Search

Objective/background: The short-term efficacy and safety of daridorexant, a dual orexin receptor antagonist, has been demonstrated in Japanese patients with insomnia disorder. The objective of this study was to evaluate, in a non-overlapping patient population to the short-term study, the long-term safety and efficacy of daridorexant in Japanese patients with insomnia disorder., Patients/methods: In this Phase 3 open-label study conducted in Japan, 154 patients with insomnia disorder were randomized to daridorexant 50 mg (n = 102) or 25 mg (n = 52) for 52 weeks. The primary objective was to assess the safety and tolerability of daridorexant for up to 1 year. Secondary exploratory objectives were to evaluate the long-term efficacy of daridorexant on subjective sleep parameters (total sleep time, latency to sleep onset and wake after sleep onset) and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire)., Results: The incidence of treatment-emergent adverse events (TEAEs) was 74 % and 58 % in the 50 mg and 25 mg groups respectively. No serious drug-related TEAEs were reported. Both doses improved next-morning sleepiness (Visual Analog Scale) throughout the study. Five adjudicated adverse events of special interest were reported; excessive daytime sleepiness (n = 1, 25 mg; n = 2, 50 mg), sleep paralysis (n = 1, 50 mg) and nightmare (n = 1, 25 mg). Improvements in sleep and daytime functioning were maintained from Week 2 (first assessment) through to Week 52 in both dose groups., Conclusions: Up to 52-weeks, daridorexant was well tolerated with sustained improvement in sleep onset, sleep maintenance and daytime functioning, supporting its long-term use in Japanese patients with insomnia disorder., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report financial support, administrative support, and writing assistance were provided by Nxera Pharma Japan Co., Ltd. All authors reports financial support was provided by Mochida Pharmaceutical Co Ltd. Naohisa Uchimura reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Naohisa Uchimura reports a relationship with MSD KK that includes: speaking and lecture fees. Motohiro Ozone reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Motohiro Ozone reports a relationship with MSD KK that includes: speaking and lecture fees. Motohiro Ozone reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Motohiro Ozone reports a relationship with Tsumura & Co that includes: speaking and lecture fees. Masahiro Suzuki reports a relationship with EA Pharma Co Ltd that includes: funding grants and speaking and lecture fees. Masahiro Suzuki reports a relationship with Eisai Co Ltd that includes: funding grants, paid expert testimony, and speaking and lecture fees. Masahiro Suzuki reports a relationship with Mochida Pharmaceutical Co Ltd that includes: funding grants, paid expert testimony, and speaking and lecture fees. Masahiro Suzuki reports a relationship with Meiji Co Ltd that includes: funding grants and speaking and lecture fees. Masahiro Suzuki reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants and speaking and lecture fees. Masahiro Suzuki reports a relationship with Shionogi and Co Ltd that includes: funding grants and speaking and lecture fees. Masahiro Suzuki reports a relationship with Sumitomo Pharma Co Ltd that includes: funding grants and speaking and lecture fees. Masahiro Suzuki reports a relationship with Kao Corporation that includes: paid expert testimony and speaking and lecture fees. Masahiro Suzuki reports a relationship with Kyowa Pharmaceutical Industry Co Ltd that includes: speaking and lecture fees. Masahiro Suzuki reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Masahiro Suzuki reports a relationship with Viatris Inc that includes: speaking and lecture fees. Masahiro Suzuki reports a relationship with Yoshitomi Pharmaceutical Corporation that includes: speaking and lecture fees. Masahiro Suzuki reports a relationship with Jazz Pharmaceuticals Inc that includes: paid expert testimony. Kenichi Kuriyama reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants. Kenichi Kuriyama reports a relationship with Eisai Co Ltd that includes: consulting or advisory, funding grants, and speaking and lecture fees. Kenichi Kuriyama reports a relationship with MSD KK that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with Takeda Pharmaceutical Company Limited that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with Meiji Co Ltd that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Yoshitomi Pharmaceuical Corporation that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Aculys Pharma, LLC. that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Nobelpharma Co Ltd that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Nxera Pharma Japan Co Ltd that includes: consulting or advisory. Osamu Togo reports a relationship with Nxera Pharma Japan Co. Ltd that includes: employment. Makoto Uchiyama reports a relationship with Nxera Pharma Japan Co. Ltd that includes: consulting or advisory. Makoto Uchiyama reports a relationship with LIXIL Corporation that includes: consulting or advisory. Makoto Uchiyama reports a relationship with Taisho Pharmaceutical Co Ltd that includes: consulting or advisory., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

ASP8302 is an orally administered positive allosteric modulator of the muscarinic M 3 receptor. Two Phase 1 studies were conducted, a first-in-human study in Europe and a Japanese phase 1 study. Both were randomized, participant- and investigator-blinded, placebo-controlled, single and multiple ascending oral doses, parallel group, clinical studies in healthy volunteers. Both studies evaluated safety and pharmacokinetics and also included salivary secretion and pupil diameter as pharmacodynamic assessments. There were no deaths, serious adverse events, or treatment-emergent adverse events reported leading to study discontinuation. There were no clinically relevant findings in any of the laboratory, vital signs, electrocardiogram assessments, or photosensitivity testing following multiple administration of up to 150 mg or up to 140 mg once daily for 14 days in the European first-in-human and Japanese Phase 1 study, respectively. The pharmacokinetics of ASP8302 were approximately linear over the dose range studied. There was no evidence of drug accumulation upon repeated dosing. In both studies, ASP8302 showed a dose-dependent pharmacodynamic effect on saliva production at doses from 100 mg onward, which was maintained during repeated dosing. No effect was observed on pupil diameter. These data supported progression of ASP8302 into Phase 2 clinical trials for further clinical development., (© 2024 Astellas Pharma Inc, Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Long-term glucocorticoids (GCs) treatment is associated with osteoporosis and fractures. We investigated whether low-dose GC treatment also increased the risk of osteoporotic fractures, and the results showed that even low-dose GC treatment increased the risk of osteoporotic fractures, especially spine fractures., Purpose: The effect of low-dose glucocorticoid (GC) therapy on the fracture risk in postmenopausal women with low bone mass was investigated., Methods: 119,790 66-year-old postmenopausal women with low bone mass based on bone mineral density (BMD) results were included. GC group consisted of patients who had been prescribed oral GCs within 6 months of BMD testing. In GC group, GCs dosage was calculated by a defined daily dose (DDD), and divided into five groups according to GC usage (Group 1[G1]; < 11.25 DDDs, G2; ≥ 11.25, < 22.5 DDDs, G3; ≥ 22.5, < 45 DDDs, G4; ≥ 45, < 90 DDDs, G5; ≥ 90 DDDs). The risk of major osteoporotic fractures (MOF) and non-MOF was analyzed and compared with that of the control group during the 1-year follow-up., Results: The risk of total fracture was higher in G3-G5 than in the control group (G3, hazard ratio (HR) 1.25, 95% confidence interval [CI] 1.07-1.46; G4, 1.37 [1.13-1.66]; G5 1.45 [1.08-1.94]). The risk of MOF was higher in all groups except G2 than in the control group (G1, 1.23 [1.05-1.45]; G3, 1.37 [1.11-1.68]; G4, 1.41 [1.09-1.83]; G5, 1.66 [1.14-2.42]). The risk of spine fracture was significantly higher in all GC groups except G2 than in the control group. The risk of non-MOF was higher only in G4 than in the control group (G4, 1.48 [1.13-1.94])., Conclusion: Low-dose GC therapy can increase the risk of osteoporotic fractures, particularly spine fractures, in postmenopausal women with low bone mass., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Background: The comparative efficacy and safety of adjusted- and standard-dose prasugrel in East Asian patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) remain unclear. This study aimed to comparatively assess the ischaemic and bleeding outcomes of adjusted-dose (maintenance dose: 3.75 mg) and standard-dose (maintenance dose: 10 mg) prasugrel in East Asian patients with AMI undergoing PCI., Methods: From a combined dataset sourced from nationwide AMI registries in Japan and South Korea (n = 17,118), patients treated with either adjusted- or standard-dose prasugrel were identified. Patients who did not undergo emergent PCI, those on oral anticoagulants, and those meeting the criteria of contraindication of prasugrel in South Korea (age ≥ 75 years, body weight < 60 kg, or history of stroke) were excluded. Major adverse cardiovascular events (MACE) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding events were compared between the adjusted-dose (n = 1160) and standard-dose (n = 1086) prasugrel groups., Results: Within the propensity-matched cohort (n = 702 in each group), no significant difference was observed in the in-hospital MACE between the adjusted- and standard-dose prasugrel groups (1.85% vs. 2.71%, odds ratio [OR] 0.68, 95% confidence interval [CI] 0.33-1.38, p = 0.286). However, the incidence of in-hospital major bleeding was significantly lower in the adjusted-dose prasugrel group than in the standard-dose group (0.43% vs. 1.71%, OR 0.25, 95% CI 0.07-0.88, p = 0.031). The cumulative 12-month incidence of MACE was equivalent in both groups (4.70% vs. 4.70%, OR 1.00, 95% CI 0.61-1.64, p = 1.000)., Conclusions: Among East Asian patients with AMI undergoing PCI, those administered adjusted-dose prasugrel exhibited a lower risk of in-hospital bleeding events than those administered standard-dose prasugrel, while maintaining a comparable 1-year incidence of MACE., Competing Interests: Declaration of competing interest Dr. Yasuda reports remuneration for lectures from Takeda, Daiichi Sankyo, and Bristol-Myers Squibb and trust research/joint research funds from Takeda and Daiichi Sankyo; Dr. Takayama reports lecture fees from Daiichi Sankyo; and Dr. Ogawa reports lecture fees and research grants from Abbot Medical Japan, Bayer, Daiichi Sankyo, Eisai, Kowa, Takeda Pharmaceutical, and Teijin. Other authors have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The aim of the study was to evaluate the safety/tolerability and pharmacokinetics of simlukafusp alfa (FAP-IL2v), an immunocytokine containing an anti-fibroblast activation protein-α (FAP) antibody and an IL2 variant, administered alone or with the PDL1 inhibitor atezolizumab, in Japanese patients with advanced solid tumors., Patients and Methods: In this phase 1, open-label, dose-escalation study, patients received i.v. FAP-IL2v at 10 or 15/20 mg alone or 10 mg when combined with i.v. atezolizumab. The primary objectives were identification of dose-limiting toxicities (DLT), recommended dose, and maximum tolerated dose, and evaluation of the safety/tolerability and pharmacokinetics of FAP-IL2v alone and combined with atezolizumab., Results: All 11 patients experienced adverse events (AE) during FAP-IL2v treatment. Although most AEs were of mild severity, four treatment-related AEs led to study treatment discontinuation in two patients: one with infusion-related reaction, hypotension, and capillary leak syndrome, and the other with increased aspartate aminotransferase. No AE-related deaths occurred. One DLT (grade 3 hypotension) occurred in a patient receiving FAP-IL2v 15/20 mg alone. The recommended dose and maximum tolerated dose could not be determined. The pharmacokinetics of FAP-IL2v remained similar with or without atezolizumab. The study was terminated early as FAP-IL2v development was discontinued because of portfolio prioritization (not for efficacy/safety reasons)., Conclusions: This study describes the safety/tolerability of FAP-IL2v 10 mg alone and in combination with atezolizumab in Japanese patients with advanced solid tumors; one DLT (hypotension) occurred with FAP-IL2v 15/20 mg. However, dose escalation of FAP-IL2v was not conducted because of early study termination., Significance: This phase I study assessed the safety/tolerability and PK of simlukafusp alfa alone or combined with atezolizumab in Japanese patients with advanced solid tumors. No notable differences in PK were noted with the combination versus simlukafusp alfa alone; however, high-dose simlukafusp alfa treatment was associated with recombinant IL2-related toxicity, despite the drug's FAP targeting and IL2Rβγ-biased IL2 variant design., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: To evaluate the 2-year efficacy, durability, and safety of faricimab in patients with diabetic macular edema (DME) in the YOSEMITE Japan subgroup., Study Design: YOSEMITE/RHINE (NCT03622580/NCT03622593) subgroup analysis: global, multicenter, randomized, double-masked, active-comparator-controlled, phase 3 faricimab trials., Methods: Patients were randomized 1:1:1 to intravitreal faricimab 6.0 mg every 8 weeks (Q8W) and per treat-and-extend (T&E) dosing, or aflibercept 2.0 mg Q8W. Outcomes were assessed through year 2 for the YOSEMITE Japan subgroup (N = 60) and the pooled YOSEMITE/RHINE global cohort (N = 1891)., Results: In the YOSEMITE Japan subgroup, 21, 19, and 20 patients were randomized to faricimab Q8W, faricimab T&E, and aflibercept Q8W, respectively (632, 632, and 627 patients in the pooled YOSEMITE/RHINE cohort). Vision gains and anatomic improvements with faricimab at year 1 were maintained over 2 years and were generally consistent between groups. Mean best-corrected visual acuity changes from baseline at year 2 (weeks 92-100 average) for the YOSEMITE Japan subgroup were +12.5, +9.0, and +5.0 letters in the faricimab Q8W, faricimab T&E and aflibercept Q8W arms, respectively (+10.8, +10.4, and +10.3 letters in the pooled YOSEMITE/RHINE cohort). At week 96, 61.1% of the YOSEMITE Japan subgroup and 78.1% of the pooled YOSEMITE/RHINE cohort were on ≥ Q12W dosing. Faricimab was well-tolerated with a safety profile comparable with aflibercept., Conclusion: Faricimab up to Q16W offered durable vision gains and anatomic improvements up to 2 years in patients with DME in the YOSEMITE Japan subgroup. Outcomes were generally consistent with the pooled YOSEMITE/RHINE cohort., (© 2024. The Author(s).)

Renal function significantly influences the appropriate warfarin dosage. However, studies investigating the impact of genetic factors on warfarin dosage, considering renal function, are limited. This study aimed to assess the role of genetic polymorphisms in VKORC1 , CYP2C9 , CYP2C19 , CYP4F2 , GGCX , and APOE in warfarin dosage adjustment considering renal function. A total of 108 outpatients receiving warfarin treatment with controlled prothrombin time-targeted international normalized ratio (1.5-3.0) were included. Patient data, warfarin dosage, and laboratory results were collected from electronic medical records. Each SNP [ VKORC1 rs9923231, CYP2C9 rs1057910, CYP4F2 rs2108622, CYP2C19 * 2 (rs4244285) and * 3 (rs4986893), GGCX rs699664 and rs12714145, and APOE rs7421] was analyzed. Multiple regression analysis revealed estimated glomerular filtration rate as the most significant factor influencing warfarin dose (p <0.001) ( β = -0.445). VKORC1 rs9923231 AA, CYP4F2 rs2108622 CT/TT, GGCX rs12714145 CT/TT, and CYP2C9 rs1057910 AC carriers were associated with warfarin dose (p <0.001, 0.015, 0.020, 0.038 and β = -0.317, 0.191, -0.188, -0.162, respectively); however, other genes showed no significant association. In conclusion, after adjusting for renal function, genetic factors of VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs12714145, and CYP2C9 rs1057910 were found to contribute to warfarin dosage, having impact in that order. In contrast, the contribution of other genes to warfarin dosage was absent or negligible.

Objective: The phase II STARLIGHT study was conducted to investigate the efficacy/safety of fezolinetant in Japanese women and identify the optimal dose for future evaluation., Method: Participants were perimenopausal/postmenopausal women aged ≥40 to ≤65 years from 36 centers in Japan seeking treatment/relief for vasomotor symptoms (VMS) associated with menopause. After screening, participants were randomized 1:1:1, stratified by menopausal status, to receive fezolinetant 15 or 30 mg or placebo orally once daily for 12 weeks. Participants completed a daily VMS diary. The primary endpoint was mean change in frequency of VMS of any severity from baseline to week 8. Secondary endpoints included mean change in VMS frequency from baseline each week up to week 12 and frequency/severity of adverse events., Results: A total of 147 participants were randomized (placebo, n  = 47; fezolinetant 15 mg, n  = 53; fezolinetant 30 mg, n  = 47). Fezolinetant 15 and 30 mg demonstrated statistically significant reductions in mean VMS frequency at week 8 versus placebo. Least-squares mean estimates of mean change in frequency of VMS from baseline to week 8 were -7.04 for fezolinetant 15mg, -6.31 for fezolinetant 30mg, and -4.55 for placebo. The difference in least-squares mean estimates was -2.50 (95% CI: -4.03, -0.96), p  = 0.002 for fezolinetant 15mg and placebo, and was -1.76 (95% confidence interval [CI]: -3.35, -0.17), p  = 0.030 for fezolinetant 30mg and placebo. Reductions from baseline in mean VMS frequency versus placebo were seen after week 1 of treatment, maintained throughout 12 weeks. Fezolinetant was well tolerated, with no safety signals of concern for either dose to week 12., Conclusion: Oral fezolinetant at once-daily doses of 15 or 30 mg was efficacious and well tolerated for treatment of mild, moderate and severe VMS associated with menopause in this Japanese study.

Background and Objectives: Nipocalimab is a high-affinity, fully human, effectorless immunoglobulin G1 monoclonal antibody targeting the neonatal Fc receptor and is currently under evaluation for the treatment of rare and prevalent immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases. This phase I, randomized, double-blind, placebo-controlled, single-dose escalation study in healthy Japanese volunteers (N = 24) assessed the safety, pharmacokinetics, and effect on the serum immunoglobulin G level of single doses of nipocalimab., Methods: Volunteers were grouped into three cohorts and received intravenous nipocalimab at 10, 30, or 60 mg/kg or placebo. To complement the study, genetic variation in the Fcγ receptor and transporter subunit of the neonatal Fc receptor was analyzed in Japanese and diverse populations., Results: Nipocalimab was generally safe and well tolerated at all dose levels, with three (12.5% [3/24]) volunteers experiencing treatment-emergent adverse events across all nipocalimab doses. Mean serum immunoglobulin G levels decreased in a dose-dependent manner from baseline with nipocalimab treatment compared with placebo. Maximum serum nipocalimab concentrations demonstrated proportional increases with dose, while the area under the concentration-time curve was dose dependent and demonstrated non-linear increases with dose. Mean observed half-life was longer as the dose increased. Analysis of genetic variation in Fcγ receptor and transporter identified no unique Japanese variants or variants that alter amino acid sequences in or near the neonatal Fc receptor immunoglobulin G binding site targeted by nipocalimab., Conclusions: The comparable pharmacokinetic/pharmacodynamic profiles and highly conserved neonatal Fc receptor structure among diverse populations further support the clinical development of nipocalimab for the treatment of various immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases across global sites and populations, including the Japanese population., (© 2024. The Author(s).)

Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren't reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy., (© 2024. The Author(s).)

Purpose: To evaluate 2-year efficacy, durability, and safety of faricimab in the TENAYA Japan subgroup and pooled global TENAYA/LUCERNE cohort of patients with neovascular age-related macular degeneration (nAMD)., Methods: Subgroup analysis of TENAYA/LUCERNE (NCT03823287/NCT03823300): phase III, multicentre, randomised, active comparator-controlled, double-masked, non-inferiority trials. Treatment-naïve patients aged ≥ 50 years with nAMD were randomised (1:1) to intravitreal faricimab (6.0 mg up to every 16 weeks [Q16W] after 4 initial Q4W doses) or aflibercept (2.0 mg Q8W after 3 initial Q4W doses). Outcomes were assessed through year 2 for the TENAYA Japan subgroup (N = 133) and global pooled TENAYA/LUCERNE cohort (N = 1329)., Results: Vision and anatomic improvements achieved with faricimab at year 1 were maintained over 2 years and were generally comparable between the TENAYA Japan subgroup and pooled TENAYA/LUCERNE cohort. Adjusted mean best-corrected visual acuity (BCVA) change from baseline at year 2 for the TENAYA Japan subgroup and global pooled TENAYA/LUCERNE cohort was +7.1 (3.7-10.5) and +4.4 (3.2-5.5) letters in the faricimab arm, respectively, and +5.2 (1.9-8.6) and +4.3 (3.1-5.4) letters in the aflibercept arm, respectively. At week 112, the proportion of faricimab-treated patients on Q16W dosing was 61.0% and 63.1% in the TENAYA Japan subgroup and pooled TENAYA/LUCERNE cohort. Faricimab was well tolerated through year 2., Conclusion: Year 2 TENAYA Japan subgroup findings for faricimab were generally consistent with the pooled global TENAYA/LUCERNE results in patients with nAMD. Vision and anatomical benefits with faricimab were similar to those with aflibercept but with fewer injections., (© 2024. The Author(s).)

Background: Previous clinical trials presented efficacy and safety of Janus kinase 1 inhibitor upadacitinib through 52 weeks for moderate-to-severe atopic dermatitis (AD)., Objectives: To assess the effectiveness and safety of upadacitinib through 48 weeks in real-world clinical practice for Japanese AD patients (aged ≥12 years)., Methods: This retrospective study included 287 patients with moderate-to severe AD treated with 15 mg ( n  = 216) or 30 mg ( n  = 71) of upadacitinib daily. Effectiveness was assessed using eczema area severity index (EASI) scores, atopic dermatitis control tool (ADCT), peak pruritus-numerical rating scale (PP-NRS), and investigator's global assessment (IGA). Safety was evaluated through the incidence of treatment-emergent adverse events., Results: From baseline, EASI, ADCT, PP-NRS, and IGA rapidly reduced at week 4, and the reduction was maintained until week 48 of treatment with upadacitinib at both doses. Achievement rates of EASI 75, EASI 90, and EASI 100 at week 48 were 63.5, 30.2, and 7.9 in 15 mg group, and 77.4, 54.8, and 3.2% in 30 mg group, respectively. Acne and herpes zoster were frequent, but no serious adverse events occurred., Conclusions: Upadacitinib was therapeutically effective and tolerable for moderate-to-severe AD through 48 weeks in real-world clinical practice.

Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma, thymus (RORγt) developed for treatment of psoriasis. This study aimed to characterize pharmacokinetics, pharmacodynamics, safety, and tolerability of cedirogant following a single oral dose in Japanese participants and multiple oral doses in Japanese and Chinese participants. The single doses evaluated in healthy Japanese participants were 75, 225, and 395 mg. The multiple doses evaluated in both healthy Japanese and Chinese participants was 375 mg once daily for 14 days. Cedirogant plasma exposure increased dose proportionally with administration of single doses. Maximum cedirogant plasma concentration was reached within a median time of 4-5 hours after dosing. The harmonic mean elimination half-life ranged from 19 to 25 hours. Cedirogant pharmacokinetics were similar between Japanese and Chinese participants. Compared with healthy Western participants in a cross-study analysis, steady-state cedirogant plasma exposure was 38%-73% higher in Japanese or Chinese participants. Ex vivo interleukin-17 inhibition increased in a dose-dependent manner and was maximized by 375 mg once-daily doses. The cedirogant regimens tested were generally well tolerated, and no new safety issues were identified. The results supported enrollment of Japanese and Chinese subjects in subsequent clinical trials for cedirogant., (© 2024 AbbVie Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Purpose: This study aimed to assess the association between antipsychotic doses and the risk of tardive dyskinesia (TD) in clinical practice using a Japanese claims database from 2010 to 2020., Methods: The study population included patients 15 years or older with a diagnosis record of schizophrenia, depression, or bipolar disorder who were prescribed antipsychotics. Using a case-control design, we categorized patients newly diagnosed with TD as cases, with corresponding 1:10 matching in the control group. The primary endpoint was the relative risk of TD in the >median dose and ≤median dose groups, as determined using conditional logistic regression analysis adjusted for age., Results: The analysis population included 58,452 patients, and the median daily antipsychotic dose was 75 mg/d of chlorpromazine equivalent (CPZE). Of these, 80 were identified as TD cases, and doses >75 mg/d were associated with a significantly increased risk of TD at the last prescription and the maximum dose, respectively, before the date of the first diagnosis of TD. Post-hoc analysis further showed a significant association between doses ≥300 mg/d and the risk of TD compared to doses ≤75 mg/d and doses >75 to <300 mg/d. Comparing ≥300 mg/d versus >75 to <300 mg/d, the odd ratios at the last prescription and maximum dose before the first diagnosis of TD were 3.40 and 3.50, respectively., Conclusions: In the Japanese medical claims database of patients receiving relatively low doses of antipsychotics, doses >75 mg/d were associated with an increased risk of TD in a dose-dependent manner., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Afferent neuronal hypersensitization via P2X3 receptor signaling has been implicated as a driver of several disorders, including refractory chronic cough, endometriosis, diabetic neuropathic pain, and overactive bladder. Eliapixant, a selective P2X3 receptor antagonist, has been in clinical development for all four disorders., Objective: This paper describes pharmacokinetic (PK) and safety data from two phase I studies of eliapixant in healthy Japanese and Chinese participants and compares those data within the two populations and with previous multiple dose data from Caucasian participants., Methods: Two separate phase I, single-center, randomized, placebo-controlled studies were conducted with healthy male participants. The Japanese study was single-blind and the Chinese study was double-blind. Eliapixant was administered as an oral amorphous solid dispersion immediate-release tablet in strengths of 25 mg, 75 mg, and 150 mg. PK characteristics after a single dose (SD) and at steady state (multiple dose [MD], twice daily), adverse events (AEs), and tolerability were evaluated. A post hoc comparison of PK characteristics after SD of eliapixant in Japanese and Chinese participants, and after MD of eliapixant in Japanese, Chinese, and Caucasian participants, was performed., Results: Overall, 36/39 participants enrolled in the Japanese/Chinese studies, respectively (mean [standard deviation] age 25.4 [6.5] and 26.7 [5.0] years, respectively). After SD administration, maximum plasma concentration (C max ) was higher among Japanese than Chinese participants in the 25 mg and 75 mg dose groups, but comparable in the 150 mg dose group. The area under the concentration-time curve (AUC) was comparable between Japanese and Chinese participants in the 25 mg and 75 mg dose groups, but lower among Japanese participants in the 150 mg group. Half-lives after SD and MD administration were also comparable in Japanese and Chinese participants. The post hoc analysis included 26 Japanese, 30 Chinese, and 50 Caucasian participants. Comparable exposure (C max,md and AUC[0-12] md ) was observed after MD administration of eliapixant in Chinese and/or Japanese compared with Caucasian participants (geometric mean inter-ethnic ratios close to 1). The trough plasma concentration after eliapixant 150 mg MD, which was assumed to be relevant to eliapixant efficacy, was comparable across all ethnicity groups. Most AEs reported in the Japanese (eliapixant 75 mg SD, n = 2; eliapixant 150 mg MD, n = 2) and Chinese participants (eliapixant 25 mg SD, n = 7; eliapixant 75 mg SD, n = 6; eliapixant 150 mg SD, n = 7; eliapixant 150 mg MD, n = 9; placebo SD, n = 5; placebo MD, n = 1) were of mild intensity. Higher incidences of AEs in the Chinese population were likely due to differing standards of AE reporting between investigators., Conclusion: Eliapixant was well tolerated by Japanese and Chinese participants. The inter-ethnic evaluation demonstrated similar PK characteristics across Japanese, Chinese, and Caucasian participants., Registration: ClinicalTrials.gov identifier numbers: NCT04265781 and NCT04802343., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Ubrogepant is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults. The objectives of this study were to evaluate (1) single-dose pharmacokinetics (PK) and dose proportionality of ubrogepant in Japanese participants, (2) the safety and tolerability of ubrogepant in healthy Japanese and White participants, and (3) to compare the PK of ubrogepant in Japanese versus White participants. A total of 48 participants were enrolled into 4 cohorts (N = 12 [9 active + 3 placebo] per cohort). A single dose was administered on Day 1 following an overnight fast to assess the PK of ubrogepant at 3 dose levels and test dose proportionality between 25 and 100 mg in Japanese participants. White participants were randomly assigned to ubrogepant (100 mg) or placebo. Dose proportionality was observed in the dose range of 25-100 mg in Japanese participants. Systemic exposure was 20% lower in Japanese participants as compared with White participants, but this difference is unlikely to be clinically relevant. Single doses of ubrogepant (25-100 mg) had a safety profile similar to placebo, and no differences in the safety profile of ubrogepant 100 mg were observed between Japanese versus White participants., (© 2024 AbbVie Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objective: In psychiatry, polypharmacy or high psychotropic drug doses increase adverse drug event (ADE) prevalence. However, the full relationship between polypharmacy and ADEs is unclear, and few studies have evaluated dose equivalents for psychotropic drugs for ADEs. Thus, we conducted a retrospective analysis to clarify the effects of polypharmacy and chlorpromazine (CP)-, diazepam (DAP)-, and imipramine- equivalent doses on all ADEs in inpatients., Methods: Psychiatric inpatients in a Japanese hospital from April 1, 2016 to March 31, 2018, were enrolled. ADE severity and causality were assessed. Multiple logistic regression analyses were performed to evaluate ADE risk factors., Results: Among 462 patients analyzed, out of 471 patients enrolled, 145 (31.4%) experienced ADEs. The causality assessment determined that "possible" was 96.5%. The most common ADEs were nervous system disorders (35%). Multiple logistic regression analyses indicated an increase in ADE prevalence with the number of drugs used (≥5; p = 0.026); CP-equivalent dose (p = 0.048); and endocrine, nutritional, and metabolic disorders (p = 0.045). DAP-equivalent dose; infectious and parasitic diseases; and injury, poisoning, and consequences of other external causes decreased ADE prevalence (p = 0.047, 0.022, and 0.021, respectively)., Conclusions: Avoiding polypharmacy in psychiatric inpatients and adjusting drug regimens to safe equivalent doses could reduce ADEs during hospitalization., (© 2024 John Wiley & Sons Ltd.)

Patients receiving interleukin (IL)-inhibiting biologics for moderate-to-severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL-inhibiting biologic treatment and ≥1 post-induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non-persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL-inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable-adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS., (© 2024 Abbvie and The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

BACKGROUND AND OBJECTIVES: BI 1358894, a novel small-molecule inhibitor of transient receptor potential canonical ion channels, is under development for treatment of major depressive disorder. Phase I trials assessing the safety and pharmacokinetics of BI 1358894 in Caucasian male healthy volunteers (HVs) have been performed. This Phase I, double-blind, placebo-controlled, parallel-group trial assessed the safety, tolerability and pharmacokinetics of BI 1358894 in Japanese male HVs., Methods: Male HVs were randomized to receive oral BI 1358894 (n = 18) or placebo (n = 6) after a high-fat, high-calorie meal within three dose groups (50 mg, 100 mg, 200 mg), administered sequentially in dose-ascending order. The primary endpoint was number of HVs with drug-related adverse events (DRAEs). Secondary endpoints were the pharmacokinetic parameters of BI 1358894., Results: Overall, 24 male HVs entered the trial [mean (standard deviation) age: 30.0 (7.6) years]. DRAEs occurred in 3/18 HVs (BI 1358894 100 mg group: one HV experienced dizziness and headache; BI 1358894 200 mg group: one HV experienced headache, another reported sleep disorder). BI 1358894 exposure increased dose dependently and proportionally, peaking 4-6 h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70 h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group., Conclusion: BI 1358894 was well tolerated with a favorable pharmacokinetic profile in Japanese male HVs, similar to findings from a previous study in Caucasian male HVs., Trial Registration: ClinicalTrials.gov (NCT03875001; 08-Mar-2019)., (© 2024. The Author(s).)

Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study., (© 2024 Daiichi Sankyo Co., Ltd. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Introduction: The aim of the study was to explore the association between urate-lowering agents and reduced response to erythropoietin-stimulating agents in patients suffering from chronic kidney disease G5., Methods: We conducted a cross-sectional, multicenter study in Japan between April and June 2013, enrolling patients aged 20 years or older with an estimated glomerular filtration rate of ≤15 mL/min/1.73 m2. Exclusion criteria encompassed patients with a history of hemodialysis, peritoneal dialysis, or organ transplantation. The patients were categorized into four groups based on the use of urate-lowering drugs: high-dose allopurinol (&gt;50 mg/day), low-dose allopurinol (≤50 mg/day), febuxostat, and no-treatment groups. We used a multivariable logistic regression model, adjusted for covariates, to determine the odds ratio (OR) for erythropoietin hyporesponsiveness, defined by an erythropoietin resistance index (ERI) of ≥10, associated with urate-lowering drugs., Results: A total of 542 patients were included in the analysis, with 105, 36, 165, and 236 patients in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The median and quartiles of ERIs were 6.3 (0, 12.2), 3.8 (0, 11.2), 3.4 (0, 9.8), and 4.8 (0, 11.2) in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The multivariate regression model showed a statistically significant association between the high-dose allopurinol group and erythropoietin hyporesponsiveness, compared to the no-treatment group (OR = 1.98, 95% confidence interval: 1.10-3.57)., Conclusions: Our study suggests that the use of high-dose allopurinol exceeding the optimal dose may lead to hyporesponsiveness to erythropoiesis-stimulating agents., (© 2024 S. Karger AG, Basel.)

Introduction: We aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors., Materials and Methods: This was a single-center, open-label, phase I study with two consecutive cohorts (250 mg and 200 mg cohorts). Patients received adavosertib at 250 mg or 200 mg, orally once daily for 5 days on and 2 days off for Weeks 1 and 2 of a 21-day cycle., Results: Dose-limiting toxicities (Grade 3 febrile neutropenia) occurred in 2/6 patients in the 250 mg cohort. None of the three patients in the 200 mg cohort developed dose-limiting toxicities. The most frequent treatment-emergent adverse event was nausea (250 mg: 83.3 %; 200 mg: 100.0 %). Median time to peak drug concentration was 4.03 and 2.08 h after the first dose and 2.82 and 1.90 h after multiple dosing in the 250 and 200 mg cohorts, respectively; respective mean terminal elimination half-lives were 7.36 and 7.30 h (first dose) and 10.55 and 8.88 h (multiple dosing). Systemic exposure increased in a slightly more than dose-proportional manner. No RECIST v1.1 response was observed. Disease control rate was 0 % and 33.3 % in the 250 and 200 mg cohorts, respectively. One patient (33.3 %) in the 200 mg cohort showed a best overall response of stable disease at ≥ 8 weeks; the rest showed progressive disease., Conclusions: Adavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown., Trial Registration: ClinicalTrials.gov, NCT04462952., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S Kondo has received research funding from AstraZeneca, Chugai, Astellas, AbbVie, Eisai, and Incyte. Y Katsuya has no conflicts of interest to disclose. K Yonemori has received honoraria from Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR Pharma, MSD, Boehringer Ingelheim, Ono, Daiichi-Sankyo, Bayer, Jansen, and Sanofi; and research funding from MSD, Daiichi-Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe. N Yamamoto has a leadership/advisory role in Healios; has received honoraria from Chugai; and has received research funding from Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, Ono, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic, InventisBio, and Rakuten Medical. K Komuro, M Sugeno, T Kawata, D Ghiorghiu, and D Meulendijks are employees of AstraZeneca and may own stock in AstraZeneca., (Copyright © 2024. Published by Elsevier Ltd.)

We investigated how a lack of placebo control affects the interpretation of results of thorough QT/QTc (TQT) study. Results of TQT study in 48 healthy Japanese subjects assessing the effects of 480 and 960 mg of carotegrast methyl (test drug) and 400 mg of moxifloxacin (positive control) on the time-matched changes in corrected QT from baseline (ΔQTcF) and the placebo-adjusted ΔQTcF (ΔΔQTcF) were analyzed with central-tendency and concentration-response analyses. In central-tendency analysis, moxifloxacin prolonged ΔQTcF and ΔΔQTcF with the largest mean values (90% confidence interval) of 12.1 ms (9.3, 14.8) and 15.4 ms (12.6, 18.1), respectively. Meanwhile, carotegrast methyl hardly altered ΔQTcF and ΔΔQTcF with the largest mean values of 0.8 ms (-2.3, 3.9) and 2.1 ms (-0.7, 4.8) for the low dose, and -0.2 ms (-3.4, 3.0) and 1.6 ms (-0.9, 4.2) for the high dose, respectively. In concentration-response analysis, moxifloxacin attained the estimated mean values for ΔQTcF and ΔΔQTcF of 11.4 ms (8.5, 14.4) and 16.7 ms (14.0, 19.4) at the mean C max , whereas carotegrast methyl provided those of -4.6 ms (-7.3, -1.9) and 0.7 ms (-1.4, 2.8), respectively. Thus, lack of placebo control did not influence the interpretation of TQT study with either of the analysis in line with updated E14/S7B Q&As., Competing Interests: Declaration of competing interest I.O., N.I., and K.M. were employees of EA Pharma Co., Ltd. A.S. and Y.K. were advisors to EA Pharma Co., Ltd. regarding drug-induced QT effects. Y.K. was a clinical investigator of Kitasato University East Hospital. The other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

This study investigated ethnic differences in the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK2831781, an anti-lymphocyte activation gene 3 (LAG3) monoclonal antibody, in healthy participants, and determined local tolerability and bioavailability following subcutaneous (SC) administration. A double-blind, randomized study of (A) single intravenous (IV) doses of GSK2831781 450 mg or placebo in Japanese and White participants; and (B) single SC doses of GSK2831781 150 or 450 mg, or placebo in White participants, was conducted. Blood samples for analyses were collected before dosing and over 112 days after dosing. GSK2831781 was well tolerated in Japanese and White participants after both IV and SC doses, with the adverse event profile in Japanese being consistent with other populations. There were no injection site adverse events. There was no evidence of differences in systemic exposure among Japanese and White participants. Systemic exposure did not vary with body weight. SC bioavailability was 76.5%, as estimated using population pharmacokinetic modeling. Full and sustained target engagement and evidence of LAG3 + cell depletion (≈53%-66%) were observed in both populations and after both administration routes. No evidence of reduced circulating regulatory T cells (CD4 + CD25 + CD127 low FoxP3 + ) was observed. Following IV and SC administration, GSK2831781 depleted circulating LAG3 + T cells with no interethnic difference observed. There were no major impacts on circulating regulatory T cells., (© 2022, The American College of Clinical Pharmacology.)

Pharmacologic knowledge is important for pediatricians conducting feasible pharmacokinetic or pharmacodynamic (PK/PD) studies or applying effective antimicrobial therapies in children. Because of the difficulties in conducting PK/PD studies in children, antimicrobial PK/PD data in children are still limited. To fill in the lack of knowledge, promotion of population PK/PD analysis, which allows us to handle sparse sampling data from individual patients, is important because it is considered a suitable methodology to conduct PK/PD studies in children with limited blood drug concentration data for PK/PD analysis. Population PK/PD analysis is also useful in the clinical setting to provide individualized optimal dosage for each patient with various conditions. Here we summarized the current aspects of pediatric PK/PD studies of antimicrobials in Japan from clinical and research perspectives, specifically focusing on the importance of population PK/PD analysis., Competing Interests: K.S. received payment for lectures from Mitsubishi Tanabe Pharma, Astellas, AbbVie GK, and G.H.N. received grants from the Japan Agency for Medical Research and Development, consulting fees from Taisho Pharmaceutical Co., Ltd., Sato Pharmaceutical Co., Ltd., Nippon Zoki Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., Eli Lilly Japan K.K. and Astra Zeneca K.K., and payment for lectures from Shionogi & Co., Ltd. and Chugai Pharmaceutical Co., Ltd. K.M. received grant support from Meiji Seika Pharma Co., Ltd. and Sumitomo Pharma Co., Ltd. and payment for lectures from Meiji Seika Pharma Co., Ltd. Y.T. received grant support from Shionogi & Co., Ltd. and payment for lectures from Astellas Pharma Inc. and MSD Japan. I.M. received payment for lectures and consultations from Sanofi, Takeda Pharmaceuticals, Astellas Pharma Inc., Janssen Pharmaceuticals, Fujifilm Toyama Chemical Co., Biomelieux Japan, Abbott Japan Co. and AbbVie GK. The other authors have have no conflicts of interest to disclose. This work was supported by the Japan Society for the Promotion of Science KAKENHI (grant no. 21K16332)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Imeglimin is a first-in-class novel oral antidiabetic marketed in Japan as TWYMEEG ® to treat type 2 diabetes mellitus. Its mode of action is distinct from all other anti-hyperglycemic classes., Objective: To assess the pharmacokinetic and safety profile of imeglimin in Caucasian and Japanese healthy individuals., Methods: Two randomized placebo-controlled phase 1 clinical studies were conducted in Caucasian subjects after single (250-8000 mg) and multiple (250-2000 mg twice daily) ascending doses and in Japanese subjects after single (500-6000 mg) and multiple (500-2000 mg twice daily) ascending doses. Imeglimin plasma and urine concentrations were measured., Results: All imeglimin doses achieved maximal concentration between 1 and 3.5 h in Caucasians, and 1.5 and 3 h in Japanese subjects. The elimination half-lives (t 1/2 ) were dose-independent and means ranged between 9.03 and 20.2 h for Caucasians, and 4.45 and 12 h for Japanese subjects. Dose-normalized area under the plasma concentration-time curve decreased with dose in the 250-8000 mg and in the 500-6000 mg dose range in Caucasians and Japanese, respectively, suggesting a dose-dependent but less than dose-proportional effect in imeglimin exposure. Plasma accumulation was minimal following repeated dosing, and food did not affect the pharmacokinetics in either population. Exposures were generally similar between Caucasian and Japanese subjects with less than 20% difference, although there was a tendency for exposures in Japanese to be slightly higher. Imeglimin had an acceptable safety and tolerability profile, with dose-dependent mild gastrointestinal adverse events., Conclusion: Imeglimin was safe and well tolerated in these two phases 1 studies, with pharmacokinetics comparable between the two populations., Clinical Trial Registrations: EudraCT 2005-001946-18 and 2014-004679-21., (© 2022. The Author(s).)

The benchmark dose (BMD) approach is updated to create an international harmonizing process following rapid theoretical sophistication. We calculated the lower limit of BMD confidence interval (BMDL) for carcinogenicity based on 193 tumorigenicity bioassay data published in 50 pesticide risk assessment reports by the Food Safety Commission of Japan (FSCJ) to validate the appropriateness and necessity for the refinement of the FSCJ-established BMD guidance. Three well-known BMD software, PROAST, BMDS, and BBMD were used to compare their BMDLs with no-observed-adverse-effect levels (NOAELs) for carcinogenicity. Recently implemented methodologies such as model averaging or Bayesian inference were also used. Our results indicate that the BMD approach provides a point of departure similar to the NOAEL approach if the data used exhibit a clear dose-response relationship. In some cases, particularly in software with a frequentist approach, the calculation failed to provide BMDL or provided considerably lower BMDLs than NOAELs. However, most of the datasets that resulted in failed calculations or extremely low BMDLs exhibited unclear dose-response relationships, i.e., non-monotonous and sporadic responses. The expert review on the shape of the dose-response plot would help better apply the BMD approach. Furthermore, we observed that Bayesian approaches provided fewer failed or extreme BMD calculations than the frequentist approaches., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Objective: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects., Methods: This was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg., Results: Following oral administration, median time to maximum observed plasma concentration (t max ) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t ½ ) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (C max ) and AUC ∞ , respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity., Conclusion: AMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF., (© 2022. The Author(s).)

Purpose: We report the dose-escalation part of a phase I study of liposomal eribulin (E7389-LF) in Japanese patients with advanced solid tumors and no alternative standard therapy., Patients and Methods: Patients ≥20 years old were enrolled. E7389-LF doses of 1.0 to 1.5 mg/m2 once every two weeks (Q2W) or 1.0 to 2.5 mg/m2 once every three weeks (Q3W) were planned. The primary objective was to determine the MTD by evaluating dose-limiting toxicities (DLT). Secondary objectives included safety/tolerability assessments, objective response rate (ORR), and progression-free survival; serum biomarker assessment was an exploratory objective., Results: Twenty-one patients were enrolled and treated; 12 in the Q3W group (1.0 mg/m2, n = 3; 1.5 mg/m2, n = 3; 2.0 mg/m2, n = 6) and 9 in the Q2W group (1.0 mg/m2, n=3; 1.5 mg/m2, n = 6). The Q3W and Q2W MTDs were 2.0 mg/m2 and 1.5 mg/m2, respectively. One patient receiving 2.0 mg/m2 Q3W had a DLT of grade 3 febrile neutropenia. The most common grade 3 treatment-emergent adverse events were neutropenia (66.7% in Q3W and Q2W) and leukopenia (Q3W, 58.3%; Q2W, 33.3%). One patient in the Q3W group (2.0 mg/m2) and 3 in the Q2W group (1.0 mg/m2, n = 1; 1.5 mg/m2, n = 2) achieved a partial response [overall ORR, 19.0%; 95% confidence interval (CI), 5.4-41.9]. Endothelial [TEK receptor tyrosine kinase (TEK), intercellular adhesion molecule 1 (ICAM1), vascular endothelial growth factor receptor 3 (VEGFR3), platelet/endothelial cell adhesion molecule 1 (PECAM1)], vasculature (collagen IV), and immune-related [interferon gamma (IFNγ), C-X-C motif chemokine ligand 11 (CXCL11), C-X-C motif chemokine ligand 10 (CXCL10)] biomarker levels were increased., Conclusions: E7389-LF was well tolerated at 2.0 mg/m2 Q3W and 1.5 mg/m2 Q2W. Considering the toxicity profile of both regimens, the recommended dose was 2.0 mg/m2 Q3W. Expansion cohorts are ongoing., (©2022 The Authors; Published by the American Association for Cancer Research.)

Objective: The goal of this study was to evaluate the efficacy and safety of duloxetine in children and adolescents (9-17 years of age) with major depressive disorder (MDD) in Japan. Methods: This study consists of two clinical trials. First, a 6-week, randomized double-blind placebo-controlled clinical trial (RCT) was conducted. The primary endpoint of RCT was the change in Children's Depression Rating Scale-Revised (CDRS-R) total scores from baseline. Following RCT, an open-label long-term extension trial (OLE) was conducted to investigate the longer-term safety of duloxetine for ∼1 year. Results: In RCT, CDRS-R total score changes from baseline to 6 weeks after the start of administration (primary endpoint) were -21.03 in the duloxetine group ( n  = 74) and -22.42 in the placebo group ( n  = 74). No significant difference was observed in the primary endpoint between the groups ( p  = 0.5587). In addition, no significant difference was observed in secondary endpoints such as CDRS-R response rates. The proportion of patients with ≥1 treatment-emergent adverse event (TEAE) in RCT was significantly higher in the duloxetine group (78.7%) than in the placebo group (62.2%), and most were mild or moderate in severity. Changes in CDRS-R total scores during OLE, in consecutive patients from the duloxetine group in RCT ( n  = 63), or placebo group ( n  = 59) in RCT, and newly enrolled patients ( n  = 28), were -12.1, -11.3, and -17.8, respectively. The proportion of patients with ≥1 TEAE in OLE was 90.5%, 88.1%, and 89.3% in the respective groups, and most of them were mild or moderate in severity. Conclusions: Duloxetine did not show superiority to placebo in efficacy in children and adolescents with MDD in Japan. Overall reported TEAEs were consistent with the currently available duloxetine safety profile and no new safety finding was observed in the two clinical trials.

This randomized, double-blind, placebo-controlled, multiple ascending-dose study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of milvexian, an oral small-molecule FXIa inhibitor, in healthy Japanese participants. Participants received oral milvexian daily under fasted (50 mg and 200 mg) or fed conditions (500 mg) or placebo over 14 days; 24 participants (8/cohort: 6 milvexian; 2 placebo) were planned. Due to an unblinding event, participants in one cohort (200 mg daily) were discontinued, and a second cohort enrolled; 32 participants were included in safety and pharmacodynamic analyses, and 24/32 in pharmacokinetic analyses. Milvexian up to 500 mg daily for 14 days was generally well tolerated, with no deaths, serious adverse events, or discontinuations due to adverse events. Milvexian exposure increased between 50-mg and 200-mg doses. Median T max was similar with 50-mg and 200-mg doses (2.5-3.0 h) and delayed under fed conditions (500 mg, 7.0-8.0 h). Median T 1/2 was similar across doses (8.9-11.9 h). Multiple oral milvexian administrations resulted in concentration-related prolongation of aPTT and decreased FXI clotting activity. Milvexian was generally safe and well tolerated. The pharmacokinetic and pharmacodynamic profile of milvexian demonstrates suitability for further clinical development in Japanese participants., (© 2022. The Author(s).)

Xentuzumab is an insulin-like growth factor (IGF) ligand-neutralizing antibody. This phase 1 trial assessed xentuzumab in Japanese patients with solid tumors. Patients aged ≥20 y old with solid tumors that were refractory or not amenable to standard therapy were enrolled. Patients received xentuzumab intravenously at a starting dose of 750 mg/wk. Dose escalation used a 3 + 3 design with dose de-escalation. The primary endpoint was to determine the maximum tolerated dose (MTD) of xentuzumab. Safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity were also assessed. Fifteen patients received xentuzumab in the dose escalation part (750 mg/wk [n = 6]; 1000 mg/wk [n = 3]; 1400 mg/wk [n = 6]). There were no dose-limiting toxicities at any dose; the MTD of xentuzumab was not reached. Xentuzumab 1000 mg/wk was recommended as the relevant biological dose. Six further patients received xentuzumab 1000 mg/wk in an expansion cohort. Of 21 patients, 13 (61.9%) experienced a drug-related adverse event, most commonly fatigue (23.8%), neutropenia (19.0%), diarrhea, nausea, white blood cell count decrease, and muscle spasms (14.3% each). No relevant deviations from dose linearity of xentuzumab exposure were observed during dose escalation. Total IGF-1 and IGF-2 levels increased and bioactive IGF levels decreased from baseline to 24 h after the first infusion in cycle 1. Partial response was observed in 2 (9.5%) patients with desmoid-type fibromatosis. Disease control was achieved in 6 (28.6%) patients (median duration 42.4 mo). Xentuzumab monotherapy was well tolerated in Japanese patients and showed evidence of anti-tumor activity. This study was registered with www.clinicaltrials.gov (NCT02145741)., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Hypertension or elevated blood pressure (BP) is an important risk factor for aortic dissection (AD); however, few prospective studies on this topic have been published. We investigated the association between hypertension/elevated BP and AD in 2 cohorts and conducted a meta-analysis of published prospective studies, including these 2 studies., Methods: We analyzed data from the J-SHC study (Japan-Specific Health Checkups) and UK Biobank, which prospectively followed up 534 378 and 502 424 participants, respectively. Multivariable Cox regression was used to estimate hazard ratios and 95% CIs for the association of hypertension/elevated BP with AD incidence in the UK Biobank and AD mortality in the J-SHC Study. In the meta-analysis, summary relative risks were calculated with random-effects models. A potential nonlinear dose-response relationship between BP and AD was tested with fractional polynomial models, and the best-fitting second-order fractional polynomial regression model was determined., Results: In the J-SHC study and UK Biobank, there were 84 and 182 ADs during the 4- and 9-year follow-up, and the adjusted hazard ratios of AD were 3.57 (95% CI, 2.17-6.11) and 2.68 (95% CI, 1.78-4.04) in hypertensive individuals, 1.33 (95% CI, 1.05-1.68) and 1.27 (95% CI, 1.11-1.48) per 20-mm Hg increase in systolic BP (SBP), and 1.67 (95% CI, 1.40-2.00) and 1.66 (95% CI, 1.46-1.89) per 10-mm Hg increase in diastolic BP (DBP), respectively. In the meta-analysis, the summary relative risks were 3.07 (95% CI, 2.15-4.38, I 2 =76.7%, n=7 studies, 2818 ADs, 4 563 501 participants) for hypertension and 1.39 (95% CI, 1.16-1.66, I 2 =47.7%, n=3) and 1.79 (95% CI: 1.51-2.12, I 2 = 57.0%, n=3) per 20-mm Hg increase in SBP and per 10-mm Hg increase in DBP, respectively. The AD risk showed a strong, positive dose-response relationship with SBP and even more so with DBP. The risk of AD in the nonlinear dose-response analysis was significant at SBP >132 mm Hg and DBP >75 mm Hg., Conclusions: Hypertension and elevated SBP and DBP are associated with a high risk of AD. The risk of AD was positively dose dependent, even within the normal BP range. These findings provide further evidence for the optimization of BP to prevent AD.

Aim: Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI., Methods: This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment., Results: Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period., Conclusions: This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.

Cenobamate (XCOPRI and ONTOZRY) is a novel antiseizure medication for the treatment of focal-onset seizures. Nonetheless, there is limited information on the pharmacokinetics (PKs), safety, and efficacy of cenobamate in Asian people, including Japanese people. This study aimed to evaluate the PKs and safety of cenobamate after a single oral dose in healthy Japanese subjects and to compare the PKs with that reported in non-Japanese subjects. A randomized, double-blind, placebo-controlled, single ascending dose study was conducted at four dose levels of 50, 100, 200, and 400 mg. Subjects were randomly assigned to cenobamate or placebo in a 6:2 ratio. Cenobamate was rapidly absorbed, reaching its maximum plasma concentration (C max ) in 0.75 to 2.25 h, and was eliminated with a mean half-life of 37.0 to 57.7 h. The C max increased dose proportionally, whereas area under the concentration-time curve increased more than dose proportionally, which was consistent with the findings in non-Japanese subjects. The systemic exposure of cenobamate was comparable between Japanese and non-Japanese subjects at all dose levels evaluated. All adverse events were mild in severity, and their incidence did not show dose-dependent trends. Furthermore, there were no clinically significant issues in safety parameters, including sedation tests, neurologic examinations, and Columbia Suicide Severity Rating Scale interviews. In conclusion, the systemic exposure of cenobamate after a single dose in Japanese subjects increased by dose, which was similar to the pattern in non-Japanese subjects. In addition, a single dose of cenobamate was well-tolerated in the dose range of 50 to 400 mg in healthy Japanese subjects., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background/aim: High-dose methotrexate (HD-MTX) is widely used to treat osteosarcoma. However, some patients develop hepatic toxicity, leading to dose modification and delays in the scheduled chemotherapy. The present study aimed to identify the risk factors of hepatotoxicity in patients with osteosarcoma., Patients and Methods: We conducted a retrospective study of patients with osteosarcoma treated with HD-MTX between January 2014 and June 2020 at the National Cancer Center Hospital, Japan. The risk factors for MTX-induced hepatotoxicity (≥grade 3) were identified using multivariate logistic regression analysis., Results: The final analysis included 88 courses of 36 patients. Hepatotoxicity occurred in 51 (58.0%) of the 88 courses. Female sex, MTX dose (>10.2 g/m 2 ), and serum calcium concentration (>9.3 mg/dl) were identified as risk factors for HD-MTX-induced hepatotoxicity., Conclusion: Identifying the risk factors of HD-MTX-induced hepatotoxicity may contribute to improvements in the safety and management of HD-MTX therapy., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Guselkumab is a human IgG1λ monoclonal antibody that has been approved for treatment of multiple immunologic diseases including palmoplantar pustulosis in Japan. The efficacy of guselkumab in reducing disease severity as compared with placebo has been demonstrated in phase 2 and 3 clinical studies. In some patients assigned to the placebo treatment, worsening of Palmoplantar Pustulosis Area and Severity Index (PPPASI) score was noted. Most of these patients were smokers, raising a possibility of an association of smoking with the disease progression. To understand the clinical implications of guselkumab dose, baseline disease severity, and smoking on the treatment effect and describe the longitudinal relationship between guselkumab exposure and the PPPASI score, a pharmacokinetic/pharmacodynamic modeling analysis was conducted using the pooled data from 1 phase 2 and 1 phase 3 study. Data from 207 Japanese patients (77% women and 60% smokers) with a median PPPASI score of 24.6 were included in the analysis. The observed treatment efficacy (the PPPASI score reduction) appeared to be similar at the current approved dose (100 mg) and the higher dose (200 mg). A greater PPPASI score reduction (in absolute points) is expected in patients with higher baseline PPPASI score (severe disease). However, the higher baseline did not translate to larger magnitude of the change from baseline (in percentage) in the PPPASI score. Incorporating a linear disease progression effect in the model significantly decreased the Nonlinear Mixed Effects Modeling objective function value (P < .001). Smoking status appeared to be related to disease worsening in some patients, but the covariate did not reach statistical significance in the model., (© 2021, The American College of Clinical Pharmacology.)

Background: To report our findings on quality of life (QoL) in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC)., Methods: Patients with HER2-negative MBC were randomly assigned to three different doses of q3w nab-PTX (SD 260 mg/m 2 vs. MD: 220 mg/m 2 vs. LD 180 mg/m 2 ). QoL was assessed at baseline and during the second, fourth and sixth courses of treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and EuroQol 5-Dimension (EQ-5D). Comparisons were performed with mixed-model repeated measures (MMRM)., Results: A total of 141 patients were enrolled in the parent study, and 136 (96%) (44, 45 and 47 in the SD, MD, and LD groups) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial outcome index at MD and LD were significantly higher than that at SD (MD vs. SD P < 0.001, LD vs. SD P < 0.001). Differences from baseline for FACT-Taxane total, physical and emotional well-being, and taxane subscale scores at MD and LD were also higher than at SD. The difference from baseline for the CFS score at LD was lower than at SD (P = 0.013) and those for EQ-5D utility scores at MD and LD were higher than at SD (MD vs. SD P = 0.011, LD vs. SD P < 0.001)., Conclusion: QoL of patients treated with 220 or 180 mg/m 2 of q3w nab-PTX was significantly better than that of patients treated with 260 mg/m 2 ., Trial Registration: The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID: UMIN000015516), on 01/11/2014. Details are available at the following address: https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000017916., (© 2021. The Japanese Breast Cancer Society.)

Left ventricular hypertrophy commonly occurs in dialysis patients and is associated with a risk of developing cardiovascular disease events and all-cause mortality. Although hypertension treatment reduces left ventricular mass index (LVMI) in hemodialysis patients, the relationships of prescription pattern, dose, and changes in the dose of antihypertensive drugs with LVMI have not been completely elucidated. Here, we hypothesized that volume reduction would lead to a decrease in the antihypertensive drug dose and subsequently to a reduction in LVMI; conversely, fluid retention would lead to an increase in the antihypertensive drug use and, subsequently, to LVMI progression. To assess this hypothesis, we investigated the relationship between changes in the dose of antihypertensive drugs and subsequent changes in LVMI in 240 patients who had just started hemodialysis using a retrospective hemodialysis cohort in Japan. Using multiple linear regression analysis, we assessed the association between changes in the antihypertensive drug dose over 1 year after hemodialysis initiation and changes in LVMI during this period. A decrease and an increase in the antihypertensive drug dose were significantly associated with a reduction in LVMI (vs. no change; β  = - 17.386, p < .001) and LVMI progression (vs. no change; β  = 16.192, p < .001), respectively. In conclusion, our findings suggested that volume reduction, leading to a decrease in the use of antihypertensive drugs, is a therapeutic strategy in patients undergoing hemodialysis to prevent LVMI progression.

Background: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies., Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib., Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (C max and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily., Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017)., (© 2021. The Author(s).)

Background: The benefits of vitamin D receptor activators (VDRAs) for patients with chronic kidney disease are well recognized. However, the optimal criteria for patient selection, dosage forms, and duration providing the highest benefit and the least potential risk remain to be confirmed., Materials and Methods: The study population was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis, a multicenter prospective cohort study of 1520 incident dialysis patients. According to the VDRA usage status in March 2015 (interim report), the 967 patients surviving after March 2015 were classified into three groups: without VDRA (NV, n  = 177), oral VDRA (OV, n  = 447), and intravenous VDRA (IV, n  = 343). Mortality rates were compared using the log-rank test, and factors contributing to all-cause mortality were examined using both univariate and multivariate Cox proportional hazard regression analyses., Results: There were 104 deaths (NV, n  = 27; OV, n  = 53; IV, n  = 24) during the follow-up period (1360 days, median), and significant differences in cumulative survival rates were observed between the three groups ( p  = 0.010). Moreover, lower all-cause mortality was associated with IV versus NV (hazard ratio, 0.46 [95% confidence interval 0.24-0.89]; p  = 0.020)., Conclusion: This study demonstrated the impact of the VDRA dosage form on the short-term survival of incident hemodialysis patients during the introduction period. Our results suggest that relatively early initiation of intravenous VDRA in patients beginning hemodialysis may have some clinical potential.

Background and Objective: AZD5718, a 5-lipoxygenase-activating protein (FLAP) inhibitor, is in clinical development for treatment of coronary artery disease (CAD) and chronic kidney disease (CKD). This study evaluated AZD5718 pharmacokinetics, pharmacodynamics, and tolerability in healthy male Japanese subjects., Methods: Four cohorts of eight Japanese subjects were randomized to receive oral doses of AZD5718 (60, 180, 360, and 600 mg) or matching placebo administered as a single dose on Day 1 and as once-daily doses from Day 3 to Day 10 in fasted conditions. Pharmacokinetic, pharmacodynamic, and safety data were collected., Results: The pharmacokinetics characteristics of AZD5718 in Japanese male subjects were similar to those reported in a previous study, and the pharmacokinetics were characterized as rapid absorption with median time to reach maximum concentration (T max ) of 1-2 h Creatine-normalized urine maximum concentration (C max ) with mean half-lives ranging from 8 to 21 h, and supra-proportional increase in exposure over the 60-600 mg dose range evaluated. Also, an increase in steady-state area under the concentration-time curve (AUC) compared to the first dose was observed. After both single and multiple doses of AZD5718, a clear dose/concentration-effect relationship was shown for urinary leukotriene E 4 (LTE 4 ) versus AZD5718 exposure with > 80 % inhibition at plasma concentrations in the lower nM range. No clinically relevant safety and tolerability findings were observed., Conclusions: The observed pharmacokinetics and pharmacodynamics were similar to reported data for non-Japanese healthy subjects, which support further evaluation of AZD5718 at similar doses/exposures in Japanese and non-Japanese subjects for future evaluation in patients with CAD and CKD., (© 2021. The Author(s).)

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis-stimulating agents (ESAs). This post-hoc analysis of a Japanese, double-blind, randomized, phase 3 study in hemodialysis-dependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA-resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high-sensitivity C-reactive protein (hs-CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight-adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 μg/kg; ERI ≥8.4, 0.91 μg/kg); the weight-adjusted AAD/6W relative to within-arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P = .089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs-CRP was not significant (estimated slope, -0.494; P = .814); a trend toward increased DA doses was observed with increasing EoT hs-CRP (estimated slope, 2.973; P = .075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs., (© 2020 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Background Increasing age predisposes patients with atrial fibrillation to both thromboembolic and bleeding events; however, data on outcomes of very elderly patients (aged ≥85 years) receiving appropriate antithrombotic therapy are still limited. Methods and Results The J-ELD AF (Multicenter Prospective Cohort Study to Investigate the Effectiveness and Safety of Apixaban in Japanese Elderly Atrial Fibrillation Patients) Registry is a multicenter prospective observational study of Japanese patients with nonvalvular atrial fibrillation aged ≥75 years taking on-label doses (standard dose of 5 mg BID or reduced dose of 2.5 mg BID) of apixaban. The entire cohort (3031 patients from 110 institutions) was divided into 3 age groups: 75 to 79 years (n=1068, 35.2%), 80 to 84 years (n=1120, 37.0%), and ≥85 years (n=843, 27.8%). The event incidence rates (/100 person-years) were 1.40, 1.55, and 1.95 for stroke or systemic embolism (log-rank P =0.65); 1.70, 1.55, and 2.61 for bleeding requiring hospitalization (log-rank P =0.33); 2.09, 2.60, and 5.29 for total deaths (log-rank P <0.001); and 0.40, 1.06, and 1.55 for cardiovascular deaths (log-rank P =0.045), respectively. After adjusting for confounders using a Cox regression analysis, age ≥85 years was identified as an independent risk of total death (hazard ratio, 1.89; 95% CI, 1.10-3.26 [ P =0.022]), but not of stroke or systemic embolism, bleeding requiring hospitalization, or cardiovascular death. Conclusions Although mortality increased with age, age ≥85 years was not a significant risk of stroke or systemic embolism, bleeding requiring hospitalization, or cardiovascular death in Japanese patients with nonvalvular atrial fibrillation taking on-label doses of apixaban. Registration URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000017895.

Purpose: Nine bladder cancer (BCa) cases were reported among aromatic amine-exposed male workers at a factory manufacturing organic dye/pigment intermediates in Japan. We aimed to evaluate the characteristics of aromatic amine-exposed workers by cross-sectional observation, and the risk of BCa by assessing the standardized incidence ratio (SIR)., Methods: In the cross-sectional study, our subjects were: 9 BCa patients, 36 aromatic amine-exposed non-patients, and 79 non-exposed workers from 3 factories. We evaluated the subjects' medical history, urinalysis, qualitative determination of nuclear matrix protein 22, and urinary cytology. For SIR assessment, 98 aromatic amine-exposed workers from 1 factory were included, and the Japanese general male population was used as a referent population. Since no direct aromatic amine-exposure data were available, we calculated surrogate exposure levels using information on job sites, exposure potency, and duration., Results: Coexistent aromatic amines were ortho-toluidine (OT), aniline, para-toluidine, ortho-anisidine, 2,4-xylidine, and ortho-chloroaniline. The prevalence rates of cystitis and bladder lesion-related symptoms in both BCa patients and aromatic amine-exposed non-patient workers were significantly higher than those of non-exposed workers. Overall, the SIR for BCa in OT-exposed workers was 56.8 (95% CI 27.7-104.3) and apparent dose-response relationships were revealed between the SIR and the surrogate exposure level in the 0-10-year lagged analyses. Overall, SIRs in other aromatic amine-exposed workers were also significantly high but no or unclear dose-response relationships were observed., Conclusions: We conclude that OT may be responsible for the increased risk of BCa. Regular monitoring of bladder lesion-related symptoms is essential for the early identification of BCa., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Dose reduction of apixaban is applied in atrial fibrillation (AF) patients fulfilling ≥ 2 of the following criteria: (1) age ≥ 80 years, (2) body weight ≤ 60 kg and (3) serum creatinine ≥ 1.5 mg/dL. However, the clinical significance of each criterion remains unclear. The J-ELD AF Registry is a prospective observational study of elderly (≥ 75 years) Japanese AF patients receiving on-label dose of apixaban. In patients receiving the standard dose (5 mg bid, n = 1243), the incidence rates (% per patient-year) of stroke or systemic embolism in those fulfilling none [n = 516] or one of the above criteria (1) [n = 328], (2) [n = 378] and (3) [n = 21] were 1.24, 2.32, 1.41 and 4.93 (log-rank P = 0.422), respectively, and those of bleeding requiring hospitalization were 1.03, 0.99, 1.98 and 4.93 (P = 0.318), respectively. In patients receiving a reduced dose (2.5 mg bid, n = 1,515), the incidences of stroke or systemic embolism in those fulfilling (1)/(2) [n = 1,331], (1)/(3) [n = 65], (2)/(3) [n = 23] and all three criteria [n = 96] were 1.38, 1.64, 4.67 and 3.51 (P = 0.295), respectively, and those of bleeding requiring hospitalization were 2.04, 1.64, 0.00 and 4.71 (P = 0.318), respectively. Univariate analysis demonstrated that the types or combinations of each criterion was not significantly associated with the incidence of thromboembolic or bleeding events. The types or combinations of the three apixaban dose reduction criteria did not have significant impact on effectiveness and safety in Japanese elderly AF patients receiving on-label dose of apixaban, although the impact of the creatinine criterion remains uncertain due to the few number of the patients.

Background: Although the prevalence of metabolic syndrome in patients with schizophrenia is higher than the prevalence in the general population, little is known regarding nonalcoholic fatty liver disease (NAFLD) in patients with schizophrenia., Procedures: We analyzed the medical records of patients with schizophrenia/schizoaffective disorder (N = 253) who received an abdominal echography., Results: In total, 108 patients (42.7%) showed NAFLD on abdominal echography. Of these, 13 patients (12.0%) showed signs of fibrosis on abdominal echography. In terms of age distribution, NAFLD was more prevalent in younger patients, particularly in female patients. We also found that body mass index, the total dose of antipsychotic drugs that carry a risk of metabolic syndrome, and the total dose of antipsychotic drugs that carry a risk of hyperprolactinemia were significantly associated with NAFLD (P < 0.001, 0.049, and 0.041, respectively). In our exploratory analysis, we found that signs of fibrosis in NAFLD were more highly associated with female patients (P = 0.023). Importantly, the risk in younger female patients may be specific to patients with schizophrenia compared with the general population., Conclusions: Considering that antipsychotic drugs were associated with the development of NAFLD, early detection and management of NAFLD should be conducted in patients with schizophrenia., Competing Interests: A.K. has received honoraria for educational materials from Sumitomo Dainippon, and T.K. has received speaker's honoraria from Otsuka, Yoshitomi, and Meiji-Seika and honoraria for educational materials from Sumitomo Dainippon within the past 3 years. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Escalation to triple therapy (long-acting muscarinic antagonist/β 2 -agonist, inhaled corticosteroid [ICS]) in chronic obstructive pulmonary disorder (COPD) is recommended for patients on LAMA/LABA combinations with frequent exacerbations and severe symptoms. An extended time-to-escalation to triple therapy suggests patients are in a stable condition and is an indicator of treatment effectiveness. No studies in Japanese clinical practice have compared the effectiveness of LAMA/LABA fixed-dose combination therapies with LAMA monotherapy in terms of time-to-escalation to triple therapy. The primary objective of this real-world study in Japan was to compare time-to-escalation to triple therapy among new users of tiotropium/olodaterol or tiotropium monotherapy for COPD without asthma., Methods: In this active-comparator cohort study, new users of tiotropium/olodaterol (n = 1436) and tiotropium monotherapy (n = 5352) were identified from a large Japanese hospital-based database (Medical Data Vision Co., Ltd., Tokyo; prespecified study period: 1 April 2015 to 31 March 2019); patients in each group were matched 1:1 using high-dimensional propensity scores (hdPS). The primary outcome was time-to-escalation to triple therapy., Results: For the prespecified study period in the hdPS-matched cohort, escalation to triple therapy was infrequent among new users of tiotropium/olodaterol (n = 1302, 7 escalation events) and tiotropium monotherapy (n = 1302, 8 escalation events). The difference in time-to-escalation to triple therapy between groups was not statistically significant (median [interquartile range]: 28 days [15.0-139.2] for tiotropium monotherapy vs 193 days [94.5-302.0] for tiotropium/olodaterol; hazard ratio: 0.89; 95% CI: 0.32-2.46). Similar findings (hazard ratio: 0.71; 95% Cl: 0.36-1.40) were observed in a post hoc analysis, which extended the study period by 1 year to 31 March 2020. Risks of first moderate and/or severe COPD exacerbation were lower for tiotropium/olodaterol than tiotropium monotherapy (between-group differences not significant). There were no significant between-group differences for the risks of all-cause inpatient mortality, major adverse cardiovascular events, and first use of home oxygen therapy., Conclusions: ICS monotherapy or ICS/LABA added to tiotropium or tiotropium/olodaterol is limited in Japanese clinical settings. The number of escalations to triple therapy was very limited in the dataset and there was insufficient power to detect differences between the treatment groups in the primary hdPS-matched cohort.

Background: Because of the burden of migraine in Japan, there is a need for safe and effective preventive treatments. This study assessed the long-term safety and tolerability of galcanezumab in Japanese patients with episodic (EM) or chronic (CM) migraine., Research Design and Methods: In this 12-month open-label study, adult patients with EM who previously completed a 6-month, double-blind, placebo-controlled trial were newly randomized to either galcanezumab dose from placebo or continued their assigned galcanezumab doses (all: 120 mg, n = 120; 240 mg, n = 126). Newly enrolled patients with CM were randomized to 120-mg (n = 32) or 240-mg (n = 33) galcanezumab. The primary outcome was long-term safety and tolerability., Results: The incidence of TEAEs was similar between treatment groups. Nasopharyngitis was the most common TEAE, followed by injection site reactions. The discontinuation rate was low (EM = 9.3%; CM = 15.4%) and no deaths were reported. Patients with EM who received galcanezumab in the placebo-controlled trial had sustained efficacy. Both doses reduced the number of migraine headache days in patients with CM., Conclusions: Long-term treatment with 120-mg or 240-mg galcanezumab was safe and effective in Japanese patients with EM or CM., Trial Registration: https://clinicaltrials.gov, identifier: NCT02959190.

We identified the major points that are described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guideline but have not been considered in the past multiregional clinical trials (MRCTs) used for drug approval in Japan to elucidate potential challenges in the implementation of the ICH E17 guideline in Japan. Based on the analysis of 167 MRCTs of 130 drugs, several points, such as the same dose setting and consistency between the overall and Japanese populations, in addition to good clinical practice compliance, have been well considered in ≥ 75% of MRCTs. In contrast, the use of relevant guidelines for disease and primary end point definitions, standardization of efficacy/safety information, sample size allocation, as well as training/validation on subject selection and primary end point, have been addressed less adequately and may need to be considered when planning future MRCTs. This study provides useful information for the implementation of the ICH E17 guideline in Japan., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)