Adult Japanese Patients Research Articles

The Effect of Antihypertensive Therapy on Skeletal Muscle Mass and Bone Mineral Density in Patients With End-Stage Kidney Disease

ObjectiveSarcopenia and osteoporosis substantially influence health and lifespan. However, the variables affecting skeletal muscle mass (SMM) or bone mineral density (BMD) remain unknown. Design and MethodsFrom August 1, 2018, to July 31, 2019, we conducted a single-center, observational cohort study with 291 Japanese adult patients on maintenance hemodialysis due to end-stage kidney disease (ESKD), who had their femoral neck BMD measured using dual-energy X-ray absorptiometry. After 1-year follow-up, we measured annual changes of BMD (ΔBMD) and SMM (ΔSMM), which was calculated through a modified creatinine index (mg/kg/day) using age, sex, serum creatinine, and single-pooled Kt/V for urea. The factors associated with ΔSMM/ΔBMD or progressive loss of SMM/BMD, defined as ΔSMM/ΔBMD <0 per year respectively, were analyzed with multivariable, linear regression or logistic regression models. ResultsThe median age of the patients was 66 years and 33% were female. Dialysis vintage and β-blocker-use were inversely correlated to ΔSMM. In comparison to nonusers, β-blockers users had 2.5-fold-higher SMM loss odd ratios [95% confidence interval (CI), 1.3–4.8]. The risk for SMM loss caused by β-blockers was not increased in users of renin-angiotensin system inhibitors (RASis). The ΔBMD was negatively correlated to the usage of calcium channel blockers (CCBs). The risk of developing osteosarcopenia, which was defined as annual loss of both SMM and BMD, increased in CCBs users. ConclusionThe use of β-blockers is associated with an elevated risk of developing sarcopenia, whereas RASis may minimize this effect in patients with ESKD. The CCB therapy was associated with a faster decline of BMD.

Clinical characteristics and antimicrobial susceptibility of non-vaccine serotype Streptococcus pneumoniae in adult Japanese patients with pneumonia

BackgroundNon-vaccine serotype (NVT) pneumococcal pneumonia in Japan has increased with the spread of pneumococcal vaccinations. However, there is no data regarding the clinical background and antimicrobial susceptibility of NVT isolates compared with those of vaccine serotype (VT) isolates in adult pneumococcal pneumonia. MethodsThe serotypes and antimicrobial susceptibilities of pneumococcal isolates obtained from patients with pneumonia at the University of Occupational and Environmental Health, Japan, from January 2011 to December 2020 were retrospectively evaluated along with the patients’ clinical information. ResultsIn total, 252 patients with pneumococcal pneumonia (98 NVT and 154 VT isolates) were included. Among NVTs, the most common serotype was 35B, followed by 15A, 34, 6C, 23A, and 15C. The MIC50 and MIC90 of each antibiotic in 35B and 15A tend to be higher than those in 34, 6C, and 23A. Regarding background characteristics, the percentages of patients with dementia and liver disease were significantly higher in patients in the VT group than in those in the NVT group (p = 0.048 and p = 0.012, respectively). There were no significant differences in the severity of pneumonia and mortality rate between patients with the VT and NVT isolates. This study first demonstrated that NVT isolates included those with reduced susceptibility to antibiotics in adult pneumonia in Japan. The data of the present study can be useful in optimizing treatment strategies for pneumococcal pneumonia because of the increasing number of NVT cases in Japan.

Prevalence, treatment status, medical costs, quality of life, and productivity loss in Japanese adult patients with anemia: a real-world database study

AimsTo investigate the prevalence, treatment status, and effect of anemia on medical costs, quality of life (QOL), and productivity loss in Japan.MethodsThis cross-sectional study used a database containing claims, health check-ups, and questionnaire data. Adults with hemoglobin data at 2020 check-ups were included. QOL and productivity loss were evaluated using EuroQol 5-Dimension (EQ-5D) and Work Productivity and Activity Impairment questionnaire data available for a subset of the population. Nationwide anemia prevalence, including both diagnosed as having anemia and undiagnosed but with low hemoglobin levels, were estimated. Treatment status was described by hemoglobin levels. Differences in medical costs, QOL, and productivity loss were compared between individuals with and without anemia. Subgroup analyses were performed using the Charlson Comorbidity Index (CCI).ResultsThe study population included 554,798 individuals. Anemia prevalence was estimated at 15.1% with 55.3% undiagnosed. In patients with anemia, 85.3% were untreated; 79.5% of the treated patients received only oral iron drugs. In patients with anemia, monthly medical costs were ¥17,766 higher, EQ-5D score was 0.0118 lower, and productivity loss was 2.6% higher than in those without anemia. The trends were consistent even in limited patients with CCI = 0. Nationwide annual excess medical costs, deficit QOL, and productivity loss in patients with anemia were estimated at ¥3.32 trillion, 138,000 quality-adjusted life-years, and ¥1.13 trillion, respectively.LimitationsAs the study population only included individuals who underwent health check-ups, they may be healthier than general population. Whether the differences in medical costs, QoL, and productivity loss are caused by anemia or other underlying differences in patient characteristics is unclear, given the likelihood of residual confounding.ConclusionsThe results suggest that more than half of patients with anemia were undiagnosed and untreated. Patients with anemia had higher medical costs, lower QOL, and greater productivity loss than those without anemia.

Clinicopathological Features of Buccal Squamous Cell Carcinoma with Focus on Patients Who Never Smoke and Never Drink.

Introduction Oral carcinoma has been reported at a substantial proportion in patients who never smoke and never drink. However, the proportion may vary by subsite and ethnicity. Objective We aimed to determine the clinicopathological features of buccal squamous cell carcinoma (SCC) in a Japanese population. Methods We retrospectively analyzed the records of patients diagnosed with buccal SCC at our institution from September 2002 to November 2015. We reviewed the gender, age, tumor status, treatment, smoking, alcohol drinking, multiple primary cancers, and prognosis of the patients. The overall and cause-specific survival rates were calculated, and the effects of clinicopathological variables were assessed by univariate analysis. Furthermore, the cause of death was evaluated. Results Among the 63 patients (men: 38; women: 25) included in the present study, 29 (46.0%) never smoked or drank. Women were almost 5 years older than men ( p = 0.014). The number of women in the group who never smoked or drank was disproportionately higher than that of those in the smoker or drinker groups ( p < 0.001). In total, 29 patients (46.0%) had 59 multiple primary cancers, including 26 oral cancers. Surgeries and radiotherapy were performed in 57 (90.5%) and 6 (9.5%) cases, respectively. The 5-year overall survival and disease-specific survival rates were 74.6 and 78.8%, respectively. Conclusion Our study confirms that buccal SCC may develop in older adult Japanese patients, especially in women who have never smoked or drank. These patients could be at risk for second primary malignancy.

Difference in Clinical Phenotype, Mutation Position, and Structural Change of RNF213 Rare Variants Between Pediatric and Adult Japanese Patients with Moyamoya Disease.

It is unclear how rare RNF213 variants, other than the p.R4810K founder variant, affect the clinical phenotype or the function of RNF213 in moyamoya disease (MMD). This study included 151 Japanese patients with MMD. After performing targeted resequencing for all coding exons in RNF213, we investigated the clinical phenotype and statistically analyzed the genotype-phenotype correlation. We mapped RNF213 variants on a three-dimensional (3D) model of human RNF213 and analyzed the structural changes due to variants. The RNF213 p.R4810K homozygous variant, p.R4810K heterozygous variant, and wild type were detected in 10 (6.6%), 111 (73.5%), and 30 (19.9%) MMD patients, respectively. In addition, 15 rare variants were detected in 16 (10.6%) patients. In addition to the influence of the p.R4810K homozygous variant, the frequency of cerebral infarction at disease onset was higher in pediatric patients with other rare variants (3/6, 50.0%, P = 0.006) than in those with only the p.R4810K heterozygous variant or with no variants (2/51, 3.9%). Furthermore, on 3D modelling of RNF213, the majority of rare variants found in pediatric patients were located in the E3 module and associated with salt bridge loss, contrary to the results for adult patients. The clinical phenotype of rare RNF213 variants, mapped mutation position, and their predicted structural change differed between pediatric and adult patients with MMD. Rare RNF213 variants, in addition to the founder p.R4810K homozygous variant, can influence MMD clinical phenotypes or structural change which may contribute to the destabilization of RNF213.

Moderate-carbohydrate diet without caloric or lipid restriction for Japanese adult patients with nonalcoholic fatty liver disease: A prospective cohort study.

Although a low-calorie diet with lipid restriction is recommended in clinical practice guidelines for nonalcoholic fatty liver disease (NAFLD), both compliance and adherence are poor. The present study aimed to evaluate the compliance, adherence, and effectiveness of a moderate-carbohydrate diet without caloric or lipid restrictions. Participants comprised 300 patients with NAFLD with elevated ALT levels who received counseling in carbohydrate restriction (150-200g/day). Complete response (CR) was defined as ALT normalization and partial response as a ≥30% reduction in ALT from baseline without CR. Dropout rates were 3% (10 of 300) after 6months and 8% (23 of 300) after 12months. Achievement rates of carbohydrate intake ≤200g/day after 1, 3, 6, and 12months were 80%, 81%, 80%, and 73%, respectively. CR and partial response rates were 60% and 31% after 6months, and 65% and 25% after 12months, respectively. Rates of achieving a ≥7% weight reduction after 6 and 12months were 51% and 49%, respectively. Significant reductions in percentage body fat and visceral fat area were obtained, along with a significant increase in liver/spleen attenuation ratio. Serum lipids, uric acid, homeostatic model assessment for insulin resistance, hemoglobin A1c, C-reactive protein, ferritin, immunoglobulin, blood cell, shear wave velocity in the liver, and Mac-2-binding protein glycosylated isomers all decreased significantly. Compliance and adherence to a moderate-carbohydrate diet without caloric or lipid restriction is high. The sustained high effectiveness of this therapy would improve the pathophysiological state of NAFLD.

Utility of scratch art therapy in adult epilepsy patients with difficulties in social adaptation.

Adult patients with epilepsy are confronted with significant psychological and psychosocial burdens. However, the role of psychological intervention to improve quality of life has not been fully established yet. The basis of art therapy is symbolic representations of inner experiences but patients may have difficulty expressing themselves. Here, we investigated utilities of scratch art therapy in Japanese adult patients with epilepsy who feel difficulties in social adaptation. Seven adult epilepsy patients (four males, age: 32.1 ± 9.9, mean ± SD) treated in epilepsy clinic of our hospital, who complained of psychosocial problems and underwent psychotherapy sessions combined with art therapy, were included. Six patients had focal epilepsy and two of them were sequelae of encephalitis. They were comorbid with depression, mood disorders, anxiety, memory disturbance, and insomnia. Psychotherapy sessions were scheduled at the same day of their clinic visit, every 4-12 weeks, 60 min per day, and art therapy was performed as a part (up to 30 min, in accord with the condition of the patient) of each session. Scratch art therapy was performed by using ready-made publications. Each patient selected favorite motives of figure out of several options suggested by the therapist. All patients quickly adapted themselves to scratch art therapy and verbally expressed their hidden emotions during drawing. One female patient with emotional lability appealed that she could stab herself by pointed end of the pen. Three patients added self-motivated lines to the designed draft. Two patients realized problems to be solved and moved to other suitable therapeutic procedures. The current case series study demonstrated utilities of scratch art therapy in Japanese adult patients with epilepsy who feel difficulties in social adaptation. Scratch art therapy is easy to introduce in adult epilepsy patients who have trouble expressing themselves or have uncontrollable emotions.

Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study of ustekinumab in Japanese patients with active polymyositis and dermatomyositis who have not adequately responded to one or more standard-of-care treatments

ObjectivesTo evaluate the efficacy and safety of ustekinumab (UST) in a multicentre, randomised, double-blind, placebo-controlled trial in adult Japanese patients with active polymyositis (PM) and dermatomyositis (DM).MethodsFifty-one Japanese adults diagnosed...

Tumor immune microenvironment and clinical outcomes in stage IV urothelial cancer: YODO study

BackgroundBladder cancer is the 10th most common cancer globally, with a growing incidence in Japan. Evaluation of molecular, genetic, and cellular biomarkers that predict treatment response and prognosis in patients with metastatic urothelial carcinoma (mUC) may help optimize sequential treatment strategies with chemotherapy and immune checkpoint inhibitors (ICIs).MethodsThis multicenter, retrospective cohort study, evaluated programmed death-ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and cancer-immune phenotype as predictive prognostic biomarkers following first-/second-line treatment in Japanese adult patients with mUC. The primary endpoint was prevalence of PD-L1 expression. Secondary endpoints were TMB, overall survival (OS), and progression-free survival (PFS) from initiation of first-line treatment, and exploratory endpoints were cancer-immune phenotype, OS, PFS, and treatment response according to potential biomarker status.ResultsOf the 143 patients included (mean age 71.7 years), PD-L1 expression was high in 29.4% of patients. Non-synonymous TMB was high in 33.6% and low in 66.4%. Cancer-immune phenotype was immune-desert in 62.9%, immune-excluded in 30.8%, and inflamed in 6.3%. Median OS and PFS following first-line treatment were 18.2 and 7.4 months, respectively. Overall response to second-line treatment was slightly better with high versus low/negative PD-L1 expression. PD-L1 expression and TMB were non-significant predictors of OS or PFS, whereas immune-excluded phenotype was associated with better OS in comparison with immune-desert phenotype.ConclusionPD-L1 expression and TMB were non-significant predictors of prognosis after first-line treatment in Japanese patients with mUC, but cancer-immune phenotype may be an important prognostic factor in chemotherapy-ICI sequential treatment strategies.Clinical trial registration number UMIN000037727.

A web-based survey on self-management for patients with inflammatory bowel disease in Japan.

Self-management (SMN) is a recognized component of care for chronic conditions, yet its importance in the context of inflammatory bowel disease (IBD) is unclear. This study evaluates the status of SMN and its relationship with quality of life (QOL) in Japanese patients with IBD. A web-based survey was conducted among adult (≥20 years old) Japanese patients with ulcerative colitis (UC) or Crohn's disease (CD). Registered members of an online IBD information platform completed a 45-item survey covering demographics, diet, treatment, physical condition, stress management, financial concerns, support services, and QOL. SMN was operationally defined by dietary and lifestyle behaviours, and contingency analysis was used to test for associated factors. Individual-level contributions to SMN were identified with logistic regression. There were 372 responses to the survey (211 with UC, 161 with CD). Approximately 60% of participants practiced SMN and these patients were 4-24% more likely to report positive QOL than those who did not. SMN was more common in patients with CD than those with UC. SMN practice was also associated with IBD-related hospitalisation/surgery and consultation with others about IBD (e.g. physicians, nurses, patients). The results of this study suggest an association between the practice of SMN and positive QOL in patients with IBD in Japan.

A prospective investigation of impacts of comorbid attention deficit hyperactivity disorder (ADHD) on clinical features and long-term treatment response in adult patients with obsessive-compulsive disorder (OCD)

BackgroundA close association between obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in children and adolescents has been investigated in previous studies. However, few studies examined the relationship between lifetime comorbidity of ADHD and OCD in adults. Therefore, we sought to investigate the clinical and psychopathological features related to comorbid ADHD in Japanese adult patients with OCD. MethodsWe assessed lifetime comorbidity of ADHD in 93 adult Japanese patients with OCD. Additionally, we used the Japanese version of Conners' Adult ADHD Rating Scales to assess the characteristics and severity of ADHD in each participant. According to the results, we excluded OCD patients that did not have ADHD but who exhibited elevated levels of ADHD traits. We compared OCD patients with ADHD (ADHD+ group) and those without ADHD or its trait (ADHD− group) in terms of background profiles and clinical features, such as OCD symptomatology and psychometric test results. Additionally, the 6-month treatment outcome was compared prospectively between groups. ResultsOf the 93 OCD participants, the prevalence of lifetime comorbidity of ADHD was estimated as 16.1%. Compared with the ADHD− group, participants in the ADHD+ group had an earlier age of onset of OCD, higher frequencies of hoarding symptoms, higher levels of depressive and anxiety symptoms and lower quality of life, more elevated levels of impulsivity, and higher rates of substance or behavioral addiction and major depression. Finally, the mean improvement rate on the Yale-Brown Obsessive Compulsive Scale after 6 months of standardized OCD treatment in the ADHD+ group (16.1%) was significantly lower than that in the ADHD− group (44.6%). ConclusionThe lifetime comorbidity of ADHD is likely to exert a significant effect on clinical features and treatment outcome in adult patients with OCD. It is important to consider that underlying ADHD pathology may function as a facilitator for increased severity of global clinical features and treatment refractory conditions in OCD patients. Further studies are required to examine treatment strategies for such patients.

Effects of Lenvatinib on Skeletal Muscle Volume and Cardiac Function in Patients with Hepatocellular Carcinoma

Introduction: Previously, we reported that the tyrosine kinase inhibitor (TKI) sorafenib decreases serum levels of carnitine and reduces skeletal muscle volume. Moreover, others reported that TKIs might lead to cardiomyopathy or heart failure. Therefore, this study aimed to evaluate the effects of lenvatinib (LEN) on skeletal muscle volume and cardiac function in patients with hepatocellular carcinoma (HCC). Methods: This retrospective study included 58 adult Japanese patients with chronic liver diseases and HCC treated with LEN. Blood samples were collected before and after 4 weeks of treatment, and serum carnitine fraction and myostatin levels were measured. Before and after 4–6 weeks of treatment, the skeletal muscle index (SMI) was evaluated from computed tomography images and cardiac function was assessed by ultrasound cardiography. Results: After treatment, SMI, serum levels of total carnitine, and global longitudinal strain were significantly lower, but serum levels of myostatin were significantly higher. Left ventricular ejection fraction showed no significant change. Conclusion: In patients with HCC, LEN decreases serum levels of carnitine, skeletal muscle volume, and worsens cardiac function.

High Albumin Clearance Predicts the Minimal Change Nephrotic Syndrome Relapse.

Although albuminuria leakage that occurs in minimal change nephrotic syndrome (MCNS) may be related to the disease state, albumin kinetics in MCNS has never been evaluated. In this study, we investigated albumin kinetics in adult Japanese patients with MCNS by the estimated 24-h albumin clearance (eCALB) and examined the association between eCALB and relapse. We retrospectively identified 103 adult patients with a histological diagnosis of MCNS from four hospitals in Japan (2010-2020). The primary outcome is the first relapse in 2 years after complete remission (CR) following corticosteroid therapy. The estimated 24-h albumin clearance (eCALB) [µL/min] was defined as (2.71828log(0.0445 + 0.9488*log(urinary protein) [g/24h]/(serum albumin [g/dL] × 1440 [min/24 h]) for women and (2.71828log(-0.1522 + 0.9742*log(urinary protein) [g/24h]/(serum albumin [g/dL] × 1440 [min/24 h]) for men. Relapse was observed in 44 patients (103 kidney biopsy samples; 42.7%). The mean patient age was 41.0 years. Patients had an estimated glomerular filtration rate (eGFR) of 71.0 mL/min/1.73 m2, urinary protein excretion (UPE) of 6.8 g/day, serum albumin of 1.4 g/dL, and eCALB of 2.27 μL/min. eCALB was strongly associated with hypoalbuminemia, severe proteinuria, lipid abnormalities, and coagulopathy. In the multivariable analysis, a high eCALB was significantly associated with relapse after adjusting for age, eGFR, time to CR, and UPE (adjusted hazard ratio = 5.027, 95% confidence interval 1.88-13.47, P = 0.001). This study revealed that eCALB, which could substitute albumin kinetics, reflected the severity of MCNS, and a high eCALB was associated with recurrence.

Efficacy and safety of baricitinib in Japanese patients with autoinflammatory type I interferonopathies (NNS/CANDLE, SAVI, And AGS)

BackgroundThis study evaluated the efficacy and safety of baricitinib (Janus kinase-1/2 inhibitor), in adult and pediatric Japanese patients with Nakajo-Nishimura syndrome/chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (NNS/CANDLE), stimulator of interferon genes-associated vasculopathy with onset during infancy (SAVI), or Aicardi-Goutières syndrome (AGS).MethodsA Phase 2/3, multicenter, open-label study (NCT04517253) was conducted across 52 weeks. Primary efficacy endpoint assessed the change in mean daily diary score (DDS) from baseline to the end of primary treatment period. Other efficacy endpoints included change in mean DDS to the end of maintenance period, daily corticosteroid use, Physician’s Global Assessment of Disease Activity (PGA) scores, and daily symptom-specific score (DSSS) from baseline to primary and maintenance treatment periods. All treatment-emergent adverse events (TEAEs) that occurred postdosing were recorded.ResultsOverall, 9 patients (5 with NNS, 3 with SAVI, and 1 with AGS) were enrolled; 55.6% were females, mean age was 26 years, and mean corticosteroid use/weight was 0.2 mg/kg. At the end of primary treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.22) and SAVI (0.21) and increased in the patient with AGS (0.07). At the end of maintenance treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.18) and SAVI (0.27) and increased in the patient with AGS (0.04). Mean percent corticosteroid use decreased by 18.4% in 3 out of 5 patients with NNS/CANDLE and 62.9% in 1 out of 3 patients with SAVI. Mean PGA score decreased from baseline in patients with NNS/CANDLE (1.60), SAVI (1.33), and AGS (1.0), and mean DSSS improved from baseline. All patients reported ≥ 1 TEAE. Frequently reported AEs included BK polyomavirus detection (3; 33.3%), increased blood creatine phosphokinase (2; 22.2%), anemia (2; 22.2%), and upper respiratory tract infection (2; 22.2%). Three (33.3%) patients reported serious adverse events, 1 of which was related to study drug. One patient with SAVI died due to intracranial hemorrhage, which was not related to study drug.ConclusionBaricitinib may offer a potential therapeutic option for patients with NNS/CANDLE, SAVI, and AGS, with a positive benefit/risk profile in a vulnerable patient population with multiple comorbidities.Trial registrationNLM clinicaltrials.gov, NCT04517253. Registered 18 August 2020.

Incidence and risk factors for venous thromboembolism in the Cancer-VTE Registry stomach cancer subcohort

BackgroundThe Cancer-VTE Registry was a large-scale, multicenter, prospective registry designed to investigate real-world data on venous thromboembolism (VTE) incidence and risk factors in adult Japanese patients with solid tumors. This pre-specified subgroup analysis aimed to estimate the incidence of VTE, including VTE types other than symptomatic VTE, and identify risk factors of VTE in stomach cancer from the Cancer-VTE Registry.MethodsStage II–IV stomach cancer patients who planned to initiate cancer therapy and underwent VTE screening within 2 months before registration were enrolled.ResultsOf 1,896 patients enrolled, 131 (6.9%) had VTE at baseline, but 96.2% were asymptomatic. Female sex, age ≥ 65 years, VTE history, and D-dimer > 1.2 μg/mL were independent risk factors of VTE at baseline. Notably, patients with D-dimer > 1.2 µg/mL at the time of cancer diagnosis had an approximately 20-fold risk of VTE. During follow-up, event incidences were symptomatic VTE, 0.3%; incidental VTE requiring treatment, 1.1%; composite VTE, 1.4%; bleeding, 1.6%; cerebral infarction/transient ischemic attack/systemic embolic events, 0.7%; and all-cause death, 15.0%. The incidence of all-cause death was higher in patients with VTE vs without VTE at baseline (adjusted hazard ratio 1.67; 95% confidence interval 1.21–2.32; p = 0.002).ConclusionsVTE prevalence at the time of cancer diagnosis was not negligible and was extremely high when the patients had high D-dimer. VTE screening by D-dimer before starting cancer treatment is advisable, even for asymptomatic patients, regardless of whether the patient is undergoing surgery or chemotherapy.Trial registrationUMIN000024942.

Safety and Effectiveness of Molnupiravir (LAGEVRIO®) Capsules in Japanese Patients with COVID-19: Interim Report of Post-marketing Surveillance in Japan.

Molnupiravir is an oral antiviral drug that received special approval for emergency use in Japan on December 24 2021 for infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This post-marketing surveillance (PMS) is underway to investigate the safety and effectiveness of molnupiravir in daily clinical practice in Japan. The interim PMS data collected from December 27 2021 to June 15 2022 are reported in this publication. This survey included adult Japanese patients treated with molnupiravir. For safety, adverse drug reactions (ADR) were assessed by physicians. Effectiveness was assessed by the composite endpoint of (1) hospitalization or (2) death in outpatients and by the composite endpoint of (3) death or (4) initiation of oxygen administration/mechanical ventilation in inpatients hospitalized for any reasons and without oxygen administration at the start of molnupiravir administration. The observation period was through 29days from the start of molnupiravir administration. Of the 1031 patients in the safety analysis set, 68 (6.60%) patients reported ADRs and four (0.39%) patients reported serious ADRs. The main ADRs observed were diarrhoea [26 patients (2.52%)], rash [six patients (0.58%)], dizziness [five patients (0.48%)], and faecessoft [four patients (0.39%)]. In the effectiveness analysis from the start date of molnupiravir administration to day 29, there were 16/612 (2.61%) hospitalizations and no deaths. Oxygen administration was newly initiated in 9/199 (4.52%) inpatients after the initiation of molnupiravir administration; 2/199 (1.01%) inpatients died. This interim analysis of molnupiravir in daily clinical practice use in Japan supports the safety and effectiveness profile of molnupiravir under pandemic conditions in which Omicron was the dominant SARS-CoV-2 variant. The results of this PMS will provide valuable information for daily clinical practice use.

Pharmacokinetics of intravenous daptomycin in Japanese pediatric patients: Pharmacokinetic comparisons supporting dosing recommendations in Japanese pediatric patients

IntroductionThe pharmacokinetics (PK) of daptomycin has not been previously characterized in Japanese pediatric patients with complicated skin and soft tissue infections (cSSTI) or bacteremia. An aim of the study includes evaluation of PK of daptomycin in Japanese pediatric patients and an appropriateness of the age-specific, weight-based dosing regimens in Japanese pediatric patients based on PK comparison with Japanese adult patients. MethodsThe phase 2 trial enrolled Japanese pediatric patients (age 1–17 years) with cSSTI (n = 14) or bacteremia (n = 4) caused by gram-positive cocci in order to evaluate safety, efficacy and PK. The Phase 3 trial in Japanese adult patients (SSTI n = 65, septicemia/right-sided infective endocarditis (RIE) n = 7) was referred to for PK comparison between adult and pediatric. Daptomycin concentrations in plasma were analyzed by reverse-phase high-performance liquid chromatography (HPLC). PK parameters were determined using non-compartmental analysis in Japanese pediatric and Japanese adult patients. The exposures in Japanese pediatric patients were graphically compared with those in Japanese adult patients. The relationship between daptomycin exposures and creatine phosphokinase (CPK) elevation was explored visually. ResultsFollowing administration of the age-specific, weight-based dosing regimens, daptomycin exposures were overlapping across age groups in pediatric patients with cSSTI with similar observations based on clearance. The distribution of individual exposure in Japanese pediatric patients was overlapping with that in Japanese adult patients. No apparent relationship between daptomycin exposures and CPK elevation in Japanese pediatric patients was observed. ConclusionsThe results suggested that the age-specific, weight-based dosing regimens are considered to be appropriate in Japanese pediatric patients.

Population pharmacokinetics and limited sampling strategy for therapeutic drug monitoring of mycophenolate mofetil in Japanese patients with lupus nephritis

BackgroundMycophenolate mofetil (MMF), a prodrug of the immunosuppressive agent mycophenolic acid (MPA), is difficult to administer because of the pharmacokinetic complexity of MPA. Although dosage adjustment according to the 12-h area under the concentration–time curve (AUC0-12) is thought to be desirable, multiple blood samplings for AUC calculation may pose a clinical challenge. A limited sampling strategy (LSS) would provide a solution; however, little is known about MPA pharmacokinetics in lupus nephritis patients, especially in those with Asian backgrounds, or few, if any, LSSs are reported for them.MethodsThirty-four adult Japanese patients receiving MMF for lupus nephritis were examined retrospectively. MPA pharmacokinetics were investigated, and a PPK model was developed using Phoenix® NLME™ software. Single and double blood sampling strategies from Bayesian estimation using the PPK model and from multiple linear regression were compared. Tolerability was also evaluated.ResultsIn the pharmacokinetic analysis, renal function and serum albumin had significant effects on dose-normalized AUC0-12; and serum albumin, concomitant proton pump inhibitor (PPI) and iron/magnesium oxide did on dose-normalized maximum concentration. As a PPK model, a two-compartment model was developed with a transit absorption model and first-order elimination, in which creatinine clearance and serum albumin were covariates for MPA clearance. The double sampling strategy at 1 and 4 h by multiple linear regression showed the best agreement with the observed AUC0-12 (r2 = 0.885). Of the single sampling strategies, the one at 6 h by Bayesian estimation performed best (r2 = 0.769). The tolerability evaluation showed that correlations were suggested for gastrointestinal involvement.ConclusionsThe present study developed the first PPK model of MPA for Japanese lupus nephritis patients. As for LSSs, a double sampling strategy at 1 and 4 h by multiple linear regression would work best; when only a single blood sampling is allowed, a strategy at 6 h by Bayesian estimation using the PPK model developed in this study would be best. The LSSs good enough for clinical use may facilitate safer, more effective, and individualized therapy.

Time to normalisation of C-reactive protein and incidence of relapse in microscopic polyangiitis: A medical records review study in Japan.

Despite the identification of risk factors for relapses in antineutrophil cytoplasmic antibody-associated vasculitis, the relationship between changes in C-reactive protein (CRP) levels after the initial treatment and the incidence of relapse remains unknown. This study aimed to assess the association between the time taken for normalisation of CRP levels and the incidence of relapse in Japanese adult patients with microscopic polyangiitis. This study included 85 consecutive patients with newly diagnosed microscopic polyangiitis who achieved remission after 6 months of immunosuppressive treatment at the Aichi Medical University Hospital between 2009 and 2017. The relationship between the time to normalisation of CRP after the initial immunosuppressive treatment and relapse incidences was evaluated using multivariable Cox proportional hazard models. During the follow-up period, 13 (30.2%), 7 (41.2%), and 16 (64.0%) patients relapsed (P = .025) within 1-14, 15-28, and ≥29 days of normalisation, respectively. The hazard ratios [95% confidence intervals (CIs)] for the time to normalisation of CRP of 1-14, 15-28, and ≥29 days were 1.00 (reference), 2.42 (95% CI: 0.92-6.39), and 3.48 (95% CI: 1.56-7.76), respectively. A significant association between the time to normalisation of CRP and the relapse incidence in Japanese patients with microscopic polyangiitis was observed.

Efficacy and safety of tisagenlecleucel in adult Japanese patients with relapsed or refractory follicular lymphoma: results from the phase 2 ELARA trial

BackgroundTisagenlecleucel yielded a high durable response rate in patients with relapsed/refractory (r/r) follicular lymphoma (FL) in the global phase 2 ELARA trial. Here, we report the efficacy, safety, and cellular kinetics of tisagenlecleucel in a subgroup of Japanese patients with r/r FL from ELARA.MethodsELARA (NCT03568461) is a global single-arm trial of tisagenlecleucel in patients with r/r FL who received ≥ 2 prior lines of therapy. The primary endpoint was the complete response rate (CRR), and the secondary endpoints were the overall response rate, duration of response, progression-free survival, overall survival, safety, and cellular kinetics.ResultsAs of March 29, 2021, nine Japanese patients were enrolled and received tisagenlecleucel with a median follow-up of 13.6 months (range, 10.5‒19.3). Per independent review committee, CRR was 100% (95% CI 63.1‒100). Within 8 weeks of infusion, cytokine release syndrome (CRS) of any grade was reported in 6 patients (66.7%); however, no grade ≥ 3 CRS or any grade serious neurological events or treatment-related deaths were observed.ConclusionTisagenlecleucel showed high efficacy and manageable safety in adult Japanese patients with r/r FL. Moreover, the clinical outcomes were similar to the global population, which supports the potential of tisagenlecleucel in Japanese patients with r/r FL.