Healthy Japanese Volunteers Research Articles

Pharmacokinetics and pharmacodynamics of the factor XIa-inhibiting antibody osocimab in healthy male East Asian volunteers: Results from two phase 1 studies.

The pharmacokinetics, pharmacodynamics, immunogenicity, and safety of osocimab single doses in healthy Chinese and Japanese volunteers over 149 days were evaluated. Two phase 1 single-blinded, placebo-controlled studies with 27 Japanese and 50 Chinese participants were conducted. Osocimab was investigated with IV doses of 0.3, 1.25, and 2.5 mg/kg (Chinese study) and 0.3, 1.25, and 5.0 mg/kg (Japanese study), as well as SC doses of 3.0 and 6.0 mg/kg (Chinese study) and 6.0 mg/kg (Japanese study). The maximum plasma concentration was reached 1-3 h and 4-6 days after IV and SC administration, respectively. Osocimab exhibited a deviation from dose-proportional pharmacokinetics for AUC but not Cmax; higher doses had higher apparent clearance and disproportionately lower total exposure. A slightly lower exposure was observed in Japanese compared with Chinese volunteers after IV administration; conversely, relatively higher exposure in Japanese volunteers with SC dosing was identified. Osocimab was associated with a dose-dependent increase in activated partial thromboplastin time (aPTT). Maximal aPTT prolongations were observed 1-4 h and 2-6 days after IV and SC administration, respectively. Anti-drug antibodies of low titer were detected in 1/9 (11.1%) Japanese volunteers administered placebo and 26/40 (65.0%) Chinese volunteers administered osocimab. Adverse events were reported in 8/18 (44.4%) Japanese and 28/40 (70.0%) Chinese volunteers who received osocimab, as well as in 1/9 (11.1%) Japanese and 6/10 (60.0%) Chinese volunteers who received placebo. In conclusion, data did not suggest a clear dose-proportionality for osocimab within the investigated dose range. The effect of osocimab on aPTT was expected per its mechanism of action. Osocimab was generally well tolerated.

Feasibility of Assessment of Habitual Salt Intake Using a 24-h Urinary Salt Excretion Self-Measuring Device.

To assess habitual salt intake, tools are needed to measure 24-h urinary salt excretion repeatedly. We developed and validated a new portable salt monitor, which measures salt excreted per urination and sums the values to provide an accurate estimate of urinary salt excretion over 24 h. A previously developed salt monitor was improved with respect to the capacity, volume sensors, and equation for urinary sodium chloride concentration estimation. In 20 healthy Japanese female volunteers, 24-h urinary salt excretion was measured using the salt monitor and a conventional 24-h urine collection method on eight nonconsecutive days. In a total of 157 days, there were no fixed or proportional errors between the methods. The mean salt intake over 8 days was 8.5 ± 2.0 g/day for the 24-h urine collection and 8.3 ± 2.3 g/day for the salt monitor, showing a strong correlation (r = 0.912, p < 0.001). At a cut-off value of 6 g, the salt monitor was able to completely classify individuals by habitual salt intake. The validity of the new salt monitor was confirmed. The device can be considered an alternative to the traditional 24-h urine collection for repeated surveys and self-management of daily salt intake.

Pharmacokinetics and Pharmacodynamics of Nipocalimab, a Neonatal Fc Receptor Blocker, in Healthy Japanese Volunteers.

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. 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. 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 theconcentration-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. 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.

Pharmacokinetics, pharmacodynamics, and safety of asundexian in healthy Chinese and Japanese volunteers, and comparison with Caucasian data.

There is an unmet clinical need for effective anticoagulant therapies for the management of thromboembolic diseases that are not associated with a relevant risk of bleeding. Asundexian (BAY 2433334) is an oral, direct, small-molecule inhibitor of activated factor XI (FXIa). Phase I data from healthy Caucasian male participants indicated predictable pharmacokinetic (PK) and pharmacodynamic (PD) profiles and no clinically relevant bleeding-related adverse events (AEs). Reported here are data from two phase I, randomized, placebo-controlled, single- and multiple-dose escalation studies of asundexian conducted in 60 healthy men: 24 Japanese and 36 Chinese. Baseline characteristics were comparable between the treatment groups. All treatment-emergent AEs were mild, with no serious AEs or AEs of special interest reported. Systemic exposure to asundexian increased dose proportionally after single or multiple dosing, with relatively low accumulation following multiple once-daily dosing in both Chinese and Japanese volunteers. Asundexian induced dose-dependent prolongation of activated partial thromboplastin time and inhibition of FXIa activity, with no effects on prothrombin time or FXI concentration in Japanese participants. There were no clinically relevant interethnic differences in PK profile across the Japanese, Chinese, and Caucasian (data from the previous phase I study) participants and no clinically relevant difference in PD response between Japanese and Caucasian participants.

Abstract 3045: Dietary Whole-grain Rice Differentially Regulates HDL-associated MicroRNAs And Hepatic Lipase In Healthy Japanese Volunteers.

Background: The Japanese population consumes a diet high in rice. Dietary whole-grain (brown) rice has advantageous health benefits over white rice, largely predicted to be conferred by brown rice bran, germ, and fiber. We have previously reported that high-density lipoproteins (HDL) transport microRNAs (miRNA) and deliver functional RNA to recipient hepatocytes. Here, we hypothesize that dietary brown rice reorganizes functional small RNA (sRNA) cargo on circulating HDL and regulates systemic lipid metabolism through hepatic HDL-miRNA uptake. Methods: Healthy subjects (n=13, 20-65 y.o., 38.5% male) consumed 150 g/serving for all 3 meals of (1) white rice, (2) brown rice, and (3) white rice for 3 days with intervals of 4 to 7 days. At day 4, plasma HDL-cholesterol (HDL-C) and total plasma lipids were measured by direct and enzymatic methods. Total RNA was isolated HDL purified by size-exclusion chromatography from human plasma. HDL-sRNA sequencing was completed using NovaSeq6000 (Illumina). HTGL protein levels were measured by ELISA (IBL). Results: Plasma cholesterol, HDL-C, and non-HDL-C levels were not immediately affected by dietary brown rice; however, HDL-C levels were increased after a delay of 10 days. Nevertheless, HDL-associated miR-203-3p and miR-205-5p were found to be significantly decreased in subjects with brown rice consumption compared to white rice. miR-203-3p is predicted to target and suppress hepatic lipase ( LIPC , HTGL). Plasma levels of HTGL were not altered by brown rice, but HTGL protein levels were found to be significantly decreased when the brown rice diet was switched back to white rice, and miR-203-3p levels returned to HDL particles. Conclusions: Dietary brown rice reduces HDL-associated miR-203-3p and miR-205-5p after 3 days and differentially regulates the systemic level of a putative miR-203-3p target gene. These results support that HDL-miR-203-3p functionality may be responsive to brown rice diets and post-transcriptionally regulate LIPC gene expression in recipient hepatocytes. These observations can potentially be used to design dietary supplements to regulate HDL-miRNA function in the liver to control systemic lipid metabolism.

Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers.

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 (50mg, 100mg, 200mg), 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. 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 4-6h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group. 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. ClinicalTrials.gov (NCT03875001; 08-Mar-2019).

Beneficial Effect of Heat-Killed Lactic Acid Bacterium Lactobacillus johnsonii No. 1088 on Temporal Gastroesophageal Reflux-Related Symptoms in Healthy Volunteers: A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group Study.

A randomized, placebo-controlled, double-blind, parallel-group clinical study was conducted to examine the effects of ingesting a heat-killed lactic acid bacterium, Lactobacillus johnsonii No. 1088 (LJ88) on temporal gastroesophageal reflux-related symptoms in healthy volunteers. A total of 120 healthy Japanese volunteers of both sexes, aged between 21 and 63 years, whose Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) total score was 8 or greater, but who were not diagnosed with functional dyspepsia according to the Rome IV classification, were enrolled. They were randomly assigned to either the LJ88 or placebo group and instructed to ingest the test food (1 billion heat-killed LJ88 or placebo) once a day for six weeks. Gastroesophageal reflux-related symptoms were evaluated using FSSG scores as a primary endpoint. The Gastrointestinal Symptoms Rating Scale (GSRS), stomach state questionnaire, and serum gastrin concentration were used as secondary endpoints. In the FSSG evaluation, the heartburn score was significantly improved at 6 weeks in the LJ88 group compared to the placebo group. No severe adverse events related to the test food were observed. In conclusion, daily ingestion of heat-killed LJ88 improved temporal heartburn symptoms in non-diseased individuals.

Pharmacokinetics, pharmacodynamics, and safety of fesomersen, a novel antisense inhibitor of factor XI, in healthy Chinese, Japanese, and Caucasian volunteers.

The inhibition of coagulation factor XI (FXI) presents an attractive approach for anticoagulation as it is not expected to increase the risk of clinically relevant bleeding and is anticipated to be at least as effective as currently available anticoagulants. Fesomersen is a conjugated antisense oligonucleotide that selectively inhibits the expression of FXI. The article describes three clinical studies that investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of fesomersen after subcutaneous (s.c.) injection to healthy participants. The studies included participants from diverse ethnic backgrounds (Caucasian, Japanese, and Chinese). Fesomersen demonstrated good safety and tolerability in all three studies. No major bleeding events were observed. After single-dose s.c. injection, fesomersen was rapidly absorbed into the systemic circulation, with maximum fesomersen-equivalent (fesomersen-eq) concentrations (Cmax) in plasma observed within a few hours. After reaching Cmax, plasma fesomersen-eq concentrations declined in a biphasic fashion. The PD analyses showed that the injection of fesomersen led to dose-dependent reductions in FXI activity and increases in activated partial thromboplastin time (aPTT). The maximum observed PD effects were reached between Day 15 and 30, and FXI activity and aPTT returned to near-baseline levels by Day 90 after a single dose. The PK/PD profiles after a single injection were similar among the various ethnic groups. Collectively, the study results suggest that fesomersen has a favorable safety profile and predictable and similar PK and PD profiles across Chinese, Japanese, and Caucasian participants.

Relationship Between Diaphragm Thickness, Thickening Fraction, Dome Excursion, and Respiratory Pressures in Healthy Subjects: An Ultrasound Study

PurposeDiaphragm ultrasonography is used to identify causes of diaphragm dysfunction. However, its correlation with pulmonary function tests, including maximal inspiratory (MIP) and expiratory pressures (MEP), remains unclear. This study investigated this relationship by measuring diaphragm thickness, thickening fraction (TF), and excursion (DE) using ultrasonography, and their relationship to MIP and MEP. It also examined the influence of age, sex, height, and BMI on these measures.MethodsWe recruited healthy Japanese volunteers and conducted pulmonary function tests and diaphragm ultrasonography in a seated position. Diaphragm ultrasonography was performed during quiet breathing (QB) and deep breathing (DB) to measure the diaphragm thickness, TF, and DE. A multivariate analysis was conducted, adjusting for age, sex, height, and BMI.ResultsBetween March 2022 and January 2023, 109 individuals (56 males) were included from three facilities. The mean (standard deviation) MIP and MEP [cmH2O] were 72.2 (24.6) and 96.9 (35.8), respectively. Thickness [mm] at the end of expiration was 1.7 (0.4), TF [%] was 50.0 (25.9) during QB and 110.7 (44.3) during DB, and DE [cm] was 1.7 (0.6) during QB and 4.4 (1.4) during DB. Multivariate analysis revealed that only DE (DB) had a statistically significant relationship with MIP and MEP (p = 0.021, p = 0.008). Sex, age, and BMI had a statistically significant influence on relationships between DE (DB) and MIP (p = 0.008, 0.048, and < 0.001, respectively).ConclusionIn healthy adults, DE (DB) has a relationship with MIP and MEP. Sex, age, and BMI, but not height, are influencing factors on this relationship.

Phase I/IIa trial of 18F-prostate specific membrane antigen (PSMA) 1007 PET/CT in healthy volunteers and prostate cancer patients.

18F-PSMA 1007 is a promising PET tracer for prostate cancer. We aimed to examine the safety, biodistribution, radiation dosimetry, and clinical effectiveness in Japanese healthy volunteers and patients with prostate cancer. Part A evaluated the pharmacokinetics and exposure doses in three healthy volunteers. Part B evaluated the diagnostic accuracy in patients with untreated preoperative prostate cancer (Cohort 1, n=7) and patients with biochemical recurrence (Cohort 2, n=3). All subjects received a single dose of 3.7MBq/kg 18F-PSMA 1007. Results: 18F-PSMA 1007 was found to be safe and well tolerated in all subjects. No serous AEs or drug-related AEs were identified during the present study. The average blood radioactivity concentration reached a maximum of 47.87±1.05 (percentage of injected dose [%ID]/ml) at 5min and then decreased to 1.60±0.78 in 6h. The systemic radioactivity reached a maximum of 211.05±6.77 (%ID$\times$103) at 5min and decreased to 7.18±3.91 in 6h. The sensitivity and positive predictive value were 100% and 100% based on both pathologic and imaging confirmation as gold standard. In Cohort 1, 15 primary foci (11.9%) were >5mm in the largest diameter and identified in 39 of 126 segments (30.1%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for 60min uptake time acquisition were 80.0, 96.5, 91.4, 91.2 and 91.3%, respectively. Our study revealed that 18F-PSMA 1007 was safe, well tolerated and showed high accuracy in the diagnosis of prostate cancer.

Safety, Tolerability, and Pharmacokinetics of Belumosudil, a Selective Rho-associated Coiled-coil-containing Protein Kinase 2 Inhibitor, in Healthy Japanese Volunteers: A PhaseⅠ, Randomized, Controlled Trial

Safety, Tolerability, and Pharmacokinetics of Belumosudil, a Selective Rho-associated Coiled-coil-containing Protein Kinase 2 Inhibitor, in Healthy Japanese Volunteers: A PhaseⅠ, Randomized, Controlled Trial

Pharmacokinetics and Safety of Tucatinib in Healthy Japanese and Caucasian Volunteers: Results From a Phase Ⅰ Study

Pharmacokinetics and Safety of Tucatinib in Healthy Japanese and Caucasian Volunteers: Results From a Phase Ⅰ Study

Range of Motion Measurements of the Hip Joint Are Useful in Screening for Acetabular Dysplasia in Healthy Young Japanese Women.

The purpose of this study is to clarify whether a hip range of motion (ROM) measurement is useful in screening for early hip osteoarthritis with acetabular dysplasia (AD). Subjects were 58 healthy Japanese women volunteers (21.1 ± 0.7 (20 - 22)). We evaluated a total of 116 hip joints in these 58 cases. Sharp angle and centeredge angle were 44.1° ± 3.1° (37.0° - 51.5°) and 30.7°± 6.2° (19.5° - 47.0°), respectively. AD was present in 47.4%, but there were no severe cases. First, we compared the ROM of the hip joints with AD (AD group) and without AD (control group) according to the Mann-Whitney U test. Extension angles and external rotation angles in the AD group were significantly smaller than in the control group (18.9°± 6.1° VS. 22.1°± 4.2°, p= 0.01636, 26.3°± 8.9° VS. 34.1°± 8.8°, p= 0.001362, respectively). Next, we evaluated the following factors associated with AD by logistic regression analysis after adjustment for age: flexion, extension and internal and external rotation angles of the hip joint. As a result, internal rotation and external rotation were extracted as related factors. The area under the ROC curve was determined to have a moderate accuracy (0.72996). Cut off values of internal rotation and external rotation angles were 50 degrees and 35 degrees, respectively. Our findings suggest that ROM measurement of the internal and external rotation angles would be useful as a screening for AD in healthy young Japanese women without symptoms.

Processing speed test: Results from a Japanese normative sample of healthy participants compared with a US normative sample

BackgroundThe Processing Speed Test (PST), a validated iPad®-based cognitive screening test for MS, has been applied to the cognitive assessment of Japanese MS patients using US normative data. MethodsTo develop PST normative data from Japanese healthy volunteers and compare the PST score distribution between Japanese and US healthy volunteers, 254 healthy Japanese-speaking volunteers were enrolled and stratified by age (20–65 years). Potential participants with a Mini-Mental State Examination score < 27 were excluded. PST raw scores (total correct) were from the Japan cohort and compared with age-restricted US normative data and propensity score-matched data created by matching sex, age, and educational level from a published study of 428 healthy participants. PST score distributions and standardized z-scores were compared using t-test and Kolmogorov–Smirnov test statistics. ResultsThe mean age of the Japan cohort was 44.1 years. The PST scores of Japanese volunteers were significantly different from those of the age-restricted (mean ± SD 61.8 ± 10.1 vs 53.7 ± 10.8; p < 0.001) and the propensity score-matched US cohort (62.1 ± 10.1 vs 53.3 ± 10.6; p < 0.001). ConclusionRegression analyses centered on US normative data could underestimate disease severity in Japanese MS patients, suggesting that separate normative data should be considered for each population sample.

Efficacy of treatment with glucagon-like peptide receptor agonists-1 in Asian patients with type 2 diabetes mellitus

The projected 68% increase in patients with type 2 diabetes mellitus (T2D) in the upcoming decades and the specific pathophysiological course of the disease are critical factors for the development of optimal disease management tactics in the Asian population. It is now known that β-cell dysfunction is dominant in the pathogenesis of T2D in Asians. In a number of Asian countries, incretin therapy is the leading therapy. To review literature on glucagon-like peptide-1 (GLP-1) secretion and clinical trial results of GLP-1 receptor agonist class (GLP-1RA) drugs as well as to evaluate their effectiveness in Asian population with T2D. A review of studies on pathophysiological aspects of GLP-1 secretion and evaluation of the efficacy of therapy with GLP-1RA preparations registered and used in clinical practice in Asian regions. Several studies in Asian countries have shown that intact GLP-1 levels were significantly lower in both T2D patients and healthy Japanese volunteers; as well as in patients with impaired glucose tolerance. It is suggested that either impaired secretion of GLP-1 in the gut, accelerated processing by dipeptidyl peptidase-4, or a combination of both are responsible for the decrease in GLP-1. The greater efficacy of GLP-1RA treatment in achieving glycemic control in Asian T2D patients was presented by Kim Y.G. et al. in a meta-analysis of 15 randomised controlled trials, the reduction in HbA1c on GLP-1RA treatment averaged -1.16% in Asian-dominated studies and -0.83% in non-Asian-dominated studies. In the PIONEER 9 clinical programme, similar results were obtained, with oral semaglutide having a more pronounced effect on glycaemic control in Japanese patients. Thus, the mean change in HbA 1c was -1.1%, 7 mg -1.5%, and 14 mg -1.7% at the 3 mg dose; whereas in the PIONEER 1 study in the global population, the mean change in HbA1c was -0.6%, -0.9% and -1.1% for 3, 7, 14 mg semaglutide, respectively. The PIONEER 10 study concluded that oral semaglutide was well tolerated by Japanese patients with T2D. Oral semaglutide reduced HbA1c (14 mg dose) and body weight (7 and 14 mg doses) more significantly compared to dulaglutide at 0.75 mg dose. Results of a pooled analysis of long-acting GLP-1RA showed a more significant reduction in cardiovascular event risk in the Asian subpopulation. The presented review describes benefits in glycemic control as well as in the reduction of relative cardiovascular event risks with GLP-1RA treatment in the Asian population, which requires further in-depth research and implies optimal management tactics in patients with T2DM.

Bioequivalence Study of Ezetimibe Tablets After a Single Oral Dose of 10mg in Healthy Japanese Subjects Under Fasting Conditions.

This study compared the pharmacokinetic and safety profiles between a new generic and a branded reference product of 10-mg ezetimibe (EZE) tablets in 24 healthy Japanese male volunteers under fasting conditions, obtaining sufficient evidence for the marketing approval of the new generic product. The bioequivalence study was conducted with an open-label, 2 × 2, single-dose, crossover design in which the test and reference products were administered to volunteers after fasting for ≥10hours. Blood samples were collected 24 times before to 72hours after the administration of the investigational drug. We evaluated the peak drug concentration and the area under the plasma concentration-time curve up to the last measured concentration of EZE, EZEG, and total EZE (EZE + ezetimibe glucuronide [EZEG]). The 90% confidence intervals of the geometric mean ratios for peak drug concentration and area under the plasma concentration-time curve up to the last measured concentration of the test and reference products fell within the bioequivalence limits of 0.80 to 1.25 for EZE, EZEG, and total EZE. The test and reference products were well tolerated, and no adverse events occurred during the study. The test product was bioequivalent to the reference product.

Beta 1,3-1,6 Glucans Produced by Two Novel Strains of Aureobasidium Pullulans Exert Immune and Metabolic Beneficial Effects in Healthy Middle-aged Japanese Men: Results of an Exploratory Randomized Control Study.

In this pilot study, we have evaluated the specific metabolic and immune-related benefits of the AFO-202 strain and N-163 strain of black yeast Aureobasidium pullulans-produced beta 1,3-1,6 glucan in healthy human subjects. Sixteen healthy Japanese male volunteers (aged 40 to 60 years) took part in this clinical trial. They were divided into four groups (n = 4 each): Group I consumed AFO-202 beta-glucan (2 sachets of 1 g each per day), IA for 35 days and IB for 21 days; Group II consumed a combination of AFO-202 beta-glucan (2 sachets of 1 g each) and N-163 beta-glucan (1 sachet of 15 g gel each per day), IIA for 35 days and IIB for 21 days. Decrease in HbA1C and glycated albumin (GA), significant increase of eosinophils and monocytes and marginal decrease in D-dimer levels, decrease in neutrophil-to-lymphocyte ratio (NLR), with an increase in the lymphocyte-to-CRP ratio (LCR) and leukocyte-to-CRP ratio (LeCR) was observed in Group I between pre- and post-treatment. Decrease in total and LDL cholesterol, a decrease of CD11b, serum ferritin, galectin-3 and fibrinogen were profound in Group II between pre- and post-treatment. However, there was no statistically significant difference between day 21 and day 35 among the groups. This outcome warrants larger clinical trials to explore the potentials of these safe food supplements in the prevention and prophylaxis of diseases due to dysregulated metabolism, such as fatty liver disease, and infections such as COVID-19 in which balanced immunomodulation are of utmost importance, besides their administration as an adjunct to existing therapeutic approaches of both communicable and non-communicable diseases.

Seroepidemiological study of factors affecting anti-spike IgG antibody titers after a two-dose mRNA COVID-19 vaccination in 3744 healthy Japanese volunteers

Several factors related to anti-spike(S) IgG antibody titers after mRNA COVID-19 vaccination have been elucidated, but the magnitude of the effects of each factor has not been fully understood. This cross-sectional study assessed anti-S and anti-nucleocapsid (N) antibody titers on 3744 healthy volunteers (median age, 36 years; IQR, 24–49 years; females, 59.0%) who received two doses of mRNA-1273 or BNT162b2 vaccine and completed a survey questionnaire. Multiple regression was conducted to identify factors associated with antibody titers. All but one participant tested positive for anti-S antibodies (99.97%). The following factors were independently and significantly associated with high antibody titer: < 3 months from vaccination (ratio of means 4.41); mRNA-1273 vaccine (1.90, vs BNT162b2); anti-N antibody positivity (1.62); age (10’s: 1.50, 20’s: 1.37, 30’s: 1.26, 40’s: 1.16, 50’s: 1.15, vs ≧60’s); female (1.07); immunosuppressive therapy (0.54); current smoking (0.85); and current drinking (0.96). The largest impact on anti-S IgG antibody titers was found in elapsed time after vaccination, followed by vaccine brand, immunosuppressants, previous SARS-CoV-2 infection (anti-N antibody positive), and age. Although the influence of adverse reactions after the vaccine, gender, smoking, and drinking was relatively small, they were independently related factors.

346. CUTOFF VALUE OF THORACOABDOMINAL PRESSURE GRADIENT FOR GASTROESOPHAGEAL REFLUX DISEASE ON STARLET HIGH-RESOLUTION MANOMETRY

Abstract Derangement of thoracoabdominal pressure gradient (TAPG) associates with gastroesophageal reflux disease (GERD). High-resolution esophageal manometry (HRM) is the gold standard to assess pathophysiology of GERD. Starlet HRM is widely used in Japan; however, TAPG values on Starlet HRM system have been unstudied. The aim of this study is to propose the cutoff value of TAPG to discriminate GERD on Starlet HRM system. We included patients who underwent both Starlet HRM and 24-hour multichannel intraluminal impedance pH study (MII-pH) at our hospital between July 2018 and February 2022. Patients were divided into 3 groups; control group (both HRM and MII-pH were within normal limits), GERD group (acid exposure time [AET] ≥4.0% and/or DeMeester score ≥ 14.72), and non-pathological reflux group. Normal MII-pH values were defined according to our previous study using healthy Japanese volunteers (Yano, et al. Esophagus, 2017); AET &amp;lt;2.5%, DeMeester score &amp;lt; 11, and liquid reflux episodes &amp;lt;80.0. TAPG and adjusted TAPG were analyzed (shown in Figure). Total 102 patients met the study criteria (mean age 53.0 ± 16.0 years, 32 females). Thirty-four patients were categorized into the control group, 31 patients were into the GERD group, and 37 patients were into the non-pathological reflux group. In the control group, 5th and 95th percentiles of TAPG were − 3.4 and 24.3 mmHg, and those of adjusted TAPG were − 50.7 and 1.6 mmHg. TAPG poorly correlated with acid exposure time (AET) (rs = 0.287, p = 0.003); however, adjusted TAPG well-correlated with AET (rs = 0.505, p &amp;lt; 0.001). ROC analysis showed that the estimated cutoff of adjusted TAPG was −11.1 mmHg (sensitivity 71.0%, specificity 71.8%, AUC 0.742, p &amp;lt; 0.001). Adjusted TAPG is associated with antireflux competency across the esophagogastric junction. Estimated cutoff value of adjusted TAPG was −11.1 mmHg in the study cohort. Further study is warrantied.

Pharmacokinetics, safety, and tolerability of sodium phenylacetate and sodium benzoate in healthy Japanese volunteers: A phase I, single-center, open-label study

TAK-123, a combination of sodium phenylacetate (NaPA) and sodium benzoate (NaBZ), is an intravenously administered drug developed for the treatment of acute hyperammonemia in infants, children, and adults with urea cycle enzyme deficiencies. The aim of the current study was to evaluate the pharmacokinetics, safety, and tolerability after intravenous infusion of TAK-123 in Japanese healthy adult volunteers. Ten volunteers received a 3.75 g/m2 loading dose of TAK-123 over a period of 1.5 h followed by a maintenance infusion of the same dose over 24 h. Phenylacetate (PA) and benzoate (BZ) and their respective metabolites, phenylacetylglutamine (PAG) and hippurate (HIP) were measured over a 24-h period using a high-performance liquid chromatography/tandem mass spectrometry method. Non-compartmental analysis was performed using WinNonlin® Professional. During the loading dose, plasma levels of both PA and BZ peaked at 1.5 h. Plasma PA levels plateaued and were maintained up to 6.5 h, whereas plasma BZ levels declined rapidly after switching to maintenance infusion. Urinary excretion ratios of PAG and HIP at 48 h after the administration were 99.3% and 104%, respectively, suggesting that almost all NaPA and NaBZ were metabolized and excreted into urine. Overall, TAK-123 was well-tolerated in healthy Japanese adults.