Healthy Japanese Research Articles

P045 Effect of Etrasimod on Circulating Lymphocyte Subsets: Data From a Randomized Phase 1 Study in Healthy Japanese and Caucasian Men.

BACKGROUND: Etrasimod, a selective sphingosine 1-phosphate (S1P) receptor 1,4,5 modulator that reduces peripheral lymphocytes and subsequently impedes their recruitment to sites of inflammation, is in development for chronic immune-mediated inflammatory diseases. Reduction in pro-inflammatory immune cells without causing broad immunosuppression is an important treatment goal in patients with these diseases. This study evaluated the effect of etrasimod on circulating lymphocyte subsets in healthy volunteers to improve understanding of its proposed mechanism of action. METHODS: In this phase 1, single-blind (subject only) pharmacokinetic (PK) and pharmacodynamic study, 49 healthy Japanese and Caucasian men were randomized to receive once daily oral etrasimod 1 mg (n = 20), 2 mg (n = 20), or matching placebo (n = 9) from Days 1 to 7, followed by a 7-day washout and a single dose on Day 15. Absolute lymphocyte counts (ALC) were determined by complete blood count with differential. Immune cell subsets were evaluated by flow cytometry from isolated peripheral blood mononuclear cells (PBMCs) collected pre-dose on Days 1, 3, 5, 7, and 15. Change from baseline on 24 different immune cell subtypes were evaluated using a mixed-effects model. Paired t-tests were computed to evaluate significant subtype modulations in etrasimod-treated groups vs placebo at Day 7. RESULTS: Compared with placebo, etrasimod 1 and 2 mg dosed daily for 7 days resulted in similar dose dependent reductions in ALC in both ethnic groups, with total lymphocytes returning to at least 84% of baseline at Day 15. Compared with placebo, etrasimod induced reductions in mean percent change from baseline to Day 7 in total T cells, total CD4+ and CD8+ T cells, naive CD4+ and CD8+ T cells, central memory CD4+ and CD8+ T cells, effector memory CD4+ and CD8+ T cells, Th2 and Th17 cells, and total B cells. Etrasimod resulted in greater decreases in naive and central memory T cells than in effector memory T cells. Decreased immune cell subsets recovered to at least 70% of baseline pre-dose on Day 15, after the 7-day washout period. No notable treatment effects were seen on monocytes, macrophages, or CD56dim NK cells. Changes in immune cell populations were similar between Japanese and Caucasian subjects. Etrasimod 1 and 2 mg once-daily dosing regimens were safe and generally well tolerated. No adverse events related to low lymphocyte values occurred. CONCLUSION: Etrasimod effects on ALC and immune cell subsets were consistent with its known mechanism of action and observations for other S1P receptor modulators. Little or no ethnic group differences in etrasimod effects on ALC and immune cell subsets were observed in this study. The effect of etrasimod on onset and offset of immune modulation is consistent with etrasimod PK, with a typical half-life of approximately 33 hours. The differential effects of etrasimod on immune cell subsets may allow for a reduction in inflammation while maintaining immune surveillance. The lymphocyte subset profile suggests that etrasimod reduces certain immune cells and behaves as a selective immunomodulator rather than as a broad immunosuppressive agent.

The Effects of an Artificial Garden on Heart Rate Variability among Healthy Young Japanese Adults.

Spending time in nature might positively influence mental health by inducing a relaxed state. Recently, gardens have been created on hospital rooftops in Japan to help inpatients recover from various physical and mental aliments. However, there is little evidence regarding any positive physiological effects of artificial gardens designed for health. The purpose of this study was to assess the psychological and cardiovascular responses incited by artificial natural environments. Japanese university students (n = 38) participated in a one-group pretest post-test experiment conducted at the Yamaguchi Flower Expo in Japan in October 2018, designed to assess whether exposure to four environments (forest, flowers, ocean, and artificial garden for health) influenced heart rate variability measures. After pretesting to determine baseline measurements, participants completed a circuit through the four natural environments. Following circuit completion, post-testing determined that the low frequency/high frequency ratio was significantly lower in the overall sample and the four areas had similar influences on heart rate variability. Findings suggest that exposure to nature by walking through natural areas and in rooftop artificial gardens might enhance the balance between the sympathetic and parasympathetic nervous systems.

Comparison of the Pharmacokinetics of RIPK1 Inhibitor GSK2982772 in Healthy Western and Japanese Subjects

Background and ObjectivesGSK2982772 is an oral small-molecule RIPK1 inhibitor with potential therapeutic efficacy in immune-mediated inflammatory diseases (IMIDs). An inter-ethnic comparison of GSK2982772 pharmacokinetics was conducted based on data from Western (Study 1) and Japanese subjects (Study 2).MethodsBoth studies were single-centre, randomised, double-blind, placebo-controlled studies with objectives to assess the safety and characterise the pharmacokinetics of GSK2982772. Western subjects in Study 1 (NCT03305419), Part A (N = 15), were randomly assigned to receive 120 mg three times daily (TID), 240 mg TID, or 360 mg twice daily (BID) doses of GSK2982772, or placebo (TID or BID) for 1 day. Part B subjects (N = 47) received GSK2982772 120 mg TID, 240 mg TID, or placebo TID for 14 days. Japanese subjects in Study 2 (N = 13) (NCT03590613) were randomly assigned to receive TID doses of GSK2982772 60, 120, 240 mg TID or placebo TID for 1 day.ResultsGSK2982772 was well tolerated and adverse events were generally mild. Maximum observed plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma drug concentration versus time curve after the first GSK2982772 dose (AUC(0–7)) of 120 and 240 mg, and (AUC(0–24)) values for the 120 and 240 mg TID doses over a single day were similar in Japanese and Western subjects.ConclusionsThe pharmacokinetics and tolerability of GSK2982772 were similar between Western and Japanese subjects, justifying inclusion of Japanese subjects in future global clinical studies to assess the therapeutic potential of RIPK1 inhibition for the treatment of IMIDs.Clinical Trials: NCT03305419 and NCT03590613 available from http://www.clinicaltrials.gov.Electronic supplementary materialThe online version of this article (10.1007/s13318-020-00652-2) contains supplementary material, which is available to authorized users.

Untargeted metabolomics reveals the effect of lovastatin on steroid-induced necrosis of the femoral head in rabbits

PurposeLovastatin is an important medicine and it shows a significant effect against glucocorticoid-induced necrosis of the femoral head. This study aimed to investigate the effect of lovastatin on preventing necrosis of the femoral head of by serum metabolomics strategy.MethodsAdult healthy adult Japanese white rabbits were divided into three groups: control group, model group, and drug group. The pathologic changes of femoral head were assessed with magnetic resonance imaging and microscope. Metabolomics based on ultra-high performance liquid chromatography tandem mass spectrometry analysis was used to analyze the collected serum sample. Data were analyzed using principal component analysis, partial least squares-discriminate analysis, and orthogonal partial least squares-discriminant analysis. All potential metabolites were identified by comparing with human metabolome database, Metlin database, lipid maps, and chemspider database.ResultsEleven potential biomarkers were noted and identified as potential biomarkers. The change of biomarkers suggested that lovastatin on preventing necrosis of the femoral head may affect glycerophospholipid metabolism, linoleic acid metabolism, sphingolipid metabolism, alpha-linolenic acid metabolism, pyrimidine metabolism, and arachidonic acid metabolism.ConclusionThe study suggested that lovastatin could prevent the glucocorticoid-induced necrosis of the femoral head of rabbits. The possible reasons were closely associated with adjusting the lipid metabolism, inhibiting adipogenesis, and delaying the osteocyte apoptosis.

A randomized study investigating the safety, tolerability, and pharmacokinetics of evinacumab, an ANGPTL3 inhibitor, in healthy Japanese and Caucasian subjects

Background and aimsEvinacumab, an angiopoietin-like protein 3 monoclonal antibody, reduced low-density lipoprotein cholesterol (LDL-C) significantly in a Phase 2 study of patients with homozygous familial hypercholesterolemia. In this double-blind, placebo-controlled Phase 1 study, we compared safety, tolerability, pharmacokinetics, and pharmacodynamics of evinacumab between healthy Japanese and Caucasian adults. MethodsSubjects with LDL-C ≥2.6 and <4.1 mmol/L were enrolled to one of four dose cohorts: evinacumab subcutaneous (SC) 300 mg single dose, SC 300 mg once weekly for eight doses, intravenous (IV) 5 mg/kg, or IV 15 mg/kg once every 4 weeks for two doses. Each cohort comprised 24 subjects (12 Japanese; 12 Caucasian), randomized (3:1) to receive evinacumab or placebo within each ethnic group with a 24-week follow-up. ResultsThe safety profile of evinacumab (IV and SC) in both ethnicities was comparable with placebo, with no serious or severe treatment-emergent adverse events. Pharmacokinetic profiles were comparable between Japanese and Caucasian subjects across IV and SC groups. Mean calculated LDL-C decreased from baseline with both IV doses, beginning on day 3 up to week 8. Triglyceride changes observed with evinacumab IV were rapid (seen by day 2) and sustained up to week 8. Evinacumab SC doses also reduced LDL-C and triglyceride levels, although lower doses induced smaller changes. Evinacumab (IV and SC) reduced other lipids, including apolipoprotein B, versus placebo. ConclusionsIn both ethnicities, evinacumab (IV and SC) was generally well tolerated, exhibiting comparable pharmacokinetic profiles. Dose-related reductions in LDL-C and triglycerides were observed with evinacumab in both ethnic groups.

ETHNIC SENSITIVITY STUDY OF THE EXTRA-FINE SINGLE-INHALER TRIPLE THERAPY BECLOMETHASONE DIPROPIONATE/FORMOTEROL FUMARATE/GLYCOPYRRONIUM BROMIDE (BDP/FF/GB) PRESSURISED METERED DOSE INHALER (PMDI) IN HEALTHY JAPANESE AND CAUCASIAN SUBJECTS

SESSION TITLE: Pharmacotherapeutics Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: The prevalence of asthma in Japan has been increasing and a substantial proportion of patients continue to suffer from uncontrolled asthma. BDP/FF/GB pMDI is a single-inhaler ICS/LABA/LAMA triple therapy developed for the maintenance treatment of patients with asthma not adequately controlled on medium-to-high doses ICS/LABA. Since responses to pharmacological therapy can be affected by race and ethnicity, we investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of BDP/FF/GB pMDI in healthy Japanese subjects in comparison to their Caucasian counterparts. METHODS: In this single-centre, randomised, double-blind, single dose, 4-way cross-over, placebo-controlled ethnic sensitivity study, healthy Japanese and Caucasian subjects received two different therapeutic doses (TD) of BDP/FF/GB, namely TD1 (200/12/25 µg) and TD2 (400/12/25 µg) and a supratherapeutic dose (STD, 800/48/100 µg), as well as a matching placebo separated by 21-day washout periods. Serial PK and PD assessments were conducted pre-dose and up to 48 hours post-dose. Vital signs, electrocardiograms (ECG) and treatment-emergent adverse events (TEAEs) were also monitored for the assessment of safety. Ethnic comparability was assessed by descriptive statistics. RESULTS: Thirty-two subjects (16 Japanese and 16 Caucasian subjects) were allocated to one of the 4 treatment sequences and thirty (93.8%) of the treated subjects completed the study. For B17MP (beclomethasone 17-monopropionate, the most active metabolite of BDP), Cmax and AUC0-t were generally comparable between Japanese and Caucasian subjects after all treatments, with geometric mean ratios from 1.17 to 1.26 (Cmax) and 1.16 to 1.22 (AUC0-t). For formoterol, Cmax and AUC0-t were higher in Japanese than in Caucasian subjects after all treatments with geometric mean ratios from 1.22 to 1.53 (Cmax) and from 1.23 to 1.40 (AUC0-t). For GB, Cmax was higher in Japanese than in Caucasian subjects after all treatments with geometric mean ratios from 1.09 to 1.42. The AUC0-t of GB was generally comparable between Japanese and Caucasian subjects after all treatments with geometric mean ratios from 0.98 to 1.17. In general, no clinically relevant differences were observed between Japanese and Caucasian subjects in PD and safety assessments. CONCLUSIONS: Exposure to extra-fine BDP/FF/GB pMDI was associated with comparable B17MP PK parameters whilst slight elevation in some PK parameters were observed for formoterol and GB in Japanese compared to Caucasian subjects. These results are in line with available literature on exposure to these drugs in Japanese subjects. CLINICAL IMPLICATIONS: No dose adjustments in Japanese are deemed necessary for BDP/FF/GB pMDI. DISCLOSURES: Employee relationship with Chiesi Farmaceutici SpA Please note: >$100000 Added 03/23/2020 by Massimo Cella, source=Web Response, value=Salary Employee relationship with Chiesi Farmaceutici S.p.A. Please note: >$100000 Added 03/21/2020 by Irisz Delestre-Levai, source=Web Response, value=Salary Employee relationship with Chiesi Farmaceutici, S.p.A. Please note: >$100000 Added 03/20/2020 by George Georges, source=Web Response, value=Salary No relevant relationships by Jorg Taubel, source=Web Response Employee relationship with Chiesi Please note: $1001 - $5000 Added 03/23/2020 by Anne Tulard, source=Web Response, value=Salary No relevant relationships by ANDREA VELE, source=Web Response

Relationships among Lifestyle Awareness, Age, and Lifestyle-related Diseases in Healthy Japanese Community Residents.

Purpose: It is widely known that the risk of lifestyle-related diseases can be reduced by reviewing lifestyles, and a variety of efforts for their prevention, such as health education, are being implemented. This study examined community residents’ lifestyle awareness, examining their views on their health and lifestyles, age, and lifestyle-related diseases.Methods: Study subjects were 180 healthy people (28 men and 152 women) who participated in a health checkup. Participants answered a questionnaire about their awareness of health and lifestyle and their views of disorders. Subsequent measurements of speed of sound (SOS), acceleration plethysmography (APG), and visceral fat area (VFA) were also obtained.Results: The results of the study suggest that age was correlated with some health-related attitudes and behaviors. When health awareness among members of a group is high, it is necessary to provide them with the required information and continuing intervention to motivate them to continue their health improvement.Conclusion: It seems that health awareness influences lifestyle, and its improvement slows the progress of lifestyle-related diseases and reduces the effects of aging.

Beneficial effects of docosahexaenoic acid-enriched milk beverage intake on cognitive function in healthy elderly Japanese: A 12-month randomized, double-blind, placebo-controlled trial

Abstract Recent approaches to the management of dementia have focused mainly on continual preventive treatment. In this study, we investigated whether intake of 297 mg docosahexaenoic acid (DHA) and 137 mg eicosapentaenoic acid (EPA) per day, which is a smaller amount than in previous reports, would maintain higher cognitive function in healthy elderly people. Eighty-seven participants were enrolled in this 12-month randomized, double-blind, placebo-controlled trial. Cognitive function test, blood biochemical analysis and anthropometry were conducted at baseline, 6 and 12 months of DHA beverage intake. Intake of DHA-enriched milk beverage for 6 and 12 months significantly increased erythrocyte plasma membrane DHA and EPA levels. Furthermore, intake of DHA-enriched milk beverage for 12 months protected against age-related cognitive decline. The preventive mechanism of this small amount of DHA is not known. Thus, further investigation is needed to reveal the mechanism underlying its role in cognitive function. Trial registration: UMIN Clinical Trial Registry, UMI31699.

Mu-Opioid Receptor Polymorphism Moderates Sensitivity to Parental Behaviors During Characterization of Personality Traits.

PurposeAttachment research shows that attachment experiences with parents in childhood influence the characterization of personality traits. Meanwhile, it is known that mu-opioid receptor function is involved in human attachment. Furthermore, a few studies suggest that the A118G polymorphism of the mu-opioid receptor gene (OPRM1) is associated with altered mu-opioid receptor function. Thus, we examined if the OPRM1 polymorphism moderates the sensitivity to parental behaviors and thereby contributes to the characterization of personality traits.Materials and MethodsParticipants were 725 healthy Japanese. Parenting practices of their parents were evaluated by the Parental Bonding Instrument (PBI) with the care and protection subscales. Personality was evaluated using the Temperament and Character Inventory (TCI). The OPRM1 A118G polymorphism was detected by a PCR method.ResultsMultiple regression analyses revealed significant effects of the interaction between the OPRM1 genotype and maternal protection on scores of the self-directedness and cooperativeness dimensions, while significant main effects of the OPRM1 genotype on scores of the TCI were not found. Further analyses showed that there were significant negative correlations between maternal protection scores and the two dimensional scores in the A/A and A/G genotypes with higher correlation coefficients in the former, but not in the G/G genotype.ConclusionThe present study suggests that the OPRM1 polymorphism contributes to the characterization of personality traits by moderating the sensitivity to parental behaviors, especially maternal protection.

Blood levels of microRNAs associated with ischemic heart disease differ between Austrians and Japanese: a pilot study

Mortality from ischemic heart disease (IHD) is significantly lower in Japan than in Western countries. The purpose of this study was to investigate differences in circulating microRNA (miRNA) levels related to IHD in Austrians and Japanese. Participants were middle-aged healthy male Austrians (n = 20) and Japanese (n = 20). Total miRNAs in serum from each participant were analyzed using the 3D-Gene miRNA Oligo chip. Twenty-one miRNAs, previously reported as associated with IHD, were compared between Austrians and Japanese. The expression levels of miR-106a-5p, miR-135a-3p, miR-150-3p, miR-16-5p, miR-17-5p. miR-191-5p, miR-320b, miR-451a, miR-486-5p, miR-663b, and miR-92a-3p were significantly higher, while the miR-2861 expression level was significantly lower in Austrians as compared to Japanese. Both in Austrians and Japanese, there were significant positive correlations between serum expression levels of each pair of the above miRNAs except for miR-2861. The expression level of miR-2861 showed significant positive correlations with the expression levels of miR-106a-5p, miR-150-3p, miR-17-5p, miR-486-5p, miR-663b and miR-92a-3p in Austrians but not in Japanese. In pathway analysis, proinflammatory cytokine production in foam cells and collagen synthesis in vascular smooth muscle cells were associated with differentially expressed miRNAs. Difference in miRNA levels may contribute to lower cardiovascular risk in Japan than in Western countries.

Association between Physical Activity Levels and Body Composition among Healthy Older Japanese Adults during a Snowy Winter: A Cross-Sectional Study.

Background: Despite a long average lifespan, increased life expectancy does not guarantee higher quality of life. Methods: To contribute in understanding some determinants of healthy life expectancies in older Japanese individuals in a snowy winter region, we investigated the indicators of health. Local residents (n = 124) in the city of Iwamizawa volunteered for health examinations from January 2016 to March 2016. We recorded activity via daily steps for 2-week periods. In addition, we measured body composition, grip strength, and assessed nutritional status. Results: Analysis of body composition and daily activity indicated that women who walked more than 4000 steps had lower fat mass and increased muscle mass. Men with >3.0 metabolic equivalents (METs) when walking had lower body fat. Conclusion: For healthy older Japanese individuals in this snowy winter region, walking >4000 steps daily for women and exercise of >3.0 METs for men may indicate health-promoting activities.

Associations between healthy Japanese dietary patterns and depression in Japanese women.

Higher quality dietary patterns such as healthy/prudent and Mediterranean dietary patterns have been protectively associated with depression. This study examined whether healthy Japanese dietary patterns, which differ from dietary patterns derived from Western areas, are associated with depressive symptoms among Japanese women. A cross-sectional study (the Nagano Nutrition and Health Study). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Dietary patterns were derived with a principal component analysis of the consumption of fifty-six food and beverage items, which were assessed by a validated brief diet history questionnaire. Nagano, Japan. Japanese women (n 1337) aged 20-72 years. We identified three dietary patterns: 'healthy Japanese', 'sweets-fat' and 'seafood-alcohol'. The highest quality dietary pattern was 'healthy Japanese'. It is characterised by a high intake of vegetables, mushrooms, seaweed, soyabean products, potatoes, fish/shellfish and fruit. The age- and multivariate-adjusted OR (95 % CI) of depressive symptoms for the highest quartiles of the 'healthy Japanese' pattern score were 0·58 (95 % CI 0·41, 0·82) and 0·69 (95 % CI 0·45, 1·06), respectively. Meanwhile, no associations were observed for 'sweets-fat' and 'seafood-alcohol' patterns. The 'healthy Japanese' pattern may be inversely associated with depressive symptoms with an exposure-response association. The specific Japanese food groups in the 'healthy Japanese' pattern included mushrooms, seaweed, soyabean products and potatoes, as well as vegetables, fish/shellfish and fruit. These seem to create an anti-inflammation-prone dietary pattern, and this factor might be associated with better mental health.

Safety, Tolerability, and Pharmacokinetics of Evinacumab, an Angiopoietin-Like Protein 3 Inhibitor, in Healthy Japanese and Caucasian Subjects†

Safety, Tolerability, and Pharmacokinetics of Evinacumab, an Angiopoietin-Like Protein 3 Inhibitor, in Healthy Japanese and Caucasian Subjects†

Effects of concomitant use of prasugrel with edoxaban on bleeding time, pharmacodynamics, and pharmacokinetics of edoxaban in healthy elderly Japanese male subjects: a clinical pharmacology study

BackgroundDual therapy with a direct oral anticoagulant (DOAC) plus a P2Y12 receptor inhibitor is recommended in patients with nonvalvular atrial fibrillation who undergo percutaneous coronary intervention. Thus, we evaluated the effects of DOAC edoxaban plus P2Y12 receptor inhibitor prasugrel on bleeding time (BT), and pharmacodynamics (PD) and pharmacokinetics (PK) of edoxaban in healthy elderly Japanese male subjects.MethodsA single-center, clinical pharmacology study with randomized, open-label, repeated dosing enrolled 24 participants in two groups of 12 receiving 30 mg edoxaban once daily for 3 days; then 30 mg edoxaban plus 2.5 mg prasugrel (Group 1) or 30 mg edoxaban plus 3.75 mg prasugrel (Group 2) once daily for 5 days. Primary endpoint was BT by the Ivy method. Secondary endpoints were the PD parameters of prothrombin time (PT), activated partial thromboplastin time (aPTT), prothrombin fragment F1 + 2 (F1 + 2), and P2Y12 reaction units (PRU), and PK profiles of edoxaban alone and in combination with prasugrel.ResultsGeometric least squares mean of BT ratios (vs. baseline) for 3-day edoxaban treatment were 1.097 (90% confidence interval (CI) 0.911–1.321) in Group 1 and 1.327 (90% CI 1.035–1.703) in Group 2; for 5-day edoxaban plus 2.5 mg and 3.75 mg prasugrel, they were 1.581 (90% CI 1.197–2.087) and 1.996 (90% CI 1.482–2.690), respectively. Contributions of prasugrel to the effects (edoxaban + prasugrel/edoxaban) were 1.442 (90% CI 1.096–1.897) in Group 1 and 1.504 (90% CI 1.172–1.930) in Group 2. Edoxaban prolonged PT and aPTT and decreased F1 + 2. Adding on prasugrel did not appreciably change PT, aPTT, or F1 + 2. Prasugrel reduced PRU, whereas edoxaban had no effect on PRU. We recorded 26 adverse events; 23 were treatment-emergent (positive fecal occult blood test). All participants with adverse events recovered during follow-up.ConclusionsCoadministration of 2.5 mg and 3.75 mg prasugrel with 30 mg edoxaban prolonged BT in healthy elderly Japanese male subjects. The effect was dependent on the dose of prasugrel. Prasugrel did not affect PD or PK profiles of edoxaban. Edoxaban had no effect on PD of prasugrel.Trial registrationJapan Registry of Clinical Trials No. jRCTs071190006; registration date, 26-April-2019.

FRI0411 SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS IN HEALTHY MALE JAPANESE SUBJECTS OF THE ADAMTS-5 INHIBITOR S201086/GLPG1972, A POTENTIAL NEW TREATMENT IN OA

Background:The disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) is a key enzyme in OA (Verma P,et al.J Cell Biochem 2011;112:3507-14). In preclinical models of OA, S201086, a potent and selective ADAMTS-5 inhibitor, protects from cartilage degradation (Clement-Lacroix,et al.Osteoarthritis Cartilage 2017;25:S58). Therefore, S201086 is co-developed by Servier and Galapagos (GLPG1972) as a potential new treatment in OA.Objectives:This phase I study was to assess and compare the safety, tolerability, pharmacokinetics and pharmacodynamics of S201086 in healthy male Japanese and Caucasian subjects.Methods:Six ascending single doses of S201086 (50 to 1500 mg) were administered orally as tablets in fasting conditions in 6 groups of 8 Japanese subjects (aged 20-45 years) and 3 ascending multiple doses (300, 600 or 1050 mg/day for 14 days) were administered orally as tablets in fed conditions in 3 groups of 8 Japanese subjects. Additionally, 2 cohorts of 8 Caucasian subjects received either a single oral dose of 300 mg or repeated oral dose of 300 mg once daily for 14 days. In each group, 6 subjects received S201086 and 2 placebo. Plasma was collected at several time points for the quantification of S201086 by LC-MS/MS. Plasma pharmacokinetic parameters were calculated via non-compartmental analysis using Phoenix® WinNonlin® software. Pharmacodynamics was assessed by measurement of the aggrecan ARGS neoepitope levels in serum by ELISA.Results:No serious adverse drug reactions were observed after administration of single and multiple ascending doses of S201086 in either Japanese or Caucasian subjects. Most adverse events were of mild to moderate intensity and were resolved by the end of the study. Following single administration to Japanese subjects, Cmax and AUC increased proportionally with doses from 50 to 600 mg and slightly less than dose-proportionally from 600 to 1500 mg, consistent with what was previously observed in the first in-human study in healthy Caucasian subjects (van der Aar E,et al.Osteoarthritis Cartilage 2018;26:S310). In Japanese subjects, after 14-days administration, a limited 1.2- to 1.4-fold accumulation was observed on both Cmax and AUC at Day14 as compared to Day1, and the steady-state exposure increased dose-proportionally within the 300-1050 mg dose range. Taking the inter-subject variability into account, no difference was observed in Cmax and AUC between Caucasian and Japanese subjects after single administrations of 300 mg and repeated administrations of 300 mg once daily for 14 days. The serum ARGS neoepitope levels decreased between baseline and last day of treatment for S201086-treated subjects but not for subjects receiving placebo. This decrease was similar for the 3 tested doses in Japanese subjects and was significant as compared to the placebo-treated subjects.Table.Comparison of ARGS concentration relative change from baseline to last day of treatment according to dose in Japanese participantsS 201086 300 mg (N = 6)S 201086 600 mg (N = 6)S 201086 1050 mg (N = 6)Placebo (N = 6)Descriptive Statistics(D14 pre-dose – Baseline) / Baselinen6646Mean ± SD-42.67 ± 8.81-53.70 ± 6.50-54.11 ± 5.2013.35 ± 16.53Statistical analysisE (SE)56.01 (6.156)67.04 (6.156)67.45 (6.883)95% CI43.08; 68.9554.11; 79.9752.99; 81.91p-value&lt; 0.0001&lt; 0.0001&lt; 0.0001Conclusion:S201086 was shown to be safe and well-tolerated in Japanese and Caucasian healthy male subjects with a suitable PK profile and a significant decrease of the ARGS neoepitope, indicating target engagement. A global Phase 2 study to evaluate the efficacy of S201086 in patients with knee OA is ongoing (NCT03595618).Disclosure of Interests:Agnès Lalande Employee of: Institut de Recherches Internationales Servier, Nadya KUZNIATSOVA-MOUCHETTE Employee of: Institut de Recherches Internationales Servier, Florian CHASSEREAU Employee of: Institut de Recherches Internationales Servier, Julia GERONIMI Employee of: Institut de Recherches Internationales Servier, Katy Bernard Employee of: Institut de Recherches Internationales Servier, Staffan Larsson: None declared, André Struglics: None declared, Stefan Lohmander: None declared, Maria Pueyo Employee of: Institut de Recherches Internationales Servier

Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy Japanese and Caucasian Subjects

Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy Japanese and Caucasian Subjects

Effect of ellagic acid on body fat and triglyceride reduction in healthy overweight volunteers: a randomized, double-blind, placebo-controlled parallel group study

Background: Worldwide, those categorized as overweight or obese are increasing at an alarming rate, posing a serious public health problem. Current management methods vary, ranging from surgery, dieting and exercise, to the use of synthetic and natural compounds. Previous studies reported the use of an Irvingia gabonensis extract containing ellagic acid in reducing weight and other related parameters in overweight participants. The present study investigated the efficacy of ellagic acid on anthropometric parameters as well as body fat ratio and blood triglyceride levels in otherwise healthy overweight Japanese adults.Participants and Methods: Overall, 32 participants (23 males and 9 females) aged between 20 and 64 years with a BMI of 25 or more but less than 30 kg/m2 and a visceral fat area of 80 cm2 or more were included in this randomized double-blind clinical trial. The 20-week intervention involved two groups of participants -placebo group and ellagic acid (3.0 mg per day) group. The placebo or ellagic acid was taken daily with water 30 minutes before the main meal. At baseline (T0) and at 6 and 12 weeks, anthropometric measurements (body weight, BMI, body fat ratio, waist circumference, hip circumference), CT scans and blood triglyceride levels were measured. Results: Compared to the placebo, ellagic acid brought about statistically significant reductions in body fat ratio, triglycerides, body weight, BMI, waist circumference, hip circumference and visceral fat over the twelve-week trial period.Conclusion: The use of 3.0 mg ellagic acid daily for a 12-week period was effective in reducing body fat ratio and blood triglycerides as well as other anthropometric parameters, confirming the potential use of ellagic acid in the management of overweight patients. Keywords: Ellagic acid, Irvingia gabonensis, overweight, obesity, body fat, triglyceride, body weight, metabolic syndrome.

Ethnicity-Dependent Effects of Schizophrenia Risk Variants of the OLIG2 Gene on OLIG2 Transcription and White Matter Integrity.

Previous studies have indicated associations between several OLIG2 gene single-nucleotide polymorphisms (SNPs) and susceptibility to schizophrenia among Caucasians. Consistent with these findings, postmortem brain and diffusion tensor imaging studies have indicated that the schizophrenia-risk-associated allele (A) in the OLIG2 SNP rs1059004 predicts lower OLIG2 gene expression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients and reduced white matter (WM) integrity of the corona radiata in normal brains among Caucasians. In an effort to replicate the association between this variant and WM integrity among healthy Japanese, we found that the number of A alleles was positively correlated with WM integrity in some fiber tracts, including the right posterior limb of the internal capsule, and with mean blood flow in a widespread area, including the inferior frontal operculum, orbital area, and triangular gyrus. Because the A allele affected WM integrity in opposite directions in Japanese and Caucasians, we investigated a possible association between the OLIG2 gene SNPs and the expression level of OLIG2 transcripts in postmortem DLPFCs. We evaluated rs1059004 and additional SNPs in the 5' upstream and 3' downstream regions of rs1059004 to cover the broader region of the OLIG2 gene. The 2 SNPs (rs1059004 and rs9653711) had opposite effects on OLIG2 gene expression in the DLPFC in Japanese and Caucasians. These findings suggest ethnicity-dependent opposite effects of OLIG2 gene SNPs on WM integrity and OLIG2 gene expression in the brain, which may partially explain the failures in replicating associations between genetic variants and psychiatric phenotypes among ethnicities.

Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects.

Background and ObjectivePeficitinib pharmacokinetics and pharmacodynamics have been characterized mainly in Caucasian subjects. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of peficitinib in healthy Japanese subjects compared with Caucasian subjects.MethodsIn this single-center, randomized, double-blind, placebo-controlled study, a cohort of healthy Japanese (n = 24) and Caucasian (n = 24) men received a single oral dose of peficitinib (20, 60, or 200 mg) or placebo. Another cohort of Japanese men (n = 24) received peficitinib (10, 30, or 100 mg) or placebo twice daily for 7 days. Pharmacokinetic and pharmacodynamic parameters were assessed, and adverse events (AEs) monitored throughout.ResultsDose proportionality of maximum plasma drug concentration (Cmax) and area under the plasma concentration–time curve extrapolated to infinity (AUCinf) was demonstrated for both ethnicities. The geometric mean ratio for dose-normalized Cmax was 45.7–98.8% higher and AUCinf was 33.8–66.4% higher in Japanese versus Caucasian subjects. Mean peak inhibition of STAT5 phosphorylation was higher in Japanese than Caucasian subjects for a given peficitinib dose, but inhibition was comparable across ethnicities for a given plasma peficitinib concentration. In the multiple-dose study, plasma peficitinib concentrations were similar on day 1 and day 7. All AEs were mild, and none resulted in study discontinuation.ConclusionsPeficitinib was well tolerated at doses up to 200 mg daily for 7 days in healthy Japanese subjects. Dose-proportional exposure was demonstrated across the single-dose range of 20–200 mg, with greater peficitinib exposure in Japanese compared with Caucasian subjects. The pharmacokinetic/pharmacodynamic relationships were considered comparable between these populations.ClinicalTrials.gov identifierNCT01225224.Electronic supplementary materialThe online version of this article (10.1007/s40261-020-00910-w) contains supplementary material, which is available to authorized users.

Associations Between the Triglyceride to High-Density Lipoprotein Cholesterol Ratio and Metabolic Syndrome, Insulin Resistance, and Lifestyle Habits in Healthy Japanese.

Background: The triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio is related to insulin resistance (IR). However, little information is available on whether TG/HDL-C is associated with IR and components of metabolic syndrome (MetS) and how lifestyle habits affect TG/HDL-C in the healthy Japanese population. Methods: In total, 1068 Japanese subjects who had undergone an annual health examination and who were not receiving medication were recruited. Determinants for TG/HDL-C ratio were investigated using multiple regression analyses. The subjects were divided into three groups by lifestyle habits (i.e., smoking, exercise, and physical activity), homeostasis model assessment of IR (HOMA-IR), and fasting plasma glucose, four groups by alcohol intake, and five groups by numbers of MetS components to compare TG/HDL-C values. All analyses were done separately by sex. Results: Multiple regression analyses revealed that waist circumference and smoking were positively associated with TG/HDL-C in both men and women, whereas physical activity was negatively associated with TG/HDL-C ratio in women. TG/HDL-C increased with increasing number of MetS in both men and women. TG/HDL-C increased as HOMA-IR increased in both men and women, when subjects were stratified according to HOMA-IR. TG/HDL-C values were lower in both men and women who exercised regularly, had high physical activity, or were nonsmokers. Independent of exercise and physical activity, TG/HDL-C was higher in smokers than in nonsmokers for both men and women. The relationship between TG/HDL-C and alcohol intake was not statistically significant in both men and women. Conclusions: The TG/HDL-C ratio is associated with IR, components of MetS, exercise, physical activity, and smoking, but not alcohol intake, in healthy Japanese subjects.