Pulmonary Sclerosing Pneumocytoma: A Case Revealed During 8-Year of Follow-up with CT imaging.

Pulmonary sclerosing pneumocytoma (PSP) is a rare, benign tumor. Given the challenges of a bronchoscopic diagnosis, surgery is performed during the early stages of the disease. Therefore, little is known about the growth pattern of PSP. This case of PSP was not diagnosed despite bronchoscopy, resulting in lung resection eight years after the anomaly was first identified on computed tomography (CT). This report compares the long-term follow-up of CT and pathological findings and discusses the difficulty in making a diagnosis using a bronchoscopic forceps biopsy to aid in future PSP diagnoses and treatment planning.

Association of xanthine oxidoreductase inhibitor use with insulin secretory capacity in patients with type 2 diabetes.

AIM/INTRODUCTION: Xanthine oxidoreductase (XOR) inhibitor treatment, which reduces reactive oxygen species (ROS) production and increases adenosine triphosphate (ATP) synthesis, has been reported to improve glycemic control. The possible protective effects of XOR inhibitor treatment on insulin secretory capacity were investigated in patients with type 2 diabetes. MATERIALS AND METHODS: This retrospective cross-sectional study included 428 patients with type 2 diabetes. Insulin secretory capacity was assessed based on fasting serum C-peptide concentration (CPR) and C-peptide index (CPI) in all subjects, while insulin resistance in non-insulin users (n = 312) was determined using the homeostasis model assessment of insulin resistance (HOMA-IR) index. RESULTS: Median values for CPR and CPI in all subjects were 2.4 ng/mL and 1.5, respectively, while that for HOMA-IR in non-insulin users was 3.2. The XOR inhibitor users (n = 72) had significantly (P < 0.001) higher CPR and CPI levels than non-users (n = 356). Multivariable regression analyses showed XOR inhibitor use was positively associated with CPR (ß = 0.153, P = 0.001) and CPI (ß = 0.144, P = 0.001). Similar results were observed in propensity score analyses. In subgroup analyses of patients with a preserved estimated glomerular filtration rate (≥60 mL/min/1.73 m2) and non-insulin users, these associations remained significant. Furthermore, the associations were significant in patients with lower (≤6.0 mg/dL) but not with higher (>6.0 mg/dL) uric acid levels (P for interaction <0.05). On the other hand, XOR inhibitor use showed no significant association with HOMA-IR. CONCLUSIONS: The results of XOR inhibitor treatment, especially a sufficient reduction in serum uric acid level, may provide protective effects on insulin secretory capacity in patients with type 2 diabetes.

Deleterious impact of trivial to severe interstitial pneumonia and emphysema on mortality and acute exacerbation of interstitial pneumonia in patients with lung cancer: a retrospective cohort study.

BACKGROUND: Interstitial pneumonia and emphysema may complicate patients with lung cancer. However, clinical significance of trivial and mild pulmonary abnormalities remains unclear. In this study, we aimed to investigate whether trivial and mild interstitial pneumonia and emphysema, in addition to their advanced forms, impact the prognosis and lead to acute exacerbation of interstitial pneumonia (AEIP) in patients with lung cancer. METHODS: This retrospective cohort study was conducted at a tertiary hospital and included patients with lung cancer. Computed tomography images were evaluated using the interstitial lung abnormality (ILA) score for interstitial pneumonia, which included no ILA, equivocal ILA, ILA, interstitial lung disease (ILD), and the Goddard score for emphysema. Cox analyses were performed using the ILA and Goddard scores as the main explanatory variables, adjusting for multiple covariates. RESULTS: Among 1,507 patients with lung cancer, 1,033 had no ILA, 160 had equivocal ILA, 174 had ILA, and 140 had ILD. In total, 474 patients (31.5%) exhibited interstitial pneumonia and 638 (42.3%) showed emphysema. The log-rank trend test showed that survival probability was significantly better in patients with no ILA, followed by those with equivocal ILA, ILA, and ILD (P < 0.001). After adjustment, the ILA and Goddard scores remained significant variables for increased hazard ratios (HR) for mortality: no ILA (HR, 1.00: reference), equivocal ILA (HR, 1.31; 95% confidence interval [CI], 1.18-1.46; P < 0.001), ILA (HR, 1.71; 95% CI, 1.39-2.12; P < 0.001), ILD (HR, 2.24; 95% CI, 1.63-3.09; P < 0.001), and Goddard score (HR, 1.03; 95% CI, 1.01-1.06; P < 0.010). Moreover, both scores were associated with increased cause-specific HRs for AEIP. CONCLUSION: Our results revealed that approximately one-third of patients with lung cancer had interstitial pneumonia when incorporating trivial and mild cases. Because interstitial pneumonia and emphysema, ranging from trivial to severe, significantly impact mortality and AEIP in patients with lung cancer, we should identify even trivial and mild cases of these pulmonary abnormalities among patients with lung cancer in addition to the advanced ones.

Successful thoracoscopic operative approach for refractory pneumothorax in interstitial lung disease under local anaesthesia.

Refractory pneumothorax associated with interstitial lung disease (ILD) remains a challenging condition due to the patient's tolerability and lung compliance that restrict the feasibility of aggressive interventions. Additionally, many cases recur after improvement with treatment, and reports of successful management for this complicated condition are limited. Herein, we report the case of a 60-year-old man with ILD, utilizing home oxygen therapy, who experienced a successful recovery from a surgical intervention under local anaesthesia for pneumothorax. This case highlights the potential for operative intervention under local anaesthesia as a viable option for patients who do not respond to internal approaches.

Empyema necessitans caused by methicillin-resistant Staphylococcus aureus: a case report and literature review.

BACKGROUND: Empyema necessitans (EN) is a rare condition characterized by pleural infection with pus spreading into adjacent soft tissues. Although Mycobacterium tuberculosis and Actinomyces israelii are common causative agents, methicillin-resistant Staphylococcus aureus (MRSA) is relatively rare, but it is associated with high mortality in empyema cases. We aimed to report a unique case of EN caused by MRSA and present a literature review to better understand this rare condition. CASE PRESENTATION: A 69-year-old man with a history of right ureteral stone presented with fever and left anterior thoracic pain. A physical examination revealed redness and swelling in the left thoracic region. Imaging studies confirmed EN with fluid accumulation around the sternocostal joint of the left first rib. MRSA was identified from blood and pleural fluid cultures. The patient received antimicrobial therapy, and a chest tube was inserted for drainage. Despite initial improvement, vertebral osteomyelitis was diagnosed on day 17. The antimicrobials were subsequently terminated after 6 weeks, but vertebral osteomyelitis recurred, and treatment was resumed and completed on day 215. CONCLUSION: EN caused by MRSA is rare, and the literature review revealed 14 cases from human sources. Positive blood cultures were observed in 40% of cases, and metastatic infections were present in 30% of cases. Osteomyelitis was the most common type of metastatic lesion. All the patients underwent drainage. Patients with MRSA-associated EN frequently develop disseminated lesions and should therefore be carefully examined. Moreover, appropriate treatment with antibiotics and drainage is necessary for a good prognosis. Although the prognosis appeared to be favorable in our review, publication bias and treatment challenges for metastatic infections should be considered.

Successful treatment with atezolizumab in a haemodialysis patient with large cell neuroendocrine carcinoma.

In this report, a modified regimen based on IMpower 133 (carboplatin + etoposide + atezolizumab) was administered to a patient diagnosed with large cell neuroendocrine carcinoma (LCNEC) who was concurrently undergoing haemodialysis. Adverse events led to the discontinuation of carboplatin and etoposide after the first course. Nevertheless, the patient exhibited reduction in pulmonary nodule and adrenal metastasis while receiving atezolizumab, indicating its sustained efficacy for a duration of 7 months. To the best of our knowledge, this is the first documented case demonstrating successful treatment with atezolizumab in LCNEC patients undergoing haemodialysis. Atezolizumab can be administered safely in patients undergoing dialysis and is a promising therapeutic option for dialysis patients with LCNEC.

Investigating Viral Involvement in Immunocompromised Patients Using Comprehensive Infectious Disease Testing Including FilmArray Respiratory Panel 2.1 on Bronchoscopy: A Retrospective Study.

Introduction Reports are rare on the usefulness of the FilmArray Respiratory Panel 2.1 (FARP) using lower respiratory tract specimens. This retrospective study assessed its use, as part of a comprehensive infectious disease panel, to detect the viral causes of pneumonia using bronchoalveolar lavage samples from immunosuppressed patients. Methods This study included immunocompromised patients who underwent bronchoalveolar lavage or bronchial washing by bronchoscopy between April 1, 2021, and April 30, 2022. The collected samples were submitted for comprehensive testing, including FARP test; reverse transcription polymerase chain reaction (RT-PCR) for cytomegalovirus, varicella-zoster virus DNA, and herpes simplex virus; PCR for Pneumocystis jirovecii DNA; antigen testing for Aspergillus and Cryptococcus neoformans; and loop-mediated isothermal amplification method for Legionella. Results Out of 23 patients, 16 (70%) showed bilateral infiltrative shadows on computed tomography and three (13%) were intubated. The most common causes of immunosuppression were anticancer drug use (n=12, 52%) and hematologic tumors (n=11, 48%). Only two (9%) patients tested positive for severe acute respiratory syndrome coronavirus 2 and adenovirus by FARP. Four patients (17%) tested positive for cytomegalovirus by RT-PCR, but no inclusion bodies were identified cytologically. Nine (39%) patients tested positive for Pneumocystis jirovecii by PCR, but cytology confirmed the organism in only one case. Conclusions Comprehensive infectious disease testing, performed using bronchoalveolar lavage samples collected from lung lesions in immunosuppressed patients, showed low positive detection by FARP. The viruses currently detectable by FARP may be less involved in viral pneumonia diagnosed in immunocompromised patients.

Difficult removal after bronchial filling of an endobronchial Watanabe spigot with N-butyl-2-cyanoacrylate for intractable pneumothorax: A case report.

A 52-year-old man developed a right pneumothorax during treatment for COVID-19. In a previous case report concerning this patient, his recovery was achieved through implanting four endobronchial Watanabe spigots (EWS) in the right B1 and B3 in two phases and spraying N-butyl-2-cyanoacrylate (NBCA). One year later, EWS removal was planned. He was intubated under bronchoscopic guidance, and the right upper lobe was observed. The right B1 and B3 inlets were found to be covered with granuloma. Despite the presence of a nylon thread for easy retrieval and partial debridement of the granulation, removal of the implanted EWS in the right B1 and B3 using grasping forceps, basket forceps, and two types of balloons under fluoroscopic guidance was challenging. NBCA spraying is a possible cause of foreign body granuloma formation. Therefore, careful consideration of the indications for the combined EWS-NBCA procedure is necessary.

Pharmacokinetics and Safety of Imeglimin in Japanese Patients With Impaired Renal Function.

Imeglimin is a diabetic drug excreted mainly in the urine; therefore, the impact of renal impairment on its pharmacokinetics (PK) is of interest. We assessed the PK and safety of imeglimin in Japanese patients with impaired renal function. This was an uncontrolled, open-label, single-dose, phase 1 study. Participants were classified into 4 groups by their estimated glomerular filtration rate (mL/min/1.73 m2 ) as follows: ≥90, normal renal function; and 60 to <90, mild; 30 to <60, moderate; and 15 to <30, severe renal impairment. All participants received imeglimin 1000 mg except those with severe renal impairment, who received imeglimin 500 mg. PK parameters were estimated using noncompartmental analysis, and those after multiple administrations were projected using a noncompartmental superposition method. In total, 24 Japanese participants (6 in each group) were enrolled and completed the study. The mean plasma imeglimin concentration reached the maximum at 2-4 hours after administration and then rapidly decreased. The geometric mean maximum observed plasma concentration and area under the plasma concentration-time curve values were higher in the impaired renal function groups versus normal renal function group. Most imeglimin was excreted in urine by 24 hours after administration. Renal clearance decreased with decreasing renal function. Projected maximum observed plasma concentration and area under the plasma concentration-time curve over the dosing interval after multiple dosing were greater in the renal impairment groups versus normal renal function group. No adverse events were observed. Considering increased plasma exposure along with decreased renal clearance, dose adjustment is required in patients with moderate and severe renal impairment with estimated glomerular filtration rate of 15 to <45 mL/min/1.73 m2 .

Naltrexone Transport by a Proton-Coupled Organic Cation Antiporter in hCMEC/D3 Cells, an in Vitro Human Blood-Brain Barrier Model.

Naltrexone is a mu-opioid receptor antagonist used in the treatment of opioid and alcohol dependence. The blood-brain barrier (BBB) transport characteristics of naltrexone was investigated by means of hCMEC/D3 cells, a human immortalized brain capillary endothelial cell line. In hCMEC/D3 cells, naltrexone is taken up in a concentration-dependent manner. Furthermore, naltrexone uptake significantly decreased in the presence of H+/organic cation (OC) antiporter substrates, during the little alteration exhibited by substrates of well-identified OC transporters classified into SLC22A family. Although naltrexone uptake by hCMEC/D3 cells was partially affected by changes of ionic conditions, it was markedly decreased in the presence of the metabolic inhibitor sodium azide. Furthermore, when treated by ammonium chloride, naltrexone uptake by hCMEC/D3 cells was altered by intracellular acidification and alkalization, suggesting the involvement of oppositely directed proton gradient in naltrexone transport across the BBB. The results obtained in the present in vitro study suggest the active transport of naltrexone from blood to the brain across the BBB by the H+/OC antiporter.

A case of a thoracic mass negative on thoracentesis diagnosed by cryobiopsy from the visceral pleura.

Thoracoscopy under local anaesthesia is recommended for malignant tumours with negative pleural effusion cytology. Cryobiopsy from the visceral pleura by thoracoscopy under local anaesthesia can provide more diagnostic options for patients with thoracentesis-negative malignant effusions. Here we present the first case in which this technique was used. The patient had a pleural metastasis that could not be diagnosed even with rapid cytology of the parietal pleura biopsy. Indications, technical pitfalls, and safety tips are discussed.

Phase 1 Study to Investigate the Safety, Tolerability, and Pharmacokinetics of EPI-589 in Healthy Participants.

EPI-589 attenuates oxidative stress due to the radical scavenging activity of the reduced form and affects mitochondrial energy metabolism as a substrate of quinone-oxidoreductases. Given the effects of EPI-589 on oxidative stress and mitochondrial dysfunction, EPI-589 shows promise as a potential therapy for patients with amyotrophic lateral sclerosis. This phase 1 study evaluated the safety, tolerability, and pharmacokinetic profiles of EPI-589. Sixty-eight healthy participants were randomly assigned to EPI-589 or placebo. All adverse events were mild or moderate in severity, and no severe adverse events were reported. After single-dose administration under fasting conditions, time to maximum plasma concentration (tmax ) occurred 0.25 to 1.00 hour after administration. Both peak plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) were approximately linear with increases in single doses over a dose range of 250-1000 mg. Under fed conditions, the Cmax decreased to 62.6% of the Cmax under fasting conditions, the AUC was slightly increased, and the tmax was delayed by 1 hour. When EPI-589 was administered daily on days 1 and 7 with twice-daily dosing on days 2 through 6, the plasma trough concentration appeared to reach steady state by day 3. At both doses studied (500 mg twice daily and 750 mg twice daily), Cmax, tmax , and AUC were generally comparable between day 1 and day 7 and between the Japanese and White participants. EPI-589 was well tolerated as a single daily dose up to 1000 mg and as twice-daily doses up to 750 mg, with a linear pharmacokinetic profile.

Elevated plasma levels of Krebs von den Lungen-6 and geographic appearance on high-resolution computed tomography are associated with diffuse alveolar damage in autopsy cases of acute respiratory distress syndrome: a retrospective study.

BACKGROUND: Although diffuse alveolar damage (DAD) is a histopathological hallmark of acute respiratory distress syndrome (ARDS), its detection without lung biopsy is challenging. In patients with ARDS, the specificity of the Berlin definition to diagnose DAD as a reference standard is not adequately high, making it difficult to adequately diagnose DAD. The purpose of this study was to investigate the relationship between DAD and clinical findings, including KL-6 and geographic appearance, in ARDS patients and to identify more specific diagnostic criteria for DAD. METHODS: Among all adult autopsy cases at a tertiary hospital in Japan between January 2006 and March 2021, patients with ARDS who met the Berlin definition criteria were included. The patients' conditions were classified according to histopathological patterns as DAD or non-DAD, and clinical characteristics, laboratory data, and high-resolution computed tomography (HRCT) findings were compared between the two groups. RESULTS: During the study period, 27 met the Berlin definition (median age: 79 years, 19 men), of whom 18 (67%) had DAD and 9 (33%) did not. In the non-DAD group, histopathologic findings revealed organizing pneumonia in seven patients and pulmonary hemorrhage in two patients. On HRCT at onset, patients with DAD had more geographic appearance than those without DAD (89% vs. 44%). In patients with geographic appearance and elevated KL-6 (> 500 U/mL), the sensitivity and specificity for DAD diagnosis were 56% and 100%, respectively. All three patients with no geographic appearance and normal KL-6 did not have DAD. CONCLUSIONS: Geographic appearance on HRCT combined with KL-6 levels may predict the presence of DAD in patients with ARDS.

Findings of virtual bronchoscopic navigation can predict the diagnostic rate of primary lung cancer by bronchoscopy in patients with peripheral lung lesions.

BACKGROUND: Despite being minimally invasive, bronchoscopy does not always result in pathological specimens being obtained. Therefore, we investigated whether virtual bronchoscopic navigation (VBN) findings were associated with the rate of diagnosis of primary lung cancer by bronchoscopy in patients with peripheral lung lesions. METHODS: This study included patients with suspected malignant peripheral lung lesions who underwent bronchoscopy at St. Luke's International Hospital between October 2013 and March 2020. Patients diagnosed with primary lung cancer were grouped according to whether their pathology could be diagnosed by bronchoscopy, and their clinical factors were compared. In addition, the distance between the edge of the lesion and the nearest branch ("distance by VBN") was calculated. The distance by VBN and various clinical factors were compared with the diagnostic rates of primary lung cancer. RESULTS: The study included 523 patients with 578 lesions. After excluding 55 patients who underwent multiple bronchoscopies, 381 patients were diagnosed with primary lung cancer. The diagnostic rate by bronchoscopy was 71.1% (271/381). Multivariate analysis revealed that the lesion diameter (odds ratio [OR] 1.107), distance by VBN (OR 0.94) and lesion structure (solid lesion or ground-glass nodule; OR 2.988) influenced the risk of a lung cancer diagnosis. The area under the receiver operating characteristic curve for diagnosis based on lesion diameter and distance by VBN was 0.810. CONCLUSION: The distance by VBN and lesion diameter were predictive of the diagnostic rates of primary lung cancer by bronchoscopy in patients with peripheral lung lesions.

Prediction of Corresponding Dose of Transdermal Blonanserin to Oral Dose Based on Dopamine D2 Receptor Occupancy: Unique Characteristics of Blonanserin Transdermal Patch.

BACKGROUND/PURPOSE: Blonanserin is an atypical antipsychotic, a potent selective antagonist of dopamine D2 receptor (D2), prescribed as oral formulations in patients with schizophrenia. Blonanserin transdermal patch was developed to provide a new treatment option, but the corresponding dose to oral blonanserin was not clear. The aims of this study were to clarify the pharmacokinetic (PK)-pharmacodynamic characteristics of blonanserin after transdermal patch application and to evaluate the corresponding dose to oral formulation based on striatal D2 occupancy. METHODS: The relationship between D2 occupancy and plasma blonanserin concentration was analyzed using an Emax model based on data from positron emission tomography study with oral and transdermal blonanserin. D2 occupancy was simulated using Emax models based on the observed plasma concentrations and the simulated plasma concentrations obtained from population PK model. RESULTS: Plasma blonanserin concentration levels after repeated patch applications were nearly stable throughout the day and no effect of sex, advanced age, or application site was detected. The concentration at half maximal D2 occupancy during transdermal patch applications, 0.857 ng/mL, was higher than that after oral doses, 0.112 ng/mL, suggesting metabolite contribution after oral doses. The median predicted D2 occupancy during blonanserin patch applications at doses of 40 and 80 mg/d was 48.7% and 62.5%, respectively, and the distribution of D2 occupancy at these doses could cover most of that at oral doses of 8 to 24 mg/d. CONCLUSIONS: Predicted D2 occupancy suggested that a 40- to 80-mg/d blonanserin transdermal patch dose corresponds to an 8- to 24-mg/d oral dose for the treatment of schizophrenia.

Combined treatment with endobronchial Watanabe spigot and N-butyl-2-cyanoacrylate for refractory pneumothorax in COVID-19.

Coronavirus disease 2019 (COVID-19) causes pneumothorax or mediastinal emphysema in approximately 1% of patients. According to the British Thoracic Society guidelines, the next treatment option for patients with persistent pneumothorax despite chest drainage is pleurodesis or surgery. In fact, there are reports of autologous blood pleurodesis or surgery for the treatment of pneumothorax caused by COVID-19. However, elderly patients or patients in poor general condition may not be able to tolerate surgical invasion. In this report, we present two patients who did not respond to chest drainage or pleurodesis and who were not suitable for surgery because of their poor general condition. These patients were successfully treated with an endobronchial Watanabe spigot and N-butyl-2-cyanoacrylate. This method may be an option for the treatment of refractory pneumothorax in COVID-19.

Single-Direction Approach for Thoracoscopic Segmentectomy of the Left Upper Lobe Anterior Segment With Mediastinal Lingular Artery.

Thoracoscopic resection of the anterior segment of the left upper lobe (S3) is technically challenging because of the intricate hilar structure and multiple intersegmental planes to be dissected. A single-direction approach for S3 segmentectomy is a technique in which surgeons dissect the hilum structures exclusively from the ventral side without dividing the interlobar fissure. Our consecutive case series and a representative surgical video demonstrated the feasibility of this approach in cases where the lingular artery arises from the first branch of the left pulmonary artery (mediastinal lingular artery).

Bronchoscopy for the diagnosis of nontuberculous mycobacterial pulmonary disease: Specificity and diagnostic yield in a retrospective cohort study.

BACKGROUND: Bronchoscopy is a recognized method for obtaining specimens for the diagnosis of nontuberculous mycobacterial pulmonary disease (NTM-PD). However, its diagnostic properties remain to be elucidated. The aim of this study was to determine the specificity of bronchoscopy for the diagnosis of NTM-PD, and to examine the diagnostic yield of bronchoscopy for detecting nontuberculous mycobacteria (NTM) when patients cannot expectorate sputum with NTM. METHODS: This retrospective cohort study included 2657 patients who underwent bronchoscopy and mycobacterial culture between January 2004 and June 2018 in a tertiary care center in Tokyo, Japan. To examine the specificity of bronchoscopy, the first cohort comprised patients who underwent bronchoscopy for the diagnosis of lung cancer and mycobacterial culture. To investigate the diagnostic yield, patients with nodular bronchiectasis who underwent bronchoscopy for the diagnosis of NTM-PD were enrolled into the second cohort. RESULTS: In total, 919 patients were diagnosed with lung cancer, 19 patients showed positive culture for NTM, and 14 patients showed findings for NTM-PD. Accordingly, the specificity was calculated as 900/905 (99.4%). In addition, NTM-PD was suspected before bronchoscopy in 199 patients; the diagnostic yield was 105/199 (52.8%). Four factors were associated with NTM-PD: upper lobe examination, absence of specific bacteria, absence of connective tissue disease, and a higher total computed tomography score. CONCLUSIONS: Bronchoscopy has a high specificity for the diagnosis of NTM-PD. In addition, even when NTM is undetected in sputum, bronchoscopy may detect mycobacteria in approximately half of the patients suspected of having NTM-PD.

Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes.

Imeglimin is an orally administered first-in-class drug to treat type 2 diabetes mellitus (T2DM) and is mainly excreted unchanged by the kidneys. The present study aimed to define the pharmacokinetic (PK) characteristics of imeglimin using population PK analysis and to determine the optimal dosing regimen for Japanese patients with T2DM and chronic kidney disease (CKD). Imeglimin plasma concentrations in Japanese and Western healthy volunteers, and patients with T2DM, including patients with mild to severe CKD with an estimated glomerular filtration rate (eGFR) greater than 14 ml/min/1.73 m2 were included in a population PK analysis. PK simulations were conducted using a population PK model, and the area under concentration-time curve (AUC) was extrapolated with power regression analysis to lower eGFR. The influence of eGFR, weight, and age on apparent clearance and of dose on relative bioavailability were quantified by population PK analysis. Simulations and extrapolation revealed that the recommended dosing regimen based on the AUC was 500 mg twice daily (b.i.d.) for patients with eGFR 15-45 ml/min/1.73 m2 , and 500 mg with a longer dosing interval was suggested for those with eGFR less than 15. Simulations revealed that differences in plasma AUCs between Japanese and Western patients at the same dose were mainly driven by a difference in the eGFR and that the plasma AUC after 1000 and 1500 mg b.i.d. in Japanese and Western patients, respectively, was comparable in the phase IIb studies. These results indicate suitable dosages of imeglimin in the clinical setting of T2DM with renal impairment.