Healthy Japanese Subjects Research Articles

A Pharmacokinetic Bioequivalence Study Comparing Different-Strength and -Size Capsules of Isavuconazonium Sulfate in Healthy Japanese Subjects.

Isavuconazonium sulfate is the water‐soluble prodrug of the novel, broad‐spectrum, triazole antifungal agent isavuconazole. A size 0 elongated hard capsule containing 100 mg equivalent of isavuconazole is the currently marketed oral formulation in countries where it is approved. An alternative oral formulation, based on a lower‐strength and smaller‐size capsule, is required for pediatric and adolescent patients, as well as for some adult Japanese patients, especially those with difficulties swallowing larger capsules. This study was conducted to evaluate the bioequivalence of a size 0 elongated capsule containing 100 mg equivalent of isavuconazole and a size 3 capsule containing 40 mg equivalent of isavuconazole, after administration of 200 mg equivalent of isavuconazole (5 size 3 capsules or 2 size 0 elongated capsules) under fasted conditions. Bioequivalence of isavuconazole between the formulations was demonstrated, since point estimates (90%CI) for the ratio of the size 0 elongated capsules vs the size 3 capsules for maximum plasma concentration and area under the plasma concentration–time curve from time 0 to the last quantifiable concentration were within the acceptable range of 0.8 to 1.25. It was confirmed that both formulations were well tolerated, and no new safety signals were observed in healthy Japanese adult male subjects.

Seasonal Variation in Thyroid Function in Over 7,000 Healthy Subjects in an Iodine-sufficient Area and Literature Review.

ContextSeasonal variation in thyroid function, especially serum free triiodothyronine (FT3) and free thyroxine (FT4) levels, in healthy subjects remains unclear.MethodsWe examined thyroid function, including serum FT3 and FT4 levels, in healthy Japanese subjects using data of more than 7,000 health check-up participants and applied the analysis of means with transformed ranks (ANOMTR) to compare each month. In addition, we reviewed reports published in the last 2 decades.ResultsThe median serum thyrotropin (TSH) level was the highest in January (1.61 mIU/L), and the lowest in May (1.16 mIU/L). ANOMTR revealed that serum TSH levels are high in winter and low in summer. Conversely, the median serum FT3 level was higher in July than in other months, and the ANOMTR plot demonstrated serum FT3 levels to be significantly higher in summer and lower in winter. In contrast, serum FT4 levels were more consistent throughout the year, but statistically, those in February and March, October, and November were higher than those in other months. ANOMTR revealed variations in serum FT4 levels to be small through the year but biphasic.ConclusionsTaken together with previous reports, our study demonstrated seasonal changes in the serum TSH levels to be high in winter in the northern hemisphere; however, the serum FT3 differed among countries, and those of Japanese, an iodine-sufficient country, were high in summer. In contrast, FT4 levels were more consistent. These changes should be taken into account to precisely evaluate thyroid function.

A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects.

Background and ObjectiveAMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects.MethodsThis was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg.ResultsFollowing oral administration, median time to maximum observed plasma concentration (tmax) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t½) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (Cmax) and AUC∞, respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity.ConclusionAMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-022-00386-3.

Evaluation of choroidal melanin-containing tissue in healthy Japanese subjects by polarization-sensitive optical coherence tomography

In this study, the choroidal melanin content in healthy eyes was evaluated with polarization-sensitive optical coherence tomography (PS-OCT). We evaluated 105 healthy eyes of 105 Japanese subjects. The mean thickness of melanin-containing tissue in the choroid (thickness of MeCh) and the choroidal melanin occupancy rate within a 5-mm circular region from the foveal center were calculated using the degree of polarization uniformity obtained by PS-OCT and compared with the choroidal thickness, patient age, and axial length. To evaluate regional variations, the 5-mm circular region was divided into a center area and an outer ring area, and the outer ring area was further divided into four areas (nasal, temporal, superior, and inferior). The mean thickness of MeCh showed a significant positive correlation with the choroidal thickness. The mean choroidal melanin occupancy rate showed a significant positive correlation with age. The mean choroidal melanin occupancy rate of the center area was significantly larger than that of the outer ring area. The mean thickness of MeCh and choroidal melanin occupancy rate of the nasal area were significantly lower than those of other areas. The distribution of melanin-containing tissue in the choroid varies significantly with age and location.

Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Isavuconazonium Sulfate in Healthy Adult Japanese Subjects.

Isavuconazonium sulfate is the water‐soluble prodrug of the novel, broad‐spectrum, triazole antifungal agent isavuconazole. This was a first‐in‐Japanese study assessing the pharmacokinetics, safety, and tolerability of isavuconazonium sulfate. The study was conducted in 2 parts: part 1 (single ascending dose; 100‐, 200‐, and 400‐mg equivalent of isavuconazole oral or intravenous administration); and part 2 (multiple doses for 16 days; 200‐mg equivalent of isavuconazole oral or intravenous administration; once‐daily administration with a loading regimen every 8 hours for the first 48 hours). A total of 60 and 16 subjects were randomized in part 1 and part 2, respectively. Observed clearance was lower in this study compared to what was previously reported in predominantly White populations and similar to clearance in non‐Japanese Asian populations. The range of the plasma isavuconazole concentration in this study was within the range of the pivotal phase 3 study, with no relationship between isavuconazole exposure and either efficacy or safety. There were no serious adverse events, and all reported treatment‐emergent adverse events were of mild intensity. This study confirmed that isavuconazonium sulfate was safe and well tolerated in healthy adult Japanese subjects.

Voxel-based analysis of age and gender effects on striatal [123I] FP-CIT binding in healthy Japanese adults.

Although previous studies have investigated age and gender effects on striatal subregional dopamine transporter (DaT) binding, these studies were mostly based on a conventional regions of interest-based analysis. Here, we investigated age and gender effects on striatal DaT binding at the voxel level, using a multicenter database of [(123)I] N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane ([(123)I] FP-CIT)-single photon emission computed tomography (SPECT) scans in 256 healthy Japanese adults. We used the Southampton method to calculate the specific binding ratios (SBRs) of each subject's striatum and then converted the [123I] FP-CIT SPECT images to quantitative SBRs images. To investigate the effects of age and gender effects on striatal DaT binding, we performed a voxel-based analysis using statistical parametric mapping. Gender differences were also compared between young to middle-aged subjects and elderly subjects (age threshold: 60years). When all subjects were explored as a group, DaT binding throughout the striatum decreased with advancing age. Among all subjects, the females showed higher DaT binding in the bilateral caudate compared to the males. In the young to middle-aged subjects, the females showed higher DaT binding throughout the striatum (with a slight caudate predominance) versus the males. In the elderly, there were no gender differences in striatal DaT binding. Our findings of striatal subregional age- and gender-related differences may provide useful information to construct a more detailed DaT database in healthy Japanese subjects.

Similar Pharmacokinetics and Pharmacodynamics of Biosimilar SAR342434 Insulin Lispro and Japan-Approved Humalog Insulin Lispro in Healthy Japanese Subjects.

This phase 1 study compared the pharmacokinetic (PK) and glucose pharmacodynamic (PD) characteristics of biosimilar SAR342434 insulin lispro and Japan‐reference Humalog insulin lispro. This was a randomized, double‐blind, 2‐period, crossover study. Thirty‐six healthy Japanese male subjects underwent a 10‐hour euglycemic clamp following a single subcutaneous 0.3‐U/kg dose of SAR342434 or Humalog. Insulin lispro concentration and blood glucose were measured, and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. Primary PK end points were maximum plasma insulin lispro concentration and area under the plasma insulin concentration–time curve (AUC) from time 0 to the last quantifiable concentration. Primary PD end points were area under the GIR–time curve from time 0 to 10 hours and maximum GIR. PK exposure (maximum plasma concentration and AUC from time 0 to the last quantifiable concentration) and PD activity (GIR‐AUC from time 0 to 10 hours and maximum GIR) were similar between treatments. Geometric mean ratios were close to 1, and the corresponding 90% and 95%CIs (PK and PD activity, respectively) were within the 0.80 to 1.25 equivalence range. SAR342434 and Humalog were well tolerated. In healthy Japanese males, SAR342434 and Humalog showed similar PK exposure profiles and PD potency, in support of SAR342434 use as a biosimilar product.

Oryza Ceramide® containing rice-derived glucosylceramides and a ceramide decreases cumulative days with cold symptoms in Japanese healthy subjects

Oryza Ceramide® containing rice-derived glucosylceramides and a ceramide decreases cumulative days with cold symptoms in Japanese healthy subjects

Effects of Genetic Polymorphisms of Cathepsin A on Metabolism of Tenofovir Alafenamide

Cathepsin A (CatA) is important as a drug-metabolizing enzyme responsible for the activation of prodrugs, such as the anti-human immunodeficiency virus drug Tenofovir Alafenamide (TAF). The present study was undertaken to clarify the presence of polymorphisms of the CatA gene in healthy Japanese subjects and the influence of gene polymorphism on the expression level of CatA protein and the drug-metabolizing activity. Single-strand conformation polymorphism method was used to analyze genetic polymorphisms in healthy Japanese subjects. Nine genetic polymorphisms were identified in the CatA gene. The polymorphism (85_87CTG>-) in exon 2 was a mutation causing a deletion of leucine, resulting in the change of the leucine 9-repeat (Leu9) to 8-repeat (Leu8) in the signal peptide region of CatA protein. The effect of Leu8 on the expression level of CatA protein was evaluated in Flp-In-293 cells with a stably expressed CatA, resulting in the expression of CatA protein being significantly elevated in variant 2 with Leu8 compared with Leu9. Higher concentrations of tenofovir alanine (TFV-Ala), a metabolite of TAF, were observed in the Leu8-expressing cells than in the Leu9-expressing cells using LC/MS/MS. Our findings suggest that the drug metabolic activity of CatA is altered by the genetic polymorphism.

Average gut flora in healthy Japanese subjects stratified by age and body mass index.

Imbalance of the gut microbiota plays an important role in the pathogenesis of various diseases. Although many clinical studies have analyzed the gut microbiota, the definition of normal gut microbiota remains unclear. In this study, we aim to establish the average gut microbiota in the healthy Japanese population. Using 16S ribosomal RNA gene sequencing, we analyzed gut microbial data from fecal samples obtained from 6,101 healthy Japanese individuals. Based on their ages, the individuals were divided into three groups: young, middle-age, and old. Individuals were further categorized according to body mass index (BMI) into lean, normal, and obese groups. The α and β diversities in the old group were significantly higher than those in the young and middle-age groups. The Firmicutes/Bacteroidetes ratio of subjects in the obese category was significantly lower compared with those of subjects in the lean and normal categories in the young and middle-age groups. Genus Bacteroides was the dominant gut microbiota across all the BMI categories in all the age groups. Among the top ten genera, the abundances of Bacteroides, Bifidobacterium, Anaerostipes, Blautia, Dorea, Fusicatenibacter, Lachnoclostridium, and Parabacteroides were significantly lower in the old group than in the young and middle-age groups. The correlation network at the genus level revealed different microbe-microbe interactions associated with age and BMI. We determined the average Japanese gut microbiota, and this information could be used as a reference. The gut microbiota greatly differs based on the life stage and metabolic status of the host, and this gives rise to a variety of host–gut microbe interactions that can lead to an increased susceptibility to disease.

628. Pharmacokinetics, Safety and Tolerability of Co-administration of Nacubactam and β-lactams after Multiple Doses in Japanese Healthy Subjects

BackgroundIncrease of carbapenem-resistant Enterobacterales (CRE) is a serious problem in the clinical setting and drugs which can treat patients with CRE are still limited. Nacubactam (OP0595) is a novel diazabicyclooctane-type β-lactamase inhibitor and being developed as a standalone drug to be co-administered with cefepime or aztreonam.MethodsA randomized, double-blind multiple dose study of nacubactam in co-administration with cefepime (Cohort 1) or aztreonam (Cohort 2) in Japanese healthy subjects was performed to assess pharmacokinetics, safety, and tolerability of co-administrations of nacubactam and cefepime or aztreonam. In each cohort, 6 subjects received 2 g of nacubactam and 2 g of concomitant drug (cefepime or aztreonam) and 2 subjects received placebo (saline) intravenously over 60 minutes, three times daily every 8 hours for 7 days. Plasma samples were collected and concentrations of each drug were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and the evaluation of changes from baseline in safety laboratory test results, 12-lead electrocardiograms (ECGs), vital signs, and physical examinations.ResultsProfiles of Cmax, tmax, AUC0-8, AUC0-∞ and t1/2 for nacubactam, cefepime and aztreonam are summarized in Table 1. Summary of Ctrough for nacubactam, cefepime and aztreonam are summarized in Table 2. Plasma concentrations of nacubactam, cefepime and aztreonam reached the steady-state by Day 4, and the mean accumulation ratios of Cmax and AUC0-8 on Day 7 to those of Day 1 were in the range of 0.91 to 1.10. As for the safety, no serious adverse event was observed in this study. There was 1 TEAE (seborrhoeic dermatitis) leading to the discontinuation in 1 subject in nacubactam/cefepime group, but it was judged as “Not related to study drug”.Table 1. PK profiles of nacubactam and concomitant drugs on Day 1 and Day 7 Table 2. Summary of Ctrough of nacubactam and concomitant drugs ConclusionIn conclusion, no remarkable change in pharmacokinetics was observed in each drug with multiple concomitant administration for 7 days and safety and tolerability of co-administrations of nacubactam and cefepime or aztreonam were confirmed. Based on these results, nacubactam is currently under further development.Disclosures All Authors: No reported disclosures

Pharmacokinetic and pharmacodynamic similarity between SAR341402 insulin aspart and Japan-approved NovoRapid in healthy Japanese subjects

This study compared the pharmacokinetic and glucodynamic profiles of biosimilar SAR341402 insulin aspart to Japan-approved insulin aspart (NovoRapid) in healthy Japanese males. In this single-center, randomized, double-blind, single-dose, two-period, crossover study, subjects received 0.3 U/kg of SAR341402 or NovoRapid before undergoing a 10 h euglycemic clamp procedure. Plasma insulin aspart concentrations and blood glucose levels were measured, and glucose infusion rates (GIRs) were assessed. Primary endpoints were maximum plasma insulin aspart concentration (INS-Cmax), area under the plasma insulin concentration–time curve to the last quantifiable concentration (INS-AUClast), area under the GIR–time curve during the clamp (GIR-AUC0–10 h), and maximum GIR (GIRmax). Forty subjects were randomized with 39 completing both treatment periods. Pharmacokinetic exposure showed a mean ratio between products of 1.00 (90% confidence interval [CI] 0.94–1.05) for INS-Cmax and 1.02 (90% CI 1.00–1.04) for INS-AUClast. Glucodynamic activity showed a mean ratio between products of 1.00 (95% CI 0.93–1.06) for GIR-AUC0–10 h and 1.01 (95% CI 0.95–1.08) for GIRmax. The 90% CIs for pairwise treatment ratios were within the predefined equivalence range of 0.80–1.25. Both treatments were well tolerated. We concluded that similar pharmacokinetic exposure and glucodynamic potency were shown for SAR341402 and NovoRapid in healthy Japanese males.

Lower limb alignment in healthy Japanese adults

BackgroundKnowledge regarding the normal alignment of the lower limb is important when considering alignment for total knee arthroplasty. However, few studies have explored the lower limb alignment of healthy Japanese subjects. MethodsBetween July and October 2020, we performed whole leg standing radiography of 120 legs of 60 healthy adult Japanese volunteers aged <50 years in the closed-leg stance. The measurement parameters were hip knee ankle angle (positive for varus), percentage of constitutional varus (hip knee ankle angle ≥ 3°), mechanical axis deviation ratio, mechanical lateral distal femoral angle, medial proximal tibial angle, joint line convergence angle (positive for lateral opening), and tibial joint line angle (positive for medial inclination). ResultsThe mean measured values for all volunteers, men and women, were as follows: hip knee ankle angle (°), 2.3, 2.6, and 2.0; mechanical axis deviation ratio, 35.8, 35.6, and 36.9; mechanical lateral distal femoral angle (°), 86.7, 87.0, and 86.7; medial proximal tibial angle (°), 85.6, 85.0, and 86.2; joint line convergence angle (°), 0.6, 0.3, and 0.8; and tibial joint line angle (°), −1.0, −0.7, −1.4, respectively. The percentage of constitutional varus was 35.8% overall, 35.8% in men and 35.3% in women. Only the medial proximal tibial angle was smaller in men than that in women (p = 0.003). ConclusionsThe mechanical lateral distal femoral and medial proximal tibial angles were smaller, hip knee ankle angle was larger, and percentage of constitutional varus was higher in Japanese subjects than those reported for subjects in other countries. Our findings improve the understanding of Japanese-specific alignments when considering alignment for lower limb surgery, especially, total knee arthroplasty.

Abstract 9741: Pharmacokinetics, Pharmacodynamics and Safety of Bempedoic Acid in a Phase 1 Clinical Trial in Healthy Japanese, Chinese and White Subjects

This study investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of bempedoic acid (BA), an inhibitor of ATP-citrate lyase that significantly lowers LDL-C levels, after single and multiple oral dose administration in White and first-, second-, or third-generation Japanese and Chinese subjects living in the US. This double-blind, placebo-controlled study was conducted at a single US site in a total of 40 healthy subjects randomized (3:1) to receive BA or placebo. The PK, PD, and safety of BA were assessed in Japanese subjects after a single dose of BA 60, 120, or 180 mg; and in Japanese, Chinese, and White subjects (baseline LDL-C 70–190 mg/dL; not receiving a statin) after daily BA 180-mg dosing for 14 days. Enrolled subjects (28% female) ranged 23-59 years of age. In Japanese subjects, single dose maximum BA plasma concentrations increased proportionally, and AUC increased slightly greater than proportional to dose. After 14 days of BA 180 mg, mean estimates of BA elimination half-life were 25.2, 20.0 and 23.9 hours in Japanese, Chinese, and White subjects, respectively. Active metabolite ESP15228 AUC exposures were approximately 20% of BA across subjects. Mean oral clearance (CL/F) in Japanese (0.494 L/h) and Chinese (0.592 L/h) subjects was 29% and 15% less and volume of distribution (V z /F) in Japanese (18.0 L) and Chinese (19.2 L) subjects was 32% and 27% less than in White subjects, respectively. Differences in CL/F and V z /F were decreased after body weight (BW) normalization, with higher mean BW for White subjects (80.6 kg) observed relative to Japanese (67.4 kg) and Chinese (74.1 kg) subjects. A reduction in fasting LDL-C, non-HDL-C, and hsCRP was observed with BA. The mean (SD) percent change from baseline in LDL-C among subjects (n=6 each) receiving BA 180 mg was –29% (14) for Japanese subjects, –39% (8) for Chinese subjects, and –17% (28) for White subjects compared with +17% (21) for subjects receiving placebo. Results from this study suggest that administration of BA 180 mg once daily over 14 days markedly reduced LDL-C and was well tolerated in all subjects. PK differences, largely explained after normalizing CL/F and V z /F by subject BW, are not expected to result in clinically meaningful differences in the efficacy or safety profiles of BA.

Pharmacokinetics and safety of cenobamate, a novel antiseizure medication, in healthy Japanese, and an ethnic comparison with healthy non-Japanese.

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

Determination of physiological cardiac myosin-binging protein levels (cMyc) in healthy populations

Abstract Background Cardiac myosin–binding protein C (cMyC) is a cardiac-restricted protein that has more abundant, rapid release and clearance kinetics than cardiac troponin. The current ESC guideline suggests the cMyC may provide value as an alternative to cardiac troponin. The 99th percentile value is universally endorsed as the reference cut off to aid in the diagnosis of acute myocardial infarction (AMI), however, none of the report of healthy population of cMyC. Purpose The aim of this study was to evaluate the distribution of cMyC values in healthy subjects. Methods We used two cohorts in this retrospective study. 1) Healthy subjects; a total of 500 subjects (250 men and 250 women) who had annual health examinations in 2012 in the area of Kamigoto, a suburb of Nagasaki city in Southern Japan were enrolled. All participants showed none of abnormal findings including cell blood counts, chemical analysis, liver function tests, general urine tests, occult blood tests of stool, barium swallow, mammography for women, abdominal ultrasound sonography, and electrocardiogram. All blood samples were obtained in a fasting state in the morning. 2) Chest pain subjects; we collected samples from 250 subjects including 50 with non-ST elevation myocardial infarction visited admitted to a university hospital for measurement of high-sensitivity troponin T and coronary artery assessment by coronary angiography. We measured cMyC level in both cohorts by HISCL™-800 system (Sysmex corporation, Japan). The assay has a limit of detection of 0.5 ng/L and a lower limit of quantification of 1.3 ng/L. Result In healthy subjects, median age (IQR) was 44 (20, 82) in men and 50 (23, 91) in women. The 99th percentile of cMyC was 27.3 ng/L, which was around one-third lower than that in previous report (87 ng/L). In chest pain subjects, the concentrations of cMyC at presentation were significantly higher in those with versus without AMI (median, 66 ng/L versus 10 ng/L, P&amp;lt;0.001). Discriminatory power for AMI, as quantified by the area under the receiver-operating characteristic curve (AUC), was comparable for cMyC (AUC, 0.85 (95% CI 0.79–0.91) and hs-cTnT (AUC, 0.81 (95% CI 0.76–0.88)). Conclusion We defined the normal range of cMyC in healthy Japanese subjects. The level of cMyC at presentation provides discriminatory power comparable to hs-cTnT in the diagnosis of AMI. To determine the physiological value of a biomarker may be necessary to evaluate enough information about their health status. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research

Pharmacokinetics and safety of rilpivirine in healthy Japanese subjects and exploration of ethnic sensitivity of rilpivirine pharmacokinetics with physiologically based pharmacokinetic model approach

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor, used for the treatment of human immunodeficiency virus type-1 infection. An open label study was conducted to investigate the pharmacokinetics (PK) and safety of a single oral dose of rilpivirine 25 mg in Japanese healthy adult subjects. No adverse events were reported. The mean Cmax (144.3 ng/mL) and AUCinf (4542 ng h/mL) in Japanese subjects were approximately 30 % higher than those reported from a similar study in Caucasian healthy subjects, whereas the median tmax and mean t1/2 values were comparable between studies. A simple physiologically based PK model was developed to characterize the rilpivirine PK profile. The model adequately described rilpivirine PK profiles, and well-predicted drug-drug interactions. With exploration using the model, body size and CYP3A4 abundance were identified as factors which explained the observed inter-ethnic difference in rilpivirine exposure. The inter-ethnic difference in rilpivirine exposure was however considered not clinically relevant, since inter-individual variabilities of those intrinsic factors are larger than inter-ethnic ones; and the observed AUCinf in Japanese subjects was within the range of AUCtau associated with efficacy and safety in Phase 3 studies. This study results support the use of rilpivirine without dose modification specific to Japanese patients.

Pharmacokinetics, Pharmacodynamics, and Tolerability of AZD5718, an Oral 5-Lipoxygenase-Activating Protein (FLAP) Inhibitor, in Healthy Japanese Male Subjects.

Background and ObjectiveAZD5718, a 5-lipoxygenase-activating protein (FLAP) inhibitor, is in clinical development for treatment of coronary artery disease (CAD) and chronic kidney disease (CKD). This study evaluated AZD5718 pharmacokinetics, pharmacodynamics, and tolerability in healthy male Japanese subjects.MethodsFour cohorts of eight Japanese subjects were randomized to receive oral doses of AZD5718 (60, 180, 360, and 600 mg) or matching placebo administered as a single dose on Day 1 and as once-daily doses from Day 3 to Day 10 in fasted conditions. Pharmacokinetic, pharmacodynamic, and safety data were collected.ResultsThe pharmacokinetics characteristics of AZD5718 in Japanese male subjects were similar to those reported in a previous study, and the pharmacokinetics were characterized as rapid absorption with median time to reach maximum concentration (Tmax) of 1–2 h Creatine-normalized urine maximum concentration (Cmax) with mean half-lives ranging from 8 to 21 h, and supra-proportional increase in exposure over the 60–600 mg dose range evaluated. Also, an increase in steady-state area under the concentration-time curve (AUC) compared to the first dose was observed. After both single and multiple doses of AZD5718, a clear dose/concentration-effect relationship was shown for urinary leukotriene E4 (LTE4) versus AZD5718 exposure with > 80 % inhibition at plasma concentrations in the lower nM range. No clinically relevant safety and tolerability findings were observed.ConclusionsThe observed pharmacokinetics and pharmacodynamics were similar to reported data for non-Japanese healthy subjects, which support further evaluation of AZD5718 at similar doses/exposures in Japanese and non-Japanese subjects for future evaluation in patients with CAD and CKD.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-021-01078-7.

Does reactogenicity after a second injection of the BNT162b2 vaccine predict spike IgG antibody levels in healthy Japanese subjects?

Adverse reactions are more common after the second injection of messenger RNA vaccines such as Pfizer/BioNTech's BNT162b2. We hypothesized that the degree and severity of reactogenicity after the second injection reflects the magnitude of antibody production against the SARS CoV-2 virus spike protein (spike IgG). Blood samples were obtained from 67 Japanese healthcare workers three weeks after the first injection and two weeks after the second injection of the BNT162b2 vaccine to measure spike IgG levels. Using questionnaires, we calculated an adverse event (AE) score (0-11) for each participant. The geometric mean of spike IgG titers increased from 1,047 antibody units (AU/mL) (95% confidence interval (95% CI): 855-1282 AU/mL) after the first injection to 17,378 AU/mL (95% CI: 14,622-20,663 AU/mL) after the second injection. The median AE score increased from 2 to 5. Spike IgG levels after the second injection were negatively correlated with age and positively correlated with spike IgG after the first injection. AE scores after the second injection were not significantly associated with log-transformed spike IgG after the second injection, when adjusted for age, sex, AE score after the first injection, and log-transformed spike IgG after the first injection. Although the sample size was relatively small, reactogenicity after the second injection may not accurately reflect antibody production.

Effects of Heat-Killed Levilactobacillus brevis KB290 in Combination with β-Carotene on Influenza Virus Infection in Healthy Adults: A Randomized Controlled Trial

Influenza, a seasonal acute respiratory disease caused primarily by the influenza virus A or B, manifests with severe symptoms leading to considerable morbidity and mortality and is a major concern worldwide. Therefore, effective preventive measures against it are required. The aim of this trial was to evaluate the preventive effects of heat-killed Levilactobacillus brevis KB290 (KB290) in combination with β-carotene (βC) on influenza virus infections in healthy Japanese subjects aged between 20 and 59 y throughout the winter season. We performed a randomized, double-blind, placebo-controlled, parallel-group trial from 16 December 2019 to 8 March 2020, comparing KB290 + βC beverage with placebo beverage. The primary endpoint was the incidence of influenza based on a doctor’s certificate. The incidence of influenza was not significantly different between the two groups. However, the subgroup analysis showed a significant difference between the two groups (influenza incidence: the KB290 + βC group 1.9%, and the placebo group 3.9%) in the subgroup of subjects aged ˂40 y, but not in the subgroup of subjects aged ≥40 y. The results of this trial suggest that the combination of KB290 and βC might be a possible candidate supplement for protection against the seasonal influenza virus infection in humans aged <40 y, although further clinical studies are needed to confirm the concrete preventive effect of this combination on influenza.