Healthy Japanese Participants Research Articles

Pharmacokinetics and safety of mavacamten in healthy Chinese participants with different CYP2C19 phenotypes.

Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II-III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This open-label, parallel-group, phase I trial aimed to determine the PK and safety of mavacamten in healthy Chinese participants with different CYP2C19 genotypes. The primary outcome was to define the PK of mavacamten in healthy Chinese participants; the secondary outcome was to examine safety and tolerability. After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, Cmax was reached within a median Tmax of 0.6-1.5 h, indicating rapid absorption. Inter-individual variability was moderate, and individuals carrying non-functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half-life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared with prior PK studies. No significant adverse events were observed in this study. Single oral administration of mavacamten at 15 mg was well tolerated across all CYP2C19 genotypes, and 25 mg dose was well tolerated in healthy participants with CYP2C19 genotypes UM/RM/NM. The PK profile of mavacamten in the healthy Chinese population was consistent with that in other healthy populations.

Racial Differences in Age-Related Changes in Left Ventricular Structural and Functional Echocardiographic Measurements Among Healthy Japanese and American Participants ― A Subanalysis of the World Alliance Society of Echocardiography Normal Values Study ―

Racial Differences in Age-Related Changes in Left Ventricular Structural and Functional Echocardiographic Measurements Among Healthy Japanese and American Participants ― A Subanalysis of the World Alliance Society of Echocardiography Normal Values Study ―

Monoglucosyl rutin, a flavonoid glycoside, improves low-density lipoprotein-cholesterol levels in healthy adults: A randomized controlled trial

Background: Atherosclerotic cardiovascular disease (ASCVD) continues to be a significant contributor to global mortality, impacting over 523 million individuals worldwide. Dyslipidemia stands as one of the foremost risk factors for ASCVD. Thus, prioritizing the reduction of low-density lipoprotein cholesterol (LDL-C) levels is essential in mitigating cardiovascular complications. Objective: This study aimed to evaluate the lipid-lowering activity of a dietary supplement containing monoglucosyl rutin (MR) in individuals with low to mild hypercholesterolemia. Methods: This was a randomized, placebo-controlled, double-blind, parallel-group study conducted from April 20 to December 24, 2022. The study population included 56 healthy Japanese adult participants with LDL-C levels between 120–139 mg/dL who were randomly allocated to either the MR or placebo groups (n = 28/group) using a computerized random number generator. 200 mg of MR or placebo divided into 3 tablets was given daily; participants were instructed to take 1 tablet with water after each meal for 12 weeks. The main focus was on measuring the serum LDL-C level as the primary outcome, with additional attention given to secondary outcomes such as serum high-density lipoprotein cholesterol (HDL-C), total cholesterol, and nonHDL-C levels. The study also evaluated the percentage of participants achieving serum LDL-C levels below 120 mg/dL after the 12-week intervention. Assessments were conducted after 4, 8, and 12 weeks of intervention. Results: There were 54 (27 in each group) participants in the per-protocol set (PPS) and 53 (placebo group, 26; MR group, 27) participants in the modified PPS (mPPS). A statistically significant group difference in serum LDL-C levels was observed (P < 0.05), with a 5.0% decrease from preintervention to after 12 weeks. The reduction in LDL-C levels coincided with (statistically significant?) decreases in total cholesterol levels, nonHDL-C levels, and the LDL-C/HDL-C ratio. During the study period, there was no adverse event or concern about the safety of MR. Conclusions: MR has potential as a preventive or therapeutic tool for improving improve long-term health and reducing cardiovascular morbidity. Keywords: monoglucosyl rutin, flavonoid glycoside, low-density lipoprotein cholesterol, hyperlipidemia, lipid profile Trial registration number: UMIN000047790

The Three-Dimensional Criteria of Developmental Dysplasia of the Hip Using the Functional Pelvic Plane Is More Useful Than That Using the Anterior Pelvic Plane.

Background: This retrospective cross-sectional study investigated the cutoff values (COVs) for developmental dysplasia of the hip (DDH) using a three-dimensional (3D) pelvic model reconstructed using computed tomography (CT). We included 107 healthy Japanese participants and 73 patients who had undergone curved periacetabular osteotomy (CPO) for DDH between 2012 and 2017. Methods: The hip CT images were adjusted to the anterior pelvic plane (APP), functional pelvic plane (FPP), sagittal anterior center-edge angle (ACEA), and sagittal posterior center-edge angle (PCEA). The lateral center-edge angle (LCEA), acetabular roof obliquity (ARO), anterior acetabular sector angle (AASA), and posterior acetabular sector angle (PASA) were measured. Receiver operating characteristic (ROC) curves were used to calculate the COVs, and the association between the parameters was analyzed using multiple logistic regression. Results: The ARO (≥10.2°) and LCEA (≤22.2°) were independent influencing factors for the APP, whereas the AASA (≤53.1°) and LCEA (≤24.5°) were independent influencing factors for the FPP. Conclusions: The 3D criteria for the diagnosis of DDH in Japanese individuals can identify DDH with insufficient anterior coverage, which anteroposterior plain radiographs cannot visualize, and can help determine indications for acetabular osteotomy.

Pharmacokinetics, Safety, and Tolerability of Cedirogant in Healthy Japanese and Chinese Adults.

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 395mg. The multiple doses evaluated in both healthy Japanese and Chinese participants was 375mg 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 375mg 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.

Pharmacokinetics of Ubrogepant in Healthy Japanese and White Adults.

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 100mg in Japanese participants. White participants were randomly assigned to ubrogepant (100mg) or placebo. Dose proportionality was observed in the dose range of 25-100mg 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 (25-100mg) had a safety profile similar to placebo, and no differences in the safety profile of ubrogepant 100mg were observed between Japanese versus White participants.

Comparability of Elezanumab Safety, Tolerability, and Pharmacokinetics in Healthy Japanese, Chinese, and White Participants.

Elezanumab is a fully human monoclonal antibody, which is directed against repulsive guidance molecule A. The safety, tolerability, pharmacokinetics (PK), and immunogenicity of elezanumab were assessed in 2 Phase 1 clinical studies. The objective of this study was to assess the PK, safety, tolerability, and immunogenicity following intravenous infusion of elezanumab in healthy adult Japanese, Han Chinese, and Caucasian participants as well as Western participants from the single-ascending-dose study. Elezanumab exposures were approximately 20% higher in Japanese and Han Chinese participants compared to White participants without controlling for body weight. After statistically controlling for body weight by including it as a covariate, the PK of elezanumab in White participants were comparable to those in Japanese and Han Chinese participants. The clinical implications of these exposure differences are yet to be determined. All adverse events were assessed by the investigator as having no reasonable possibility of being related to the study drugs and were mild in severity. No positive immunogenicity effect was observed that impacted elezanumab exposure or safety.

Acetaldehyde-mediated increase in glutamatergic and N-acetylaspartate neurometabolite levels in the midcingulate cortex of ALDH2*1/*2 heterozygous young adults.

To elucidate the neurobiology underlying alcohol's effect on the human brain, we examined the acute effects of moderate alcohol administration on levels of glutamatergic neurometabolites and N-acetylaspartate, an amino acid found in neurons, may reflect disordered neuronal integrity. Eighteen healthy Japanese participants (7 males/11 females) aged 20-30 years who were heterozygous for an inactive allele of acetaldehyde dehydrogenase-2 (ALDH/*1/*2) were included. Participants underwent an intravenous alcohol infusion using the clamp method at a target blood alcohol concentration (BAC) of 0.50 mg/mL for 90 min within a range of ±0.05 mg/mL. We examined glutamate + glutamine (Glx) and N-acetylaspartate N-acetylaspartylglutamate (NAA) levels in the midcingulate cortex (MCC) using 3 T 1 H-MRS PRESS at baseline, 90 min, and 180 min (i.e., 90 min after alcohol infusion was finished). A two-way repeated-measures analysis of variance was used to assess longitudinal changes in Glx and NAA levels, with time and sex as within- and between-subject factors, respectively. Pearson's correlation coefficients were calculated among neurometabolite levels and BAC or blood acetaldehyde concentration (BAAC). Both Glx (F(2,32) = 8.15, p = 0.004, η2 = 0.15) and NAA (F(2,32) = 5.01, p = 0.04, η2 = 0.07) levels were increased after alcohol injection. There were no sex or time × sex interaction effects observed. NAA levels were positively correlated with BAAC at 90 min (r(13) = 0.77, p = 0.01). There were no associations between neurometabolite levels and BAC. Both Glx and NAA levels in the MCC increased in response to the administration of moderate concentrations of alcohol. Given positive associations between NAA levels and BAAC and the hypothetical glutamate release via dopamine pathways, the effects of drinking on the MCC in the acute phase may be ascribed to acetaldehyde metabolized from alcohol.

Pharmacokinetics, pharmacodynamics and safety profile of the dual orexin receptor antagonist vornorexant/TS-142 in healthy Japanese participants following single/multiple dosing: Randomized, double-blind, placebo-controlled phase-1 studies.

The pharmacokinetics, pharmacodynamics and safety profile of vornorexant were investigated in healthy Japanese participants in three double-blind studies: a single ascending dose of 1-30 mg (Study 101; n = 6) and multiple ascending doses of 10-30 mg (Study 102; n = 6). Study 202 consisted of two steps: an open-label, 20 mg repeated-dose in non-elderly individuals (Step 1; n = 12) and a double-blind, 20 mg repeated-dose in elderly individuals (Step 2; n = 8/3 for vornorexant/placebo). Vornorexant was rapidly absorbed and eliminated under fasting conditions, with a time to maximum plasma concentration of 0.500-3.00 h (range) and elimination half-life of 1.32-3.25 h. The area under the plasma concentration-time curve (AUC) of vornorexant increased proportionally with dose increments. Sleepiness-related pharmacodynamic outcome changes (Karolinska sleepiness scale, digit symbol substitution test and psychomotor vigilance task) were generally increased with dose increments at 1 and 4 h post-dose, whereas no consistent dose-related changes were detected the next morning. Food intake did not affect the maximum observed plasma concentration of vornorexant but increased the AUC0-inf . Exposure in elderly individuals was generally comparable to that in non-elderly individuals. Altogether, vornorexant may have a favourable profile for insomnia treatment, including rapid onset of action and minimal next-day residual effects.

Pharmacokinetics and Bioequivalence of Mirogabalin Orally Disintegrating Tablets and Conventional Tablets in Healthy Japanese Participants.

This single-center, randomized, open-label, single-dose, 2-group, 2-stage crossover trial evaluated the bioequivalence of 15mg of mirogabalin as orally disintegrating tablets (ODTs) with conventional mirogabalin tablets in healthy Japanese men. The trial involved two studies: in Study 1, the ODT formulation was taken without water, and in Study 2, the ODT formulation was taken with water. The conventional tablet was taken with water in both studies. We investigated the pharmacokinetic parameters and bioequivalence of the 2 formulations, including the maximum plasma concentration and the area under the plasma concentration-time curve up to the last quantifiable time. The plasma concentrations of mirogabalin were determined by a validated liquid chromatography with tandem mass spectrometry method. A total of 72 participants were enrolled and completed the trial. The geometric least-squares mean ratios of maximum plasma concentration of the ODT formulation to the conventional formulation were within the prespecified bioequivalence range of 0.80-1.25 (Study 1, 0.995; Study 2, 1.009), as was the area under the plasma concentration-time curve up to the last quantifiable time (Study 1, 1.023; Study 2, 1.035). No serious adverse events were observed. In conclusion, mirogabalin 15-mg ODTs, either with or without water, were bioequivalent to conventional 15-mg tablets.

Protection of Liver Functions and Improvement of Kidney Functions by Twelve Weeks Consumption of Cuban Policosanol (Raydel®) with a Decrease of Glycated Hemoglobin and Blood Pressure from a Randomized, Placebo-Controlled, and Double-Blinded Study with Healthy and Middle-Aged Japanese Participants.

Policosanol consumption has been associated with treating blood pressure and dyslipidemia by increasing the level of high-density lipoproteins-cholesterol (HDL-C) and HDL functionality. Although policosanol supplementation also ameliorated liver function in animal models, it has not been reported in a human clinical study, particularly with a 20 mg doage of policosanol. In the current study, twelve-week consumption of Cuban policosanol (Raydel®) significantly enhanced the hepatic functions, showing remarkable decreases in hepatic enzymes, blood urea nitrogen, and glycated hemoglobin. From the human trial with Japanese participants, the policosanol group (n = 26, male 13/female 13) showed a remarkable decrease in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from baseline up to 21% (p = 0.041) and 8.7% (p = 0.017), respectively. In contrast, the placebo group (n = 26, male 13/female 13) showed almost no change or slight elevation. The policosanol group showed a 16% decrease in γ-glutamyl transferase (γ-GTP) at week 12 from the baseline (p = 0.015), while the placebo group showed a 1.2% increase. The policosanol group exhibited significantly lower serum alkaline phosphatase (ALP) levels at week 8 (p = 0.012), week 12 (p = 0.012), and after 4-weeks (p = 0.006) compared to those of the placebo group. After 12 weeks of policosanol consumption, the ferric ion reduction ability and paraoxonase of serum were elevated by 37% (p < 0.001) and 29% (p = 0.004) higher than week 0, while placebo consumption showed no notable changes. Interestingly, glycated hemoglobin (HbA1c) in serum was lowered significantly in the policosanol group 4 weeks after consumption, which was approximately 2.1% (p = 0.004) lower than the placebo group. In addition, blood urea nitrogen (BUN) and uric acid levels were significantly lower in the policosanol group after 4 weeks: 14% lower (p = 0.002) and 4% lower (p = 0.048) than those of the placebo group, respectively. Repeated measures of ANOVA showed that the policosanol group had remarkable decreases in AST (p = 0.041), ALT (p = 0.008), γ-GTP (p = 0.016), ALP (p = 0.003), HbA1c (p = 0.010), BUN (p = 0.030), and SBP (p = 0.011) from the changes in the placebo group in point of time and group interaction. In conclusion, 12 weeks of 20 mg consumption of policosanol significantly enhanced hepatic protection by lowering the serum AST, ALT, ALP, and γ-GTP via a decrease in glycated hemoglobin, uric acid, and BUN with an elevation of serum antioxidant abilities. These results suggest that improvements in blood pressure by consumption of 20 mg of policosanol (Raydel®) were accompanied by protection of liver function and enhanced kidney function.

Evaluation of the Drug-Drug Interaction Potential of Ensitrelvir Fumaric Acid with Cytochrome P450 3A Substrates in Healthy Japanese Adults.

Management of drug-drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day -2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day -2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study. The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications. Japan Registry of Clinical Trials identifier: jRCT2031210202.

The Validation of Automated Social Skills Training in Members of the General Population Over 4 Weeks: Comparative Study.

Social skills training by human trainers is a well-established method of teaching appropriate social and communication skills and strengthening social self-efficacy. Specifically, human social skills training is a fundamental approach to teaching and learning the rules of social interaction. However, it is cost-ineffective and offers low accessibility, since the number of professional trainers is limited. A conversational agent is a system that can communicate with a human being in a natural language. We proposed to overcome the limitations of current social skills training with conversational agents. Our system is capable of speech recognition, response selection, and speech synthesis and can also generate nonverbal behaviors. We developed a system that incorporated automated social skills training that completely adheres to the training model of Bellack et al through a conversational agent. This study aimed to validate the training effect of a conversational agent-based social skills training system in members of the general population during a 4-week training session. We compare 2 groups (with and without training) and hypothesize that the trained group's social skills will improve. Furthermore, this study sought to clarify the effect size for future larger-scale evaluations, including a much larger group of different social pathological phenomena. For the experiment, 26 healthy Japanese participants were separated into 2 groups, where we hypothesized that group 1 (system trained) will make greater improvement than group 2 (nontrained). System training was done as a 4-week intervention where the participants visit the examination room every week. Each training session included social skills training with a conversational agent for 3 basic skills. We evaluated the training effect using questionnaires in pre- and posttraining evaluations. In addition to the questionnaires, we conducted a performance test that required the social cognition and expression of participants in new role-play scenarios. Blind ratings by third-party trainers were made by watching recorded role-play videos. A nonparametric Wilcoxson Rank Sum test was performed for each variable. Improvement between pre- and posttraining evaluations was used to compare the 2 groups. Moreover, we compared the statistical significance from the questionnaires and ratings between the 2 groups. Of the 26 recruited participants, 18 completed this experiment: 9 in group 1 and 9 in group 2. Those in group 1 achieved significant improvement in generalized self-efficacy (P=.02; effect size r=0.53). We also found a significant decrease in state anxiety presence (P=.04; r=0.49), measured by the State-Trait Anxiety Inventory (STAI). For ratings by third-party trainers, speech clarity was significantly strengthened in group 1 (P=.03; r=0.30). Our findings reveal the usefulness of the automated social skills training after a 4-week training period. This study confirms a large effect size between groups on generalized self-efficacy, state anxiety presence, and speech clarity.

Age- and sex-stratified normal values for circulatory and ventilatory power during ramp exercise derived from a healthy Japanese population.

Circulatory power (CP) and ventilatory power (VP), obtained by cardiopulmonary exercise testing (CPX), have been suggested to be excellent prognostic markers for heart failure. However, the normal values of these parameters in healthy Japanese populations remain unknown; thus, we aimed to investigate these values in such a population. A total of 391 healthy Japanese participants, 20-78years of age, underwent CPX with a cycle ergometer with ramp protocols. Systolic blood pressure (SBP), heart rate, oxygen uptake ([Formula: see text]O2) at peak exercise, and the slope of minute ventilation ([Formula: see text]E) versus carbon dioxide ([Formula: see text]CO2) ([Formula: see text]E vs. [Formula: see text]CO2 slope) were measured. CP was calculated by multiplying the peak [Formula: see text]O2 and SBP values, and VP was calculated by dividing the peak SBP value by the [Formula: see text]E versus [Formula: see text]CO2 slope. For males and females, the average CP values were 6119 ± 1280 (mean ± standard deviation) and 4775 ± 914mmHg·mL/min/kg, respectively (p < 0.001). The average VP values for males and females were 8.0 ± 1.3 and 6.9 ± 1.3mmHg (p < 0.001). CP decreased with age in both sexes. VP increased with age in females, with no significant change in males. We calculated the normal values for CP and VP in a healthy Japanese population. The results can contribute to the evaluation of patients' CPX results as a reference.

Seasonal Variation and Thyroid Function Testing: Source of Misdiagnosis and Levothyroxine Over-Prescription.

Thyroid function tests are some of the most commonly ordered tests in the USA (1). Meanwhile, levothyroxine is also the most prescribed drug in the USA, with an estimated 23 million people who have an active prescription (2). However, studies have raised concerns about levothyroxine overuse, with some suggesting that approximately 90% of prescriptions are inappropriate because they were given to patients with mild subclinical hypothyroidism or who were euthyroid without significant changes in patterns over time or any improvement in health-related quality of life (2). The recent publication by Yamada et al. (3) in the Journal of the Endocrine Society describes the effect of seasonal variation in thyroid function results in >7000 healthy Japanese participants and directly links that to a fraction of subclinical dysfunction diagnoses (subclinical hyperthyroidism and subclinical hypothyroidism). This study showed that thyrotropin-stimulating hormone (TSH) varies widely throughout the seasons, peaking in the winter months (January–February) with its nadir in the summer months (June–August). However, free thyroxine (Free T4) was relatively stable. These seasonal changes in healthy individuals, with TSH going up while Free T4 remains stable, are not captured by our reference intervals and may lead to false diagnoses of subclinical hypothyroidism and unnecessary prescriptions of levothyroxine to euthyroid individuals. This is clearly demonstrated in Yamada et al.’s study, in which the healthy population’s upper 97.5th percentile ranges for TSH exceeded the manufacturer-recommended limit for the months of January and February, leading to higher rates of subclinical hypothyroidism diagnoses. In addition to seasonal variability, there are other factors associated with TSH variation that may contribute to misdiagnoses, including: age, sex, time-of-day, and transient elevation during nonthyroidal illness (4).

Abstract P555: Variants of Neurocan, a Nonalcoholic Fatty Liver Disease Risk Allele, Are Associated With Plaque Development in the Carotid Artery Over 5 Years

Introduction: Nonalcoholic fatty liver disease (NAFLD) genetic risk alleles are associated with lipid metabolism. However, the association between those variants and atherosclerosis has not yet been fully evaluated. Hypothesis: We hypothesized that NAFLD risk alleles are associated with the progression of atherosclerosis. Methods: A total of 1,050 Japanese men and women (median age 55 years and median body mass index 22.9 kg/m2) free of cardiovascular disease, dyslipidemia, hypertension, and diabetes were studied. . Among NAFLD risk SNPs, variants of patatin-like phospholipase domain containing 3 ( PNPLA3 ), transmembrane 6 superfamily member 2 ( TM6SF2 ), glucokinase regulator ( GCKR ), and neurocan ( NCAN ) were assessed. Plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), small dense LDL-C, LDL-triglycerides, high-density lipoprotein cholesterol (HDL-C), HDL3-C, triglycerides, remnant-like particle cholesterol, lipoprotein(a), and adiponectin were also measured. At both baseline and after a five-year follow-up, carotid intima-media thickness (cIMT) was assessed. Atherosclerosis was defined as cIMT ≥ 1.1mm or the presence of a plaque. Univariate and multivariate analyses and chi-square and Fisher’s exact tests were performed to examine the associations between NAFLD risk SNPs, lipoproteins, and progression of atherosclerosis. Results: Both median and maximum cIMT of total participants did not differ between baseline and after a five-year follow-up. Among participants without atherosclerosis at baseline, the rate of plaque development was 13.8% (121/880) with the major allele (CC) of NCAN being significantly higher than other alleles. Variants of NCAN were associated with the development of plaque ( P = 0.04, Fisher’s exact test). Participants with the CT allele of NCAN had significantly lower RLP cholesterol at baseline than those with the CC allele (7.6 mg/dl vs. 10.5 mg/dl, P = 0.02). Variants of PNPLA3 , TM6SF2 , GCKR , and NCAN were not associated with changes in lipoproteins. Conclusions: A NCAN variant, one of the NAFLD risk SNPs, was associated with the development of plaque independent of lipoprotein alterations among healthy Japanese participants.

Pharmacokinetic, Safety, and Tolerability Evaluations of Gepotidacin (GSK2140944) in Healthy Japanese Participants.

Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic in late-phase development for uncomplicated urinary tract infection and uncomplicated urogenital gonorrhea. Two clinical studies were conducted to assess the pharmacokinetics (PK) and interethnic comparisons of oral gepotidacin (free-base and to-be-marketed mesylate formulations) administered as single doses ranging from 1500 to 3000mg in fed and fasted states, and as 2×3000-mg doses given 12hours apart under fed conditions in healthy participants of Japanese ancestry. Dose proportionality was observed in plasma exposures, and comparable area under the concentration-time curve (AUC) and maximum concentration were observed in fed and fasted states. Interethnic comparisons for Japanese versus non-Japanese participant data showed slightly higher plasma maximum concentration (7%-30%) yet similar plasma AUCs; slightly lower urine AUCs (11%-18%) were observed. The slightly higher plasma exposures in healthy Japanese versus White participants in the same study were attributed to lower mean body weights (64kg versus ≈80kg). Adverse events were primarily gastrointestinal, and when administered with food, gastrointestinal tolerability was improved. Overall, the gepotidacin PK and safety-risk profiles in healthy Japanese support potential evaluation of the global clinical doses in future studies.

Comparability of Foslevodopa/Foscarbidopa Pharmacokinetics in Healthy Asian and White Participants.

This phase 1 study assessed the safety, tolerability, and pharmacokinetics of a single 24-hour continuous subcutaneous dose of foslevodopa/foscarbidopa in healthy adult Japanese (N = 24), Han Chinese (N = 8), and White (N = 24) participants. Three doses of foslevodopa/foscarbidopa were evaluated in healthy participants for this study: 480/24, 960/48, and 1440/72 mg/day. Serial blood samples for measurement of levodopa, carbidopa, foslevodopa, foscarbidopa, and 3-O-methyldopa concentrations were collected for 48 hours after foslevodopa/foscarbidopa administration. Safety and tolerability were assessed throughout the study. Point estimates for ratios of central values indicated that the exposure difference between Japanese and White participants was <10%. The maximum concentration and area under the plasma concentration-time curve for both LD and CD following foslevodopa/foscarbidopa continuous subcutaneous infusion were comparable between Han Chinese and White participants. Point estimates for ratios of central values indicated that the exposure difference between Han Chinese and White participants was <14%. The regimens tested were generally well tolerated, and no new safety issues were identified in this study. There were no clinically meaningful differences in LD and CD exposures or pharmacokinetics following administration of foslevodopa/foscarbidopa among White, Japanese, and Han Chinese participants.

Abstract 11228: Association Between Nonalcoholic Fatty Liver Disease Risk Alleles and Atherosclerosis

Introduction: Nonalcoholic fatty liver disease (NAFLD) risk alleles are associated with lipid metabolisms. However, the association between those variants and atherosclerosis has not yet been fully evaluated. Hypothesis: We hypothesized that NAFLD genetic risk alleles are associated with the progression of atherosclerosis. Methods: A total of 1,050 Japanese men and women (median age 55 years and median body mass index 22.9 kg/m2) free of cardiovascular disease, dyslipidemia, hypertension, and diabetes were studied. Among NAFLD risk SNPs, variants of patatin-like phospholipase domain containing 3 ( PNPLA3 ), transmembrane 6 superfamily member 2 ( TM6SF2 ), glucokinase regulator ( GCKR ), and neurocan ( NCAN ) were assessed. Plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), small dense LDL-C, LDL-triglycerides, high-density lipoprotein cholesterol (HDL-C), HDL3-C, triglycerides, remnant-like particle cholesterol, lipoprotein(a), and adiponectin were also measured. At both baseline and after a five-year follow-up, carotid intima-media thickness (cIMT) was assessed. Atherosclerosis was defined as cIMT more than 1.1mm or the presence of a plaque. Univariate and multivariate analyses and chi-square and Fisher’s exact tests were performed to examine the associations between NAFLD risk SNPs, lipoproteins, and progression of atherosclerosis. Results: Both median and maximum cIMT of total participants did not differ between baseline and after a five-year follow-up. Among participants without atherosclerosis at baseline, the rate of plaque development was 13.8% (121/880) with the major allele (CC) of NCAN being significantly higher than other alleles. Variants of NCAN were associated with the development of plaque ( P = 0.04, Fisher’s exact test). Variants of PNPLA3 , TM6SF2 , GCKR , and NCAN were not associated with changes in lipoproteins. Conclusions: A NCAN variant, one of the NAFLD risk SNPs, was associated with the development of plaque independent of lipoproteins alterations among healthy Japanese participants.

Pharmacokinetics and pharmacodynamics of once-weekly administration of JR-142, a long-acting albumin-fused human growth hormone: A rondemized, placebo-controlled phase 1 study

ObjectiveUnder clinical development for patients with growth hormone deficiency, JR-142 is a long-acting growth hormone with a half-life extended by fusion with modified serum albumin. We conducted a Phase 1 study to investigate the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of once-weekly subcutaneous administrations of JR-142. The study consisted of two parts: an open-label single ascending dosing study (Part 1), and a randomized, placebo-controlled, assessor-blinded multiple ascending dosing study (Part 2). DesignA total of 31 healthy Japanese male participants were enrolled. In Part 1, seven of them received a single subcutaneous injection of JR-142 each at dosages of 0.15 mg/kg (n = 1), 0.25 mg/kg (n = 2), 0.5 mg/kg (n = 2), or 1.0 mg/kg (n = 2). In Part 2, one weekly subcutaneous injection of JR-142 at 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg or a placebo were given for four weeks to each of the other 24 participants (six in each group). Plasma JR-142 and serum insulin-like growth factor-1 (IGF-1) concentrations were measured for PK and PD assessments. Safety was evaluated on the basis of adverse events (AEs), laboratory tests, and other measures. ResultsJR-142 induced dose-dependent increases in the maximum plasma JR-142 concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to τ (AUC0-τ). A similar dose-response relationship was observed in serum IGF-1 concentrations. All trough IGF-1 levels were well sustained one week after the final administrations of JR-142 at the three dosages, while the peak concentrations of IGF-1 remained mildly elevated. No serious AEs were observed, and laboratory tests, including assessment of anti-drug antibodies, uncovered no significant safety issues. ConclusionsOnce-weekly subcutaneous injections of JR-142 produced positive dose-dependent PK and PD profiles over the dosage range. Drug accumulation was observed after the four-week administration period but did not raise safety concerns, indicating that JR-142 is well-tolerated in healthy participants. The PD profiles observed in terms of IGF-1 concentrations were also positive, and we believe the encouraging results of this study warrant substantiation in further clinical trials in patients with GHD. EthicsThis clinical study was conducted at one investigational site in Osaka, Japan, where the clinical study and the non-clinical data of JR-142 were reviewed and approved by its Institutional Review Board on 9th May 2019. The study was conducted in compliance with the approved study protocol, the Declaration of Helsinki, 1964, as revised in 2013, and Good Clinical Practice.