colony-stimulating factor (G-CSF) preparations have been accumulated, its actual causality is still unclear. To investigate the association between G-CSF preparations (filgrastim, nartograstim, lenograstim, and pegfilgrastim) available in Japan and thrombocytopenia in patients treated with antineoplastic agents, a nested case-control study was conducted using the Medical Information Database NETwork (MID-NET®) with the cohort of the Japanese population taking antineoplastic agents between 2009 and 2018. A case of thrombocytopenia was defined as a patient who had decreased platelet counts (< 50,000/mm3 ). We identified a maximum of 10 controls for each case matched on the index date. Adjusted odds ratios (aORs) and their 95% confidence intervals (CIs) of thrombocytopenia for the use of G-CSF preparations compared with nonuse were estimated using conditional logistic regression. From the cohort in which 33,124 patients were included, 733 cases and 5,592 controls were identified. Compared with the nonuse of G-CSF preparations, the use of any G-CSF preparations increased the risk of thrombocytopenia (aOR: 5.7, 95% CI: 4.3-7.5). More detailed analysis showed that a distinctive increased risk was observed when pegfilgrastim was prescribed at 2-7 days before the index date (aOR: 7.4 95% CI: 2.0-28.1). Associations of the other G-CSF preparations with thrombocytopenia were unclear due to the inconsistent results among different analyses. A significantly increased risk of thrombocytopenia associated with pegfilgrastim was identified, leading to a revision of precautions in the package inserts of pegfilgrastim as a regulatory safety action.

Characteristics on Drug Safety Measures in Japan Stratified by System Organ Classes and Therapeutic Categories in Relation to the Approval Date.

Revisions of drug package inserts (PIs) may be made immediately after approval or after considerable clinical experience; however, it is unclear whether there is a relationship between the characteristics of these safety measures and the period since drug approval. Here, we analyzed 209 cases of safety measures (revisions of the PIs) taken in Japan over 5 years (FY2014 to FY2018). The median, minimum, and maximum period from approval date in Japan to PI revision date was 6.29 years (interquartile range 2.68-15.53 years), 0.16 years, and 59.69 years, respectively. The cases were classified into four groups depending on types of adverse reaction and therapeutic category in relation to the national approval date and international birth date, resulting in the grouping together of particular adverse reactions and therapeutic drugs. For example, "Hepatobiliary disorders", "Blood and lymphatic system disorders", "Respiratory, thoracic and mediastinal disorders", "Antineoplastics", "Chemotherapeutics", and "Other agents affecting metabolism" were associated with the group of safety measures taken early after approval of a drug soon after the international birth date, suggesting that careful attention at an earlier stage after approval is necessary for these adverse reactions and drugs. Understanding such features of PI revisions makes pharmacovigilance planning more appropriate, contributing to the implementation of rapid and proper safety measures after drug approval.

Absence of ethnic differences in the pharmacokinetics of moxifloxacin, simvastatin, and meloxicam among three East Asian populations and Caucasians.

AIM: To examine whether strict control of clinical trial conditions could reduce apparent differences of pharmacokinetic (PK) parameters among ethnic groups. METHODS: Open-label, single dose PK studies of moxifloxacin, simvastatin and meloxicam were conducted in healthy male subjects from three East Asian populations (Japanese, Chinese and Koreans) and one Caucasian population as a control. These three drugs were selected because differences in PK parameters have been reported, even though the backgrounds of these East Asian populations are similar. Moxifloxacin (400 mg) was administered orally to 20 subjects, and plasma and urine levels of moxifloxacin and its metabolite (M2) were measured. Simvastatin (20 mg) was given to 40 subjects, and plasma levels of simvastatin and simvastatin acid were measured. Meloxicam (7.5 mg) was given to 30 subjects and its plasma concentration was determined. Intrinsic factors (polymorphism of UGT1A1 for moxifloxacin, SLCO1B1 for simvastatin, and CYP2C9 for meloxicam) were also examined. RESULTS: AUCinf values for moxifloxacin, simvastatin and meloxicam showed no significant differences among the East Asian groups. Cmax values of moxifloxacin and simvastatin, but not meloxicam, showed significant differences. There were no significant differences of data for M2 or simvastatin acid. Genetic analysis identified significant differences in the frequencies of relevant polymorphisms, but these differences did not affect the PK parameters observed. CONCLUSIONS: Although there were some differences in PK parameters among the three East Asian groups, the present study performed under strictly controlled conditions did not reproduce the major ethnic differences observed in previous studies.

Comparison of Drug Use Between Clinical Practice and Regulatory Approval: Results in Older Japanese Patients With Rheumatoid Arthritis, Diabetes, High Blood Pressure, or Depression.

BACKGROUND: In this study, differences in older patients between drug use as reported in clinical practice and in clinical trials for regulatory approval were examined. METHODS: Electronic medical record (EMR) data such as patient background (age, sex), concomitant drugs, data on laboratory tests, and prescribed doses of drugs from outpatients with rheumatoid arthritis, diabetes, high blood pressure, or depression at Chiba University Hospital were obtained for the period from January 2003 to December 2012. These data were compared with data from relevant clinical trials for regulatory approval in order to examine differences in drug use. RESULTS: There were 5134 eligible patients. The prescribed doses of drugs were lower than the standard approved doses for depression and rheumatoid arthritis but were generally within the approved dose range for type 2 diabetes mellitus and hypertension. When comparing the characteristics of older patients taking tacrolimus, 5.6% to 17.0% of those would not be able to participate in clinical trials because of liver or renal abnormality, and the incidence rates of some adverse drug events (ADEs) differed significantly between clinical practice and clinical trials. CONCLUSIONS: Appropriate doses of drugs for older patients may differ from approved doses in certain diseases. Complex situations such as a lot of polypharmacy, comorbidity, and functional impairment in older patients in clinical practice make it difficult to evaluate safety based on data from clinical trials. In the future, utilization of a database created from the EMR of older patients should be considered for assessment of drug safety in older patients in clinical practice.

Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis.

In a longitudinal clinical study to compare two groups, the primary end point is often the time to a specific event (eg, disease progression, death). The hazard ratio estimate is routinely used to empirically quantify the between-group difference under the assumption that the ratio of the two hazard functions is approximately constant over time. When this assumption is plausible, such a ratio estimate may capture the relative difference between two survival curves. However, the clinical meaning of such a ratio estimate is difficult, if not impossible, to interpret when the underlying proportional hazards assumption is violated (ie, the hazard ratio is not constant over time). Although this issue has been studied extensively and various alternatives to the hazard ratio estimator have been discussed in the statistical literature, such crucial information does not seem to have reached the broader community of health science researchers. In this article, we summarize several critical concerns regarding this conventional practice and discuss various well-known alternatives for quantifying the underlying differences between groups with respect to a time-to-event end point. The data from three recent cancer clinical trials, which reflect a variety of scenarios, are used throughout to illustrate our discussions. When there is not sufficient information about the profile of the between-group difference at the design stage of the study, we encourage practitioners to consider a prespecified, clinically meaningful, model-free measure for quantifying the difference and to use robust estimation procedures to draw primary inferences.

Characteristics of pharmacogenomics/biomarker-guided clinical trials for regulatory approval of anti-cancer drugs in Japan.

Pharmacogenomics (PGx) or biomarker (BM) has the potential to facilitate the development of safer and more effective drugs in terms of their benefit/risk profiles by stratifying population into categories such as responders/non-responders and high-/low-risks to drug-induced serious adverse reactions. In the past decade, practical use of PGx or BM has advanced the field of anti-cancer drug development. To identify the characteristics of the PGx/BM-guided clinical trials for regulatory approval of anti-cancer drugs in Japan, we collected information on design features of 'key trials' in the review reports of anti-cancer drugs that were approved after the implementation of the 'Revised Guideline for the Clinical Evaluation of Anti-cancer drugs' in April 2006. On the basis of the information available on the regulatory review data for the newly approved anti-cancer drugs in Japan, this article aims to explain the limitations and points to consider in the study design of PGx/BM-guided clinical trials.

Similarities and differences between US and Japan as to pharmacogenomic biomarker information in drug labels.

Pharmacogenomics (PGx) has been utilized as a tool to improve a drug's benefit/risk ratio and the efficiency of drug developments. In order to examine what factors are involved to determine the level of contexts (contents and descriptions) of drug-PGx biomarker information, we graded sections of Japanese package inserts and US drug labels into six levels according to the importance of cautions in regards to clinical practice and compared similarities and differences of the contexts between the two countries. Out of 54 contexts identified, 33 (61%) were graded differently between Japan and the US. The different contexts were mainly related to metabolizing enzymes used in terms of safety, therapeutic areas other than oncology, outcome before 1993, Japan-based companies having marketing authorization and no PGx data on the Japanese population. We describe the potential reasons that could lead to the differences between the two countries such as genetic differences and quantitative evidence in the Japanese population, and also discuss future perspectives to improve PGx utilization in clinical practices in Japan.