Comparison of self-reported symptoms in COVID-19 patients who had or had not previously received COVID-19 mRNA vaccination.

Although mRNA coronavirus disease 2019 (COVID-19) vaccines have been reported for high effectiveness against symptoms, it remains unclear whether post-vaccination infections are less symptomatic than infections in vaccine-naive individuals. We included patients with COVID-19 diagnosed by polymerase chain reaction tests during Japan's alpha and delta variant epidemics. COVID-19 symptoms at approximately 4 weeks were compared based on COVID-19 vaccination status. In total, 398 cases (372 symptomatic and 26 asymptomatic; 286 unvaccinated, 66 vaccinated with one dose, and 46 with two doses) were analyzed. The most common symptoms were fever (78.4%), fatigue (78.4%), cough (74.4%), loss of taste or smell (62.8%), and headache (59.8%). Post-vaccination infections were significantly less likely to be symptomatic. Possible confounder-adjusted odds ratios of two vaccine doses against fatigue, dry eyes and mouth, insomnia, fever, shortness of breath, unusual muscle pains, and loss of taste or smell were 0.18 (95% confidence interval [CI]: 0.09-0.38), 0.22 (95% CI: 0.08-0.59), 0.33 (95% CI: 0.14-0.80), 0.31 (95% CI: 0.15-0.63), 0.36 (95% CI: 0.16-0.76), 0.40 (95% CI: 0.19-0.82), and 0.44 (95% CI: 0.22-0.87), respectively. Post-vaccination infections after two mRNA COVID-19 vaccine doses show milder and fewer symptoms than infections in unvaccinated patients, highlighting the effectiveness of vaccination.

Effectiveness of Live Attenuated Varicella-Zoster Vaccine in Adults Older than 50 Years in Japan: A Retrospective Cohort Study.

Background: In Japan, freeze-dried live attenuated varicella-zoster vaccine BIKEN is available for adults aged ≥50 years to prevent herpes zoster (HZ). A prospective cohort study of 1200 healthy adults and 300 patients with underlying illness confirmed vaccine safety between 2016 and 2017. However, evidence of vaccine effectiveness (VE) is limited. Methods: VE against HZ and postherpetic neuralgia (PHN) was evaluated in the vaccinated cohort of the previous safety study in a follow-up study between 2021 and 2022 and compared with unvaccinated family members. Self-administered questionnaires determined retrospective experiences of HZ and PHN diagnosis. Logistic regression estimated the VE by calculating the outcome odds ratio (OR) in vaccinated vs. unvaccinated groups: VE = (1 - OR) × 100(%). Results: Overall, 1098 vaccinated and 518 unvaccinated subjects were analysed. Between 2016 and 2022, 26 vaccinated (2.4%) and 22 unvaccinated (4.2%) subjects reported HZ diagnosis, and 3 vaccinated (0.3%) and 2 unvaccinated (0.4%) subjects reported PHN. Adjusted VE against a clinical diagnosis was 41% for HZ [-6% to 67%], with marginal significance, and 16% [-408% to 86%] for PHN. Stratification by age, sex, or comorbidities had an adjusted VE against HZ of ~40%, which was similar between strata. Conclusion: Freeze-dried live attenuated varicella-zoster vaccine reduces the risk of HZ regardless of age, sex, or comorbidities.

Real-World Effectiveness of the mRNA COVID-19 Vaccines in Japan: A Case-Control Study.

The real-world effectiveness of the coronavirus disease 2019 (COVID-19) vaccines in Japan remains unclear. This case-control study evaluated the vaccine effectiveness (VE) of two doses of mRNA vaccine, BNT162b2 or mRNA-1273, against the delta (B.1.617.2) variant in the Japanese general population in the period June-September 2021. Individuals in close contact with COVID-19 patients were tested using polymerase chain reaction (PCR). A self-administered questionnaire evaluated vaccination status, demographic data, underlying medical conditions, lifestyle, personal protective health behaviors, and living environment. Two vaccine doses were reported by 11.6% of cases (n = 389) and 35.2% of controls (n = 179). Compared with controls, cases were younger and had a lower proportion who always performed handwashing for ≥20 s, a higher proportion of alcohol consumers, and a lower proportion of individuals living in single-family homes or with commuting family members. After adjusting for these confounding factors and day of PCR testing by multivariate logistic regression analysis, the VE in the period June-July (delta variant proportion 45%) was 92% and 79% in the period August-September (delta variant proportion 89%). The adjusted VE for homestay, hotel-based isolation and quarantine, and hospitalization was 78%, 77%, and 97%, respectively. Despite declining slightly, VE against hospitalization remained robust for ~3 months after the second dose. Vaccination policymaking will require longer-term monitoring of VE against new variants.

Cerebrospinal Fluid Protein Concentration in Healthy Older Japanese Volunteers.

The concentration of cerebrospinal fluid total protein (CSF-TP) is important for the diagnosis of neurological emergencies. Recently, some Western studies have shown that the current upper reference limit of CSF-TP is quite low for older patients. However, little is reported about the concentration of CSF-TP in the older Asian population. In this study, we retrospectively analyzed the CSF-TP concentrations in healthy older Japanese volunteers. CSF samples in 69 healthy Japanese volunteers (age range: 55-73 years) were collected by lumbar puncture, and the data of CSF were retrospectively analyzed. The mean (standard deviation) CSF-TP was 41.7 (12.3) mg/dL. The older group (≥65 years old) had higher CSF-TP concentration than the younger group (55-64 years old). The 2.5th percentile and 97.5th percentile of CSF-TP were estimated as 22.5 and 73.2 mg/dL, respectively, which were higher than the current reference range in Japan (10-40 mg/dL). Conclusions: The reference interval of CSF-TP in the older population should be reconsidered for the precise diagnosis of neurological emergencies.

Statistical Analysis of the Axillary Temperatures Measured by a Predictive Electronic Thermometer in Healthy Japanese Adults.

Body temperature is important for diagnosing illnesses. However, its assessment is often a difficult task, considering the large individual differences. Although 37 °C has been the gold standard of body temperature for over a century, the temperature of modern people is reportedly decreasing year by year. However, a mean axillary temperature of 36.89 ± 0.34 °C reported in 1957 is still cited in Japan. To assess the measured axillary temperature appropriately, understanding its distribution in modern people is important. This study retrospectively analyzed 2454 axillary temperature measurement data of healthy Japanese adults in 2019 (age range, 20-79 years; 2258 males). Their mean temperature was 36.47 ± 0.28 °C (36.48 ± 0.27 °C in males and 36.35 ± 0.31 °C in females). Approximately 5% of the 20-39-year-old males had body temperature ≥37 °C, whereas 8% had a temperature ≥ 37 °C in the afternoon. However, none of the subjects aged ≥50 years reported body temperature ≥37 °C. In multivariable regression analysis, age, blood pressure, pulse rate, and measurement time of the day were associated with axillary temperature. Our data showed that the body temperature of modern Japanese adults was lower than that reported previously. When assessing body temperature, the age, blood pressure, pulse rate, and measurement time of the day should be considered.

SARS-CoV-2 Seroprevalence among Healthcare Workers in General Hospitals and Clinics in Japan.

Coronavirus disease 2019 (COVID-19) has become a serious public health problem worldwide. In general, healthcare workers are considered to be at higher risk of COVID-19 infection. However, the prevalence of COVID-19 among healthcare workers in Japan is not well characterized. In this study, we aimed to examine the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies among 2160 healthcare workers in hospitals and clinics that are not designated to treat COVID-19 patients in Japan. The prevalence of SARS-CoV-2 immunoglobulin G was 1.2% in August and October 2020 (during and after the second wave of the pandemic in Japan), which is relatively higher than that in the general population in Japan (0.03-0.91%). Because of the higher risk of COVID-19 infection, healthcare workers should be the top priority for further social support and vaccination against SARS-CoV-2.

Variability of post-void residual urine volume and bladder voiding efficiency in patients with underactive bladder.

OBJECTIVES: Post-void residual urine volume (PVR) and bladder voiding efficiency (BVE) are widely used as clinical parameters to evaluate patients with voiding dysfunction. The present study was conducted to assess the variability of PVR and BVE determinations in patients with underactive bladder (UAB). In addition, we focused on the bladder volume prior to voiding (BVvoid ) that may influence PVR and BVE, and investigated a correlation between PVR and BVvoid , and between BVE and BVvoid . METHODS: Ten patients with a symptom complex of UAB, who had PVR of 50 mL or greater, were admitted to hospital during a 24-hour period for the measurement of voided volume (VV) and PVR. PVR was measured by transabdominal ultrasonography. BVE was expressed by a fraction (%) of bladder volume evacuated ([VV/BVvoid ] × 100). RESULTS: Ten patients, five men (mean age of 65.0 years) and five women (mean age of 70.2 years), participated in this study. Regardless of gender, there was a large variation in repeated measurements of PVR in an individual patient. PVR increased with an increase in BVvoid , and there was a significant linear relationship between PVR and BVvoid . BVE was approximately constant after every voiding in each patient, and there was no significant linear relationship between BVE and BVvoid . CONCLUSIONS: Measurement of PVR was unreliable because of wide variation in the same individual. The variation of BVE was much smaller than PVR. BVE would be a reliable parameter with good reproducibility for the assessment of emptying function.

TAS-303 effects on urethral sphincter function in women with stress urinary incontinence: phase I study.

INTRODUCTION AND HYPOTHESIS: TAS-303, which selectively inhibits noradrenaline reuptake, was developed for treating stress urinary incontinence (SUI). The proximal urethra mainly comprises smooth muscle fibers in which α1 adrenergic receptors are abundant. This study was conducted to evaluate the effect of TAS-303 on urethral function and its safety profile in female patients with SUI. METHODS: In total, 16 women (age, 20-64 years) with SUI and > 5.0 g of leakage in the 1-h pad test at screening were randomized and administered the assigned treatment in a double-blind manner. The primary end point was change in the maximal urethral closure pressure (MUCP) at 6 h post-dose. The secondary end point was change in the urethral closure pressure of the entire urethra and each urethral region (proximal, middle, and distal) at 6 h post-dose. The results were analyzed using a t-test. RESULTS: The mean change ± standard deviation in MUCP at 6 h post-dose was 3.473 ± 12.154 cmH2O for TAS-303 and 2.615 ± 9.794 cmH2O for placebo (between-group difference: 0.858 cmH2O, P = 0.8047). The mean changes ± standard deviation in urethral closure pressure of the proximal urethra at 6 h after the administration of TAS-303 18 mg and placebo were 3.863 ± 10.941 and 1.634 ± 12.093, respectively (between-group difference: 2.229 cmH2O, P = 0.5976). CONCLUSIONS: No significant difference in MUCP and urethral closure pressure was found between TAS-303 and placebo. However, the change in the proximal urethral closure pressure with TAS-303 was larger than that with placebo. This suggests that TAS-303 has pharmacological effects on urethral sphincteric function.

Comparison of immunogenicity between candidate influenza A(H3N2) virus vaccine strains in Japan: A randomized controlled trial using a monovalent vaccine of A/Saitama/103/2014 (CEXP-002) and A/Hong Kong/4801/2014 (X-263).

BACKGROUND: For the 2017-18 influenza season, A/Saitama/103/2014 (CEXP-002) (Saitama strain) was antigenically more similar to prior circulating strains than A/Hong Kong/4801/2014 (X-263) (Hong Kong strain) in a ferret model and was selected as the A(H3N2) vaccine virus strain in Japan. However, the Saitama strain grew poorly, and the Japanese government switched to the Hong Kong strain, raising public concerns of poor effectiveness. To enhance understanding of the correlation between antigenicity in experimental models and immunogenicity, as a surrogate measure of vaccine effectiveness, in the human population, we compared the immunogenicity of specially-prepared single dose monovalent influenza A(H3N2) vaccines containing the Saitama or the Hong Kong strain. METHODS: A randomized controlled trial of 100 healthy adults aged 20-64 years (n = 50/group) was conducted. Virus neutralization assay was performed on sera from days 0 (pre-vaccination) and 21 (post-vaccination). Geometric mean titer (GMT), mean fold rise (MFR), seroconversion proportion (SCP), and seroprotection proportion (SPP) were calculated for vaccine strains and a representative circulating A(H3N2) virus strain (A/Osaka/188/2017). RESULTS: For the Hong Kong strain, post-vaccination GMT was significantly higher in the Hong Kong vaccine recipients (1:546 vs 1:260, p < 0.01), but MFR, SCP, and SPP were similar for both vaccine groups. For the Saitama strain, post-vaccination GMT (1:116 vs 1:61, p = 0.01) and SPP (86% vs 68%, p = 0.03) were significantly higher in the Hong Kong vaccine recipients, but MFR and SCP were similar for both vaccine groups. Against A/Osaka/188/2017, post-vaccination GMT and MFR were similar in both vaccine groups, but SCP (32% vs 4%, p < 0.01) and SPP (28% vs. 6%, p < 0.01) were significantly higher in the Hong Kong vaccine recipients. CONCLUSION: The Hong Kong vaccine induced better or equivalent immunogenicity in comparison to the Saitama vaccine. Our trial showed that antigenic similarity in experimental models does not necessarily correlate with immunogenicity in the human population. CLINICAL TRIAL REGISTRATION: UMIN000029293.

Pharmacokinetic interactions of esaxerenone with amlodipine and digoxin in healthy Japanese subjects.

BACKGROUND: To investigate the effects of coadministration of esaxerenone with amlodipine on the pharmacokinetics (PK) of each drug, and of esaxerenone on the PK of digoxin. METHODS: In three open-label, single-sequence, crossover studies, healthy Japanese males received single oral doses of esaxerenone 2.5 mg (Days 1, 15), with amlodipine 10 mg/day (Days 8-18) (Study 1, N = 24); single doses of amlodipine 2.5 mg (Days 1, 21), with esaxerenone 5 mg/day (Days 8-25) (Study 2; N = 20); or digoxin 0.25 mg/day (Days 1-15) with esaxerenone 5 mg/day (Days 11-15) (Study 3; N = 20). PK parameters and safety were assessed. RESULTS: Study 1: esaxerenone peak plasma concentration (Cmax) and time to Cmax were unaltered by amlodipine coadministration, but mean half-life was slightly prolonged from 18.5 to 20.9 h. Geometric least-squares mean (GLSM) ratios for Cmax, area under the plasma concentration-time curve (AUC) from zero to last measurable concentration and from zero to infinity for esaxerenone + amlodipine versus esaxerenone were 0.958, 1.154, and 1.173, respectively. Study 2: corresponding GLSM ratios for amlodipine + esaxerenone versus amlodipine were 1.099, 1.185, and 1.214. Study 3: esaxerenone did not markedly alter digoxin PK. GLSM ratios for Cmax, trough plasma concentration, and AUC during a dosing interval for digoxin versus esaxerenone + digoxin were 1.130, 1.088, and 1.072, respectively. CONCLUSIONS: No drug-drug interactions are expected during combination therapy with esaxerenone and either amlodipine or digoxin, based on a lack of any clinically relevant PK changes. TRIAL REGISTRATION: Studies 1 and 2: JapicCTI-163379 (registered on 20 September 2016); Study 3: JapicCTI-163443 (registered on 24 November 2016).

Effects of itraconazole and rifampicin on the single-dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy Japanese subjects.

AIMS: To investigate the effects of the strong cytochrome P450 (CYP) 3A inhibitor itraconazole and the strong CYP3A inducer rifampicin on the pharmacokinetics of single-dose esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, in healthy Japanese subjects. METHODS: Two open-label, single-sequence, crossover studies were conducted in healthy Japanese males aged 20-45 years. In Study 1 (n = 20), subjects received a single oral 2.5 mg dose of esaxerenone (Days 1, 13), with itraconazole 200 mg twice daily (Day 8) and once daily (Days 9-16). In Study 2 (n = 12), subjects received a single oral 5 mg dose of esaxerenone (Days 1, 13), with rifampicin 600 mg once daily (Days 8-16). The plasma concentration of esaxerenone and esaxerenone metabolites were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis, and safety was assessed. RESULTS: Esaxerenone exposure increased when coadministered with itraconazole. Geometric least-square mean ratios (90% confidence interval) of peak plasma esaxerenone concentration (Cmax ), area under the plasma concentration-time curve (AUC) from zero until the last measurable concentration (AUClast ) and AUC from zero until infinity (AUCinf ) were 1.13 (1.05, 1.20) ng mL-1 , 1.47 (1.40, 1.54) ng h mL-1 and 1.53 (1.45, 1.62) ng h mL-1 , respectively. Esaxerenone exposure decreased when coadministered with rifampicin. Geometric least-squares mean ratios (90% confidence interval) of esaxerenone Cmax , AUClast and AUCinf were 0.659 (0.599, 0.724), 0.315 (0.300, 0.332) and 0.312 (0.297, 0.328), respectively. CONCLUSION: Itraconazole increased esaxerenone AUCinf by 53.1%, and rifampicin decreased esaxerenone AUCinf by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.

Levocetirizine Oral Disintegrating Tablet: A Randomized Open-Label Crossover Bioequivalence Study in Healthy Japanese Volunteers.

Levocetirizine is classified as a second-generation antihistamine. Levocetirizine is available for the treatment of allergic disorders such as allergic rhinitis and chronic idiopathic urticaria. This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male subjects consisting of 2 parts. Part 1 compared the bioavailability of levocetirizine oral disintegrating tablet (ODT) and levocetirizine immediate-release tablet (IRT) taken with water in the fasted state in 24 subjects; all subjects completed this part of the trial. In part 2, the bioavailability of levocetirizine ODT without water was compared with that of levocetirizine IRT with water in the fasted state in 48 subjects; 47 subjects completed this part of the trial. Bioequivalence was demonstrated between levocetirizine IRT 5 mg and ODT 5 mg. The safety profiles were generally similar between levocetirizine ODT and levocetirizine IRT, with no serious adverse events, deaths, or adverse events leading to withdrawal reported during the study.

Determination of the Kinetic Parameters for 123I Uptake by the Thyroid, Thyroid Weights, and Thyroid Volumes in Present-day Healthy Japanese Volunteers.

The purpose of this study was to evaluate the kinetic parameters that determine the uptake rate of radioiodide in the thyroid over 24 h after administration and to estimate thyroid volumes/masses of present-day Japanese. Methods: We determined the thyroid uptake rate of I in healthy male Japanese after oral administration (4.5-8.0 MBq) without iodine restriction. Masses of thyroid glands were collected in 2012-2016 during autopsies of 7,651 male and 3,331 female subjects. Volumes of thyroid glands were estimated by ultrasonography and magnetic resonance imaging in 52 male subjects. Results: The thyroid uptake rate of I for 24 h was 16.1 ± 5.4%. Kinetic model analysis was conducted to obtain the clearances (L h) for thyroid uptake and urinary excretion of I (0.499 ± 0.258 and 2.10 ± 0.39 L h, respectively). The masses of thyroid glands were on average 19.8 g (95% confidence interval of 18.3-19.5 g) and 15.5 g (95% confidence interval of 14.7-16.2 g) in male and female subjects aged 19-52 y, respectively. Volumes of thyroid glands estimated by ultrasonography and magnetic resonance imaging were 17.5 ± 5.2 and 14.2 ± 5.3 mL, respectively. In healthy Japanese, there has been no significant change for at least 50 y in the thyroid uptake of radioiodide over 24 h or in its kinetic parameters. These Japanese-specific kinetic parameters will allow quantitative estimation of the radiation exposure from the Fukushima accident and its variance during the individual's evacuation from or stay in Fukushima.

A Phase 1, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of Subcutaneous Tezepelumab in Healthy Japanese Men.

Tezepelumab, a human immunoglobulin G2 monoclonal antibody against thymic stromal lymphopoietin, is currently under clinical development for the treatment of severe, uncontrolled asthma. This phase 1, randomized, placebo-controlled, single-ascending-dose study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tezepelumab in healthy Japanese men. Participants were assigned to 1 of 3 tezepelumab dose cohorts (35, 105, or 280 mg; n = 8 per cohort) and randomized (6:2) to receive a single subcutaneous dose of tezepelumab or placebo, with a follow-up period of 84 to 112 days. The overall incidences and severities of treatment-emergent adverse events were similar across tezepelumab doses and between the tezepelumab and placebo groups. Tezepelumab was absorbed slowly, reaching a maximum serum concentration (mean, 5.2-39.7 µg/mL) after 7 to 10 days. Area under the concentration-time curve (mean, 207.2-1612.0 µg · day /mL) increased in an approximate dose-proportional manner. Tezepelumab had a long terminal serum half-life (mean, 23.9-26.3 days) and a small apparent distribution volume, suggesting limited distribution into peripheral tissues. No participants developed anti-tezepelumab antibodies. Single-dose, subcutaneous administration of tezepelumab 35 to 280 mg resulted in an acceptable safety profile with linear pharmacokinetics in healthy Japanese men. No clear differences in tezepelumab safety and pharmacokinetics between Japanese and non-Japanese populations were identified.

Elucidation of N 1-methyladenosine as a Potential Surrogate Biomarker for Drug Interaction Studies Involving Renal Organic Cation Transporters.

Endogenous substrates are emerging biomarkers for drug transporters, which serve as surrogate probes in drug-drug interaction (DDI) studies. In this study, the results of metabolome analysis using wild-type and Oct1/2 double knockout mice suggested that N 1-methyladenosine (m1A) was a novel organic cation transporter (OCT) 2 substrate. An in vitro transport study revealed that m1A is a substrate of mouse Oct1, Oct2, Mate1, human OCT1, OCT2, and multidrug and toxin exclusion protein (MATE) 2-K, but not human MATE1. Urinary excretion accounted for 77% of the systemic elimination of m1A in mice. The renal clearance (46.9 ± 4.9 ml/min per kilogram) of exogenously given m1A was decreased to near the glomerular filtration rates by Oct1/2 double knockout or Mate1 inhibition by pyrimethamine (16.6 ± 2.6 and 24.3 ± 0.6 ml/min per kilogram, respectively), accompanied by significantly higher plasma concentrations. In vivo inhibition of OCT2/MATE2-K by a single dose of 7-[(3R)-3-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxoquinoline-3-carboxylic acid in cynomolgus monkeys resulted in the elevation of the area under the curve of m1A (1.72-fold) as well as metformin (2.18-fold). The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. The renal clearance of m1A in younger (21-45 year old) and older (65-79 year old) volunteers (244 ± 58 and 169 ± 22 ml/min per kilogram, respectively) was about 2-fold higher than the creatinine clearance. The renal clearances of m1A and creatinine were 31% and 17% smaller in older than in younger volunteers. Thus, m1A could be a surrogate probe for the evaluation of DDIs involving OCT2/MATE2-K. SIGNIFICANCE STATEMENT: Endogenous substrates can serve as surrogate probes for clinical drug-drug interaction studies involving drug transporters or enzymes. In this study, m1A was found to be a novel substrate of renal cationic drug transporters OCT2 and MATE2-K. N 1-methyladenosine was revealed to have some advantages compared to other OCT2/MATE substrates (creatinine and N 1-methylnicotinamide). The genetic or chemical impairment of OCT2 or MATE2-K caused a significant increase in the plasma m1A concentration in mice and cynomolgus monkeys due to the high contribution of tubular secretion to the net elimination of m1A. The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. Thus, m1A could be a better biomarker of variations in OCT2/MATE2-K activity caused by inhibitory drugs.

G protein-coupled receptor 119 agonist DS-8500a effects on pancreatic ß-cells in Japanese type 2 diabetes mellitus patients.

AIMS/INTRODUCTION: Pancreatic ß-cell dysfunction contributes to type 2 diabetes mellitus progression. Drugs that improve insulin secretion might be a valuable treatment approach. The present study aimed to evaluate the effect of the G protein-coupled receptor 119 agonist DS-8500a on insulin secretory capacity in Japanese type 2 diabetes mellitus patients. MATERIALS AND METHODS: This single-center, 4-week, randomized, double-blind, cross-over study enrolled 21 Japanese drug-naïve type 2 diabetes mellitus patients aged ≥20 years with glycated hemoglobin ≥7.0 and <9.0% (NCT02669732, JapicCTI 163126). Patients received 75 mg of DS-8500a or a placebo orally daily for 4 weeks in a random order. A combined euglycemic-hyperinsulinemic and hyperglycemic clamp test was carried out to assess insulin secretion and insulin sensitivity before and after each 4-week treatment period. Primary end-points were first-phase insulin secretion (insulin area under the curve [AUC]180-190 min and C-peptide AUC180-190 min during the clamp test) and second-phase insulin secretion (insulin AUC190-300 min and C-peptide AUC190-300 min ). Insulin sensitivity (M and M/I values), disposition index and changes in lipid profile were also assessed. RESULTS: DS-8500a significantly increased first- and second-phase insulin AUC (P = 0.0011, P = 0.0112) and C-peptide AUC (P = 0.0012, P < 0.0001) compared with the placebo. At day 28, M and M/I values were comparable with those of the placebo, whereas the disposition index for insulin and C-peptide was significantly increased (P = 0.0108, P = 0.0002). Total cholesterol, low-density lipoprotein cholesterol and triglyceride concentrations were significantly reduced, and high-density lipoprotein cholesterol concentrations were significantly increased compared with the placebo. No significant treatment-emergent adverse events occurred. CONCLUSION: DS-8500a enhanced insulin secretory capacity, but not insulin sensitivity.

Treatment Recommendations for Urological Symptoms in Cancer Patients: Clinical Guidelines from the Japanese Society for Palliative Medicine.

BACKGROUND: Urological symptoms such as gross hematuria, lower and upper urinary tract symptoms, and bladder pain are common in and distressing for patients with advanced cancer. Although palliation of urological symptoms is important to improve the quality of life of cancer patients and their families and caregivers, clinical guidelines for managing urological symptoms in patients with cancer have not been published. METHODS: Following the formal guideline development process, the Japanese Society for Palliative Medicine (JSPM) developed comprehensive clinical guidelines for the management of urological symptoms in patients with cancer. RESULTS: This article summarizes the recommendations and their rationales and provides a short summary of the development process of the JSPM urological symptom management guidelines. We established five recommendations, all of which were based on the best available evidence and expert consensus. CONCLUSION: JSPM released the first edition of the "Clinical Guidelines for Urological Symptoms in Cancer Patients." Future clinical research and continuous guideline updates are required to improve the quality of managing urological symptoms in patients with cancer.

Effect of OATP1B1 genotypes on plasma concentrations of endogenous OATP1B1 substrates and drugs, and their association in healthy volunteers.

This study aimed to elucidate the impact of OATP1B1 genotype (*1b/*1b, *1b/*15, and *15/*15) on plasma concentrations of endogenous OATP1B1 substrates. Healthy volunteers with OATP1B1 *1b/*1b (n = 10), *1b/*15 (n = 7), or *15/*15 (n = 2) received oral administration of a cocktail of statins (atorvastatin, pitavastatin, rosuvastatin, and fluvastatin). Mean area under the plasma concentration of atorvastatin, pitavastatin, and rosuvastatin in OATP1B1 *15/*15 were 2.2, 1.7 and 1.58-times greater than the corresponding values in OATP1B1 *1b/*1b, respectively, whereas that of fluvastatin was identical to those in other OATP1B1 genotypes. OATP1B1 *15/*15 also showed higher mean plasma concentrations of OATP1B1 endogenous substrates compared with the other OATP1B1 genotypes, such as coproporphyrin I, glycochenodeoxycholate sulfate (GCDCA-S), lithocholate sulfate (LCA-S), glycolithocholate sulfate (GLCA-S) and taurolithocholate sulfate (TLCA-S), but not total or direct bilirubin, chenodeoxycholate-24-glucuronide, or ω-dicarboxylic long-chain fatty acids. Area under the plasma concentration-time curves of plasma coproporphyrin I and GLCA-S discriminated OATP1B1 genotype *15/*15 from the other genotypes. In combination with previously published clinical studies, these results support the notion that coproporphyrin I, and GLCA-S and GCDCA-S could be a surrogate probe for assessing human in vivo OATP1B1 activities.

Pharmacokinetics of Tenofovir Alafenamide, Tenofovir, and Emtricitabine Following Administration of Coformulated Emtricitabine/Tenofovir Alafenamide in Healthy Japanese Subjects.

A fixed-dose combination of tenofovir alafenamide (TAF) and emtricitabine (FTC) is available in 2 tablet strengths in Japan (FTC/TAF 200/10 mg and FTC/TAF 200/25 mg). These are used once daily in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 infection. The primary objective of this study was to investigate if there is any clinically relevant pharmacokinetic difference for TAF, tenofovir (TFV), and FTC between Japanese and non-Japanese with historical data. Three treatment groups were set in the study; FTC/TAF 200/10 mg in combination with darunavir (DRV) 800 mg + ritonavir (RTV) 100 mg (treatment A) or DRV/cobicistat (COBI) 800/150 mg (treatment B) and FTC/TAF 200/25 mg alone (treatment C). Especially for treatment C, it was designated for another purpose to evaluate the pharmacokinetic boosting effects of RTV and COBI on TAF bioavailability. As a result, the mean exposure of TAF among treatment groups was 125 to 154 ng/mL for Cmax and 119 to 179 ng·h/mL for AUCinf , which were comparable with the historical data in non-Japanese. The exposures of TFV and FTC were also consistent with the historical data. Therefore, no clinically relevant pharmacokinetic differences for TAF, TFV, and FTC were observed between Japanese and non-Japanese. Boosting effects of RTV and COBI on TAF bioavailability were slightly lower than we expected, less than a 2.5-fold increase, but it was within the range of exposures associated with efficacy and safety in phase 3 studies. Therefore, it was not considered clinically relevant.

Effects of magnesium oxide on pharmacokinetics of L-dopa/carbidopa and assessment of pharmacodynamic changes by a model-based simulation.

BACKGROUND: Magnesium oxide (MgO) is often co-prescribed with L-dopa/carbidopa (LDCD) to improve constipation in Parkinson's disease patients. The mixing of L-dopa and MgO has been shown to degrade L-dopa; however, there is no interaction study on humans. We proposed mechanisms for the interaction between LDCD and MgO and conducted pharmacokinetic studies on rats and humans. To assess pharmacodynamic changes with the MgO treatment, we applied a model-based meta-analysis (MBMA). METHODS: The effects of MgO on the stabilities of L-dopa and carbidopa were evaluated in in vitro studies. We conducted pharmacokinetic interaction studies of MgO and LDCD on rats and healthy volunteers. A clinical study was conducted with an open-label, non-randomized, single-arm, and two-phase study. In MBMA, we constructed a population pharmacokinetic/pharmacodynamic model of L-dopa and predicted the effects of the MgO treatment on the pharmacodynamics of L-dopa. RESULTS: In vitro results suggested that carbidopa was unstable under alkaline pH conditions. Reductions in plasma LDCD concentrations were observed after oral-MgO/oral-LDCD, but not in oral-MgO/i.v.-LDCD treatments in rats, suggesting that the gastrointestinal tract is an interaction site. A healthy volunteer study showed that MgO was also associated with significant decreases of 35.3 and 80.9% in the AUC0-12 of L-dopa and carbidopa, respectively. A model-based simulation suggested that the MgO treatment was undesirable for the effectiveness of L-dopa. CONCLUSIONS: This is the first study to show a clear pharmacokinetic interaction between LDCD and MgO in humans. Further investigations to confirm the effects of MgO on the pharmacodynamics of L-dopa are required.