Real-world outcomes of avelumab plus axitinib as first-line therapy in patients with advanced renal cell carcinoma in Japan: A multicenter, retrospective, observational study (J-DART).

OBJECTIVES: In the phase 3 JAVELIN Renal 101 trial in patients with advanced renal cell carcinoma (aRCC), objective response rate (ORR) and progression-free survival (PFS) were significantly improved in patients treated with first-line avelumab plus axitinib vs sunitinib. Here we evaluate real-world outcomes with first-line avelumab plus axitinib in Japanese patients with aRCC. METHODS: In this multicenter, noninterventional, retrospective study, clinical data from patients with aRCC treated with first-line avelumab plus axitinib between December 2019 and December 2020 in Japan were reviewed. Endpoints included ORR and PFS per investigator assessment, and time to treatment discontinuation (TTD). RESULTS: Data from 48 patients (median age, 69 years) from 12 sites were analyzed. Median follow-up was 10.4 months (range, 2.6-16.5), and median duration of treatment was 7.4 months (range, 0.5-16.5). International Metastatic RCC Database Consortium risk category was favorable, intermediate, or poor in 16.7%, 54.2%, and 29.2% of patients, respectively. The ORR was 48.8% (95% CI, 33.3%-64.5%), including complete response in 3/43 patients (7.0%). Thirteen patients (27.1%) had disease progression or died, and median PFS was 15.3 months (95% CI, 9.7 months - not estimable). At data cutoff, 24 patients (50.0%) were still receiving avelumab plus axitinib, and median TTD was 15.2 months (95% CI, 7.4 months - not estimable). Three patients (6.3%) received high-dose corticosteroid treatment for immune-related adverse events, and 8 (16.7%) received treatment for infusion-related reactions. CONCLUSIONS: We report the first real-world evidence of the effectiveness and tolerability of first-line avelumab plus axitinib in Japanese patients with aRCC. Results were comparable with the JAVELIN Renal 101 trial.

Development and Validation of a Proteomic Correlation Profiling Technique to Detect and Identify Enzymes Involved in Metabolism of Drugs of Concern.

To predict the variation of pharmacological or toxicological effect caused by pharmacokinetic variance, it is important to be able to detect previously unknown and unsuspected enzymes involved in drug metabolism. We investigated the use of proteomic correlation profiling (PCP) as a technique to identify the enzymes involved in metabolism of drugs of concern. By evaluating the metabolic activities of each enzyme (including isoforms of cytochrome P450, uridine 5' diphospho-glucuronosyltransferase, and hydrolases, plus aldehyde oxidase and carbonyl reductase) on their typical substrates using a panel of human liver samples, we were able to show the validity of PCP for this purpose. R or Rs and P values were calculated for the association between the protein abundance profile of each protein and the metabolic rate profile of each typical substrate. For the 18 enzymatic activities examined, 13 of the enzymes reported to be responsible for the reactions had correlation coefficients higher than 0.7 and were ranked first to third. For the remaining five activities, the responsible enzymes had correlation coefficients lower than 0.7 and lower rankings. The reasons for this were diverse, including confounding resulting from low protein abundance ratios, artificially high correlations of other enzymes due to limited sample numbers, the presence of inactive enzyme forms, and genetic polymorphisms. Overall, PCP was able to identify the majority of responsible drug-metabolizing enzymes across several enzyme classes (oxidoreductase, transferase, hydrolase); use of this methodology could allow more timely and accurate identification of unknown drug-metabolizing enzymes. SIGNIFICANCE STATEMENT: Proteomic correlation profiling using samples from individual human donors was proven to be a useful methodology for the identification of enzymes responsible for drug-metabolism. This methodology could accelerate the identification of unknown drug-metabolizing enzymes in the future.

Characterization of Enzymes Involved in Nintedanib Metabolism in Humans.

Nintedanib, which is used to treat idiopathic pulmonary fibrosis and non-small cell lung cancer, is metabolized to a pharmacologically inactive carboxylate derivative, BIBF1202, via hydrolysis and subsequently by glucuronidation to BIBF1202 acyl-glucuronide (BIBF1202-G). Since BIBF1202-G contains an ester bond, it can be hydrolytically cleaved to BIBF1202. In this study, we sought to characterize these metabolic reactions in the human liver and intestine. Nintedanib hydrolysis was detected in human liver microsomes (HLMs) (Clearance [CL int]: 102.8 ± 18.9 µL/min per mg protein) but not in small intestinal preparations. CES1 was suggested to be responsible for nintedanib hydrolysis according to experiments using recombinant hydrolases and hydrolase inhibitors as well as proteomic correlation analysis using 25 individual HLM. BIBF1202 glucuronidation in HLM (3.6 ± 0.3 µL/min per mg protein) was higher than that in human intestinal microsomes (1.5 ± 0.06 µL/min per mg protein). UGT1A1 and gastrointestinal UGT1A7, UGT1A8, and UGT1A10 were able to mediate BIBF1202 glucuronidation. The impact of UGT1A1 on glucuronidation was supported by the finding that liver microsomes from subjects homozygous for the UGT1A1*28 allele showed significantly lower activity than those from subjects carrying the wild-type UGT1A1 allele. Interestingly, BIBF1202-G was converted to BIBF1202 in HLS9 at 70-fold higher rates than the rates of BIBF1202 glucuronidation. An inhibition study and proteomic correlation analysis suggested that ß-glucuronidase is responsible for hepatic BIBF1202-G deglucuronidation. In conclusion, the major metabolic reactions of nintedanib in the human liver and intestine were quantitatively and thoroughly elucidated. This information could be helpful to understand the inter- and intraindividual variability in the efficacy of nintedanib. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study to characterize the enzymes responsible for each step of nintedanib metabolism in the human body. This study found that ß-glucuronidase may contribute to BIBF1202-G deglucuronidation.

Identification of HSD17B12 as an enzyme catalyzing drug reduction reactions through investigation of nabumetone metabolism.

Nabumetone, a nonsteroidal anti-inflammatory prodrug, is converted to a pharmacologically active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA); however, it is 11-fold more efficiently converted to 4-(6-methoxy-2-naphthyl)butan-2-ol (MNBO) via a reduction reaction in human hepatocytes. The goal of this study was to identify the enzyme(s) responsible for MNBO formation from nabumetone in the human liver. MNBO formation by human liver microsomes (HLM) was 5.7-fold higher than in the liver cytosol. In a panel of 24 individual HLM samples with quantitative proteomics data, the 17ß-hydroxysteroid dehydrogenase 12 (HSD17B12) protein level had the high correlation coefficient (r = 0.80, P < 0.001) among 4457 proteins quantified in microsomal fractions during MNBO formation. Recombinant HSD17B12 expressed in HEK293T cells exhibited prominent nabumetone reductase activity, and the contribution of HSD17B12 to the activity in the HLM was calculated as almost 100%. MNBO formation in HepG2 and Huh7 cells was significantly decreased by the knockdown of HSD17B12. We also examined the role of HSD17B12 in drug metabolism and found that recombinant HSD17B12 catalyzed the reduction reactions of pentoxifylline and S-warfarin, suggesting that HSD17B12 prefers compounds containing a methyl ketone group on the alkyl chain. In conclusion, our study demonstrated that HSD17B12 is responsible for the formation of MNBO from nabumetone. Together with the evidence for pentoxifylline and S-warfarin reduction, this is the first study to report that HSD17B12, which is known to metabolize endogenous compounds, such as estrone and 3-ketoacyl-CoA, plays a role as a drug-metabolizing enzyme.

Functional coupling of organic anion transporter OAT10 (SLC22A13) and monocarboxylate transporter MCT1 (SLC16A1) influencing the transport function of OAT10.

OAT10 (SLC22A13) is a transporter highly expressed in renal tubules and transporting organic anions including nicotinate, ß-hydroxybutyrate, p-aminohippurate, and orotate. In transport assays using Xenopus oocytes and HEK293 cells, we found that apparent substrate selectivity of OAT10 was different between the expression systems, particularly less pronounced uptake of ß-hydroxybutyrate in HEK293 cells. Because functional coupling between transporters may interfere with functional properties of the transporter, we searched for endogenous transporters in HEK293 cells that could affect OAT10. By means of comprehensive approach with co-immunoprecipitation followed by LC-MS/MS analysis, we identified monocarboxylate transporter MCT1 (SLC16A1) as physically coupled with OAT10. The knockdown of MCT1 in OAT10-expressing HEK293 cells increased the uptake of ß-hydroxybutyrate and nicotinate, common substrates of OAT10 and MCT1, whereas the uptake of orotate, a substrate of only OAT10, was not affected. MCT1 is supposed to act as an escape route and mediate the efflux of nicotinate and ß-hydroxybutyrate taken up by OAT10 localized nearby MCT1, as suggested by co-immunoprecipitation. This functional coupling would explain altered apparent substrate selectivity in HEK293 cells compared with Xenopus oocytes. The findings in this study warn in transporter studies that the expression system can interfere with assessing correct transport properties due to unexpected interactions with endogenous transporters.

In Vivo Gene Expression Profile of Human Intestinal Epithelial Cells: From the Viewpoint of Drug Metabolism and Pharmacokinetics.

Orally administered drugs are absorbed and metabolized in the intestine. To accurately predict pharmacokinetics in the intestine, it is essential to understand the intestinal expression profiles of the genes related to drug absorption, distribution, metabolism, and excretion (ADME). However, in many previous studies, gene expression analysis in the intestine has been carried out using specimens from patients with cancer. In this study, to obtain more accurate gene expression profiles, biopsy samples were collected under endoscopic observation from the noninflammatory regions of 14 patients with inflammatory bowel disease, and RNA-seq analysis was performed. Gene expression analysis of drug-metabolizing enzymes (cytochromes P450), non-cytochrome P450 enzymes, nuclear receptors, drug-conjugating enzymes (UDP-glucuronosyltransferases and sulfotransferases), and apical and basolateral drug transporters was performed in biopsy samples from the duodenum, ileum, colon, and rectum. The proportions of the cytochromes P450 expressed in the ileum were 25% (CYP3A4), 19% (CYP2C18), and 14% (CYP3A5). CYP3A4 and CYP2C19 were highly expressed in the duodenum and ileum, but not in the colon and rectum. In the ileum, apical transporters such as P-gp, peptide transporter 1, breast cancer resistance protein, MRP2, and ASBT were strongly expressed, and the expression levels of P-gp and ASBT in the ileum were higher than those in other regions. In the ileum, basolateral transporters such as OSTα, OSTß, and MRP3 were strongly expressed. We succeeded in obtaining gene expression profiles of ADME-related genes in human intestinal epithelial cells in vivo. We expect that this information would be useful for accurate prediction of the pharmacokinetics of oral drugs. SIGNIFICANCE STATEMENT: To obtain gene expression profiles of ADME-related genes in human intestinal epithelial cells in vivo, biopsy samples were collected under endoscopic observation from the noninflammatory regions of 14 patients with inflammatory bowel disease, and RNA-seq analysis was performed. Gene expression profiles of drug-metabolizing enzymes (cytochromes P450), non-cytochrome P450 enzymes, nuclear receptors, drug-conjugating enzymes (UDP-glucuronosyltransferases and sulfotransferases), and apical and basolateral drug transporters in biopsy samples from the duodenum, ileum, colon, and rectum were obtained in this study.

Quantitative Expression of Hepatobiliary Transporters and Functional Uptake of Substrates in Hepatic Two-Dimensional Sandwich Cultures: A Comparative Evaluation of Upcyte and Primary Human Hepatocytes.

Deficient functional expression of drug transporters incapacitates most hepatic cell lines as a reliable tool for evaluating transporter-mediated drug-drug interactions. Recently, genetically modified cells (referred to as upcyte hepatocytes) have emerged as an expandable, noncancerous source of human hepatic cells. Herein, we quantified mRNA and protein levels of key hepatobiliary transporters and we assessed associated uptake activity in short- and long-term cultures of upcyte human hepatocytes (UHH) in comparison to cryopreserved primary human hepatocytes (cPHH). Expression of canalicular efflux pumps, such as MRD1/ABCB1, MATE1/SLC47A1, and MRP2/ABCC2, was relatively well preserved in UHH. By contrast, long-term cultivation of UHH in a two-dimensional sandwich configuration [sandwich-cultured upcyte human hepatocytes (SCUHH)] was required to upregulate organic anion-transporting polypeptide OATP1B1/SLCO1B1, OATP2B1/SLCO2B1, NTCP/SLC10A1, and OCT1/SLC22A1 mRNA expression, which correlated well with respective protein abundances. However, mRNA and protein levels of sinusoidal solute carrier transporters, except for NTCP and OATP2B1, remained low in SCUHH compared to sandwich-cultured cPHH. OCT1- and NTCP-mediated uptake of N-methyl-4-phenylpyridinium acetate and taurocholate was demonstrated in both hepatic models, whereas active uptake of OATP1B1/1B3-selective marker substrates, paralleled by markedly reduced SLCO1B1/1B3 expression, were not detectable in SCUHH. Uptake studies under Na+-depletion and excess of taurocholate confirmed the presence of functional NTCP protein and indicated that NTCP, apart from OATP2B1, contributed substantially to the overall hepatic uptake of rosuvastatin in SCUHH. In conclusion, our data suggest that SCUHH, despite their limitation for evaluating OATP1B1/1B3-mediated transport processes, retain NTCP, OATP2B1, and OCT1 transport activities and thus may be considered as a tool for elucidating compensatory uptake pathways for OATP1B1/1B3 substrates.

Efficacy and safety of subgroup analysis stratified by baseline HbA1c in a Japanese phase 3 study of dulaglutide 0.75 mg compared with insulin glargine in patients with type 2 diabetes.

The efficacy and safety of once-weekly dulaglutide 0.75 mg (dulaglutide) compared with once-daily insulin glargine (glargine) in Japanese patients with type 2 diabetes were evaluated according to subgroups stratified by baseline glycated hemoglobin (HbA1c) (≤8.5% or >8.5%). This exploratory analysis of a randomized, open-label, phase 3 study included 361 patients. In both HbA1c subgroups (patients with baseline HbA1c ≤8.5% or >8.5%), a statistically significantly greater reduction in HbA1c was observed in dulaglutide-treated patients compared with glargine-treated patients after 26 weeks of treatment (HbA1c ≤8.5%: dulaglutide, -1.27%; glargine, -0.72%; HbA1c >8.5%: dulaglutide, -2.04%; glargine, -1.47%; p < 0.001 for both). Mean body weight was decreased from baseline in both subgroups of the dulaglutide group and increased in both subgroups of the glargine group; there were statistically significant differences between the treatment groups in both subgroups (p < 0.05 for both). In both subgroups, similar reductions in fasting blood glucose were observed for dulaglutide- and glargine-treated patients, and a greater reduction in postprandial blood glucose was observed for dulaglutide-treated patients compared with glargine-treated patients. Although dulaglutide increased gastrointestinal adverse events compared with glargine in both subgroups, all gastrointestinal events of diarrhea, nausea, constipation, and vomiting in dulaglutide-treated patients were mild in intensity and well tolerated. In both subgroups, there was a lower incidence of hypoglycemia with dulaglutide than with glargine. Dulaglutide demonstrated significantly greater HbA1c reduction compared with glargine, with an acceptable safety profile, regardless of baseline HbA1c.

Analysis of efficacy and safety of dulaglutide 0.75 mg stratified by sex in patients with type 2 diabetes in 2 randomized, controlled phase 3 studies in Japan.

We analyzed the efficacy and safety of once weekly dulaglutide 0.75 mg by sex in 2 randomized, controlled phase 3 studies in Japanese patients with type 2 diabetes (a 52-week monotherapy study [comparator liraglutide 0.9 mg] and a 26-week combination therapy study [comparator insulin glargine]). Females comprised 18% of patients in the monotherapy study and 29% of patients in the combination therapy study. Mean reductions from baseline in glycated hemoglobin (HbA1c) were similar between the sexes for dulaglutide- and liraglutide-treated patients (range -1.17% to -1.49%). Females had numerically greater weight loss or less weight gain than males across all treatment groups. The percentages of patients with reductions in both HbA1c and weight from baseline were also greater for females than for males in all treatment groups. In all treatment groups, the incidences of treatment-emergent adverse events tended to be greater among females than among males. No differences in the incidences of total or nocturnal hypoglycemia were observed between the sexes in any treatment group. Overall, in 2 studies in Japan, across all treatment groups it appeared that HbA1c lowering was unaffected by patient sex, while female patients had greater weight loss or less weight gain and greater incidence of adverse events, including nausea, compared to male patients. Incidences of patients discontinuing dulaglutide early due to adverse event were low (<10%) for both sexes, and no new safety concerns related to dulaglutide were identified for either sex. Therefore, the benefit/risk ratio for dulaglutide remains unchanged, positive for both sexes.

Pancreatic safety in Japanese patients with type 2 diabetes treated with once weekly dulaglutide 0.75 mg up to 52 weeks in phase 3 clinical trials.

The effects of incretin therapies on pancreatic safety are currently being evaluated. In 3 phase 3 clinical studies of once weekly dulaglutide 0.75 mg (dulaglutide) in Japanese patients with type 2 diabetes (T2D), symptoms suggestive of acute pancreatitis as well as pancreatic enzymes were assessed and the risk of acute pancreatitis was evaluated. Patients who met any of the predefined criteria (clinical signs/symptoms of acute pancreatitis, confirmed amylase or lipase level ≥3 times the upper limit of normal [ULN], abdominal imaging of the pancreas) were adjudicated for acute pancreatitis by a blinded external committee. A total of 43 events in 40 patients (dulaglutide, 35/917 patients; liraglutide, 2/137 patients; insulin glargine, 2/180 patients; and placebo, 2/70 patients) were adjudicated (1 patient had events adjudicated during both placebo and dulaglutide treatment); 2 patients treated with dulaglutide had acute pancreatitis confirmed (2/917 [0.2%]; 2.651 patients/1,000 patient-years). One of these patients was diagnosed by the investigator with acute pancreatitis related to dulaglutide, but there was no typical abdominal pain. The event in the other patient occurred following an endoscopic ultrasound-guided fine needle aspiration. Transient increases in lipase ≥3×ULN were observed in 2% of patients in both the dulaglutide and liraglutide groups; the incidence in dulaglutide-treated patients was not significantly different from the incidences in liraglutide, placebo-, or insulin glargine-treated patients. Results of systematic assessments of pancreatic safety in 3 phase 3 studies for up to 52 weeks do not suggest an increased risk of acute pancreatitis in Japanese patients treated with dulaglutide.

Efficacy and safety analyses across 4 subgroups combining low and high age and body mass index groups in Japanese phase 3 studies of dulaglutide 0.75 mg after 26 weeks of treatment.

In 855 Japanese patients with type 2 diabetes receiving once weekly dulaglutide 0.75 mg in 3 phase 3 studies, the effects on efficacy and safety at week 26 (last observation carried forward) were investigated in a post hoc descriptive analysis of subgroups of age (<65 years [young], ≥65 years [elderly]) and body mass index (BMI [<25 kg/m2, ≥25 kg/m2]). The 4 subgroups were as follows: 1) the young/low-BMI subgroup (Y/L) (n = 255); 2) the young/high-BMI subgroup (Y/H) (n = 386), 3) the elderly/low-BMI subgroup (E/L) (n = 137), and 4) the elderly/high-BMI subgroup (E/H) (n = 77). The mean changes from baseline in glycated hemoglobin (HbA1c) and body weight, respectively, were -1.69% and -0.29 kg in the Y/L subgroup; -1.48% and -0.09 kg in the Y/H subgroup; -1.68% and -0.20 kg in the E/L subgroup; and -1.72% and -0.26 kg in the E/H subgroup. The incidences of nausea and hypoglycemia, respectively, were 6.7% and 11.0% in the Y/L subgroup; 7.0% and 8.0% in the Y/H subgroup; 10.2% and 18.2% in the E/L subgroup; and 3.9% and 22.1% in the E/H subgroup. Dulaglutide improved HbA1c regardless of age or BMI; a higher incidence of hypoglycemia was observed in elderly patients compared to younger patients.

The combination of dulaglutide and biguanide reduced bodyweight in Japanese patients with type 2 diabetes.

The efficacy and safety of once-weekly dulaglutide 0.75 mg (dulaglutide) in Japanese patients with type 2 diabetes (T2D) were evaluated according to subgroups defined by concomitant oral hypoglycaemic agents. This exploratory analysis included data from a randomized, open-label, phase III study that compared dulaglutide with insulin glargine (glargine) (n = 361). The three subgroups were dulaglutide or glargine in combination with sulphonylurea (SU) alone, biguanide (BG) alone or SU and BG combined. There were no clinically relevant differences in glycated haemoglobin (HbA1c) changes among the three subgroups in the dulaglutide group; in the glargine group, a numerically greater reduction was observed in combination with BG alone compared to the other two groups (SU alone and SU + BG). Weight loss was observed with dulaglutide in combination with BG alone or with SU + BG. The incidence of adverse events among subgroups was significantly different in the glargine group but not in the dulaglutide group. Incidence of hypoglycaemia was highest in combination with SU for both treatments. For patients with T2D, dulaglutide added to concomitant BG may be more likely to result in weight loss than dulaglutide added to concomitant SU.

Iminium ion metabolites are formed from nintedanib by human CYP3A4.

Nintedanib is used to treat idiopathic pulmonary fibrosis, systemic sclerosis, interstitial lung disease, and progressive fibrotic interstitial lung disease. It is primarily cleared via hepatic metabolism, hydrolysis, and glucuronidation. In addition, formation of the iminium ion, a possible reactive metabolite, was predicted based on the chemical structure of nintedanib. To obtain a hint which may help to clarify the cause of nintedanib-induced liver injury, we investigated whether iminium ions were formed in the human liver. To detect unstable iminium ions using liquid chromatography-tandem mass spectrometry (LC-MS/MS), potassium cyanide was added to the reaction mixture as a trapping agent. Human liver and intestinal microsomes were incubated with nintedanib in the presence of NADPH to form two iminium ion metabolites on the piperazine ring. Their formation is strongly inhibited by ketoconazole, a potent cytochrome P450 (CYP) 3A4 inhibitor. Among the recombinant P450s, only CYP3A4 formed cyanide adducts. The role of CYP3A4 was supported by the positive correlation between CYP3A4 protein abundance, as determined by LC-MS-based proteomics, and the formation of cyanide adducts in 25 individual human liver microsomes. In conclusion, we have demonstrated that iminium ion metabolites are formed from nintedanib by CYP3A4 as potential reactive metabolites.

One year safety and immunogenicity of AZD1222 (ChAdOx1 nCoV-19): Final analysis of a randomized, placebo-controlled phase 1/2 trial in Japan.

BACKGROUND: Long duration trial data for two-dose COVID-19 vaccines primary series' are uncommon due to unblinding and additional doses. We report one-year follow-up results from a phase 1/2 trial of AZD1222 (ChAdOx1 nCoV-19) in Japan. METHODS: Adults (n = 256) seronegative for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were stratified by age, 18-55 (n = 128), 56-69 (n = 86) and ≥70-year-old (n = 42), and randomized 3:1 to AZD1222 or placebo. Safety, immunogenicity, and exploratory efficacy data were collected until study Day 365. RESULTS: Safety was consistent with previous reports. In AZD1222 vaccinees, humoral responses against SARS-CoV-2 steadily declined over time. By Day 365, anti-SARS-CoV-2 spike-binding (spike) and receptor-binding domain (RBD) mean antibody titers remained above Day 15 levels and pseudovirus neutralizing antibodies were undetectable in many participants. CONCLUSIONS: AZD1222 is immunogenic and well tolerated in Japanese adults. Expected waning in anti-SARS-CoV-2 humoral responses was observed; spike and RBD antibody titers remained elevated. (ClinicalTrials.gov: NCT04568031).

Immunogenicity and safety of AZD1222 (ChAdOx1 nCoV-19) against SARS-CoV-2 in Japan: a double-blind, randomized controlled phase 1/2 trial.

BACKGROUND: Immunogenicity and safety of the AZD1222 (ChAdOx1 nCoV-19) vaccine was evaluated in Japanese adults in an ongoing phase 1/2, randomized, double-blind, parallel-group, placebo-controlled, multi-centre trial (NCT04568031). METHODS: Adults (n=256, age ≥18 years) seronegative for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were stratified by age into 18-55- (n=128), 56-69- (n=86) and ≥70-year-old cohorts (n=42), and randomized 3:1 to receive AZD1222 or placebo (two intramuscular injections 4 weeks apart). Immunogenicity and safety were coprimary endpoints. Data collected up to Day 57 are reported. RESULTS: Positive seroresponses to SARS-CoV-2 spike and receptor-binding domain antigens were seen in all 174 participants who received two doses of AZD1222. Neutralizing antibody seroresponses were seen in 67.5%, 60.3% and 50.0% of participants receiving AZD1222 aged 18-55, 56-69 and ≥70 years, respectively. Solicited adverse events (AEs) were typically mild/moderate in severity and included pain and tenderness at the injection site, malaise, fatigue, muscle pain and headache. Common unsolicited AEs included pain and tenderness at the injection site, fatigue and elevated body temperature. No vaccine-related serious AEs or deaths were reported. CONCLUSIONS: AZD1222 elicited a strong humoral immune response against SARS-CoV-2, and was well tolerated in Japanese participants, including elderly participants.

Subgroup Analysis Stratified by Baseline Pancreatic ß-cell Function in a Japanese Study of Dulaglutide in Patients with Type 2 Diabetes.

INTRODUCTION: This analysis investigated the relationship between baseline fasting pancreatic ß-cell function and efficacy in Japanese patients with type 2 diabetes (T2D) treated with once-weekly dulaglutide 0.75 mg (dulaglutide) or once-daily liraglutide 0.9 mg (liraglutide) for up to 52 weeks. METHODS: In a 52-week study of monotherapy in Japanese patients with T2D, patients were categorized into three subgroups defined by tertiles (low, medium, and high) of baseline values of three pancreatic ß-cell function parameters [fasting C-peptide, C-peptide index, and secretory units of islets in transplantation (SUIT) index]. Associations between these parameters and efficacy [defined by changes from baseline in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), postprandial blood glucose (PBG), mean of all meals blood glucose excursion, and body weight] in the dulaglutide group (280 patients) or the liraglutide group (137 patients) were evaluated. RESULTS: Patients in the subgroups with high insulin-secreting ability (based on pancreatic ß-cell function) were younger and had shorter disease duration and higher body mass index compared to those with low insulin-secreting ability. No specific trend was observed between baseline pancreatic ß-cell function and changes in HbA1c or FBG. Reductions from baseline in mean PBG and excursion were greatest for patients in the low ß-cell function tertiles. Inconsistent trends in body weight were observed across the treatment groups and ß-cell function parameters. CONCLUSION: In Japanese patients with T2D, changes in HbA1c and body weight after 52 weeks of treatment with dulaglutide or liraglutide could not be predicted by patients' fasting pancreatic ß-cell function before treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01558271). FUNDING: Eli Lilly K.K. (Kobe, Japan).

Recent Trends in the Practice of Procedural Sedation Under Local Anesthesia for Catheter Ablation, Gastrointestinal Endoscopy, and Endoscopic Surgery in Japan: A Retrospective Database Study in Clinical Practice from 2012 to 2015.

OBJECTIVES: To investigate changes in sedation practice during 2012-2015, using a large health claims database, for catheter ablation (CA), gastrointestinal endoscopic examination (EE), and surgery (ES) after dexmedetomidine (DEX) was approved for procedural sedation in 2013. We assessed the trends of sedative utilization, sedative-analgesic combinations, and, additionally, incidence of complications from 2012 to 2015. METHODS: Using the database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan), annual utilization proportions of the sedatives and sedative-analgesic combinations and occurrence of complications were calculated in patients with a record of local anesthesia and CA, EE, and/or ES but without general anesthesia used on the same day. The sedatives studied were DEX, propofol (PF), midazolam (MDZ), diazepam, flunitrazepam, thiamylal (TIA), thiopental (TIO), and ketamine. RESULTS: DEX was used most often for CA, followed by PF. From 2012 to 2015, the proportion of DEX increased from 30 to 36%, and that of PF slightly decreased from 29 to 27%. The order of utilization proportions did not change for EE or ES. The use of benzodiazepines, particularly MDZ, predominated. The top five sedative-analgesic combination patterns changed during the study period for CA, but not for EE or ES. The most common complications with CA, EE, and ES were bradycardia, nausea and vomiting, and respiratory depression, respectively. There were no changes in the complications' trends for the procedures. CONCLUSION: The approved use of DEX for procedural sedation resulted in changes for CA, but not for EE or ES. The complication trends did not change.

SFTG international collaborative study on in vitro micronucleus test IV. Using CHL cells.

In this report, are presented the results of an international collaborative study on the in vitro micronucleus assay, using CHL cells. Fourteen laboratories participated in this study which was coordinated by an organizing committee supported by the SFTG (the French branch of the European Environmental Mutagen Society). Nine coded substances, having different modes of action and at different levels were assessed in the in vitro micronucleus test, using a common protocol. Mitomycin C was used as a positive control. In order to help to define a standard protocol on CHL cells, short and long treatment periods followed by various recovery times, with or without cytochalasin B, were compared. After an evaluation of the acceptability of the assays, the tested chemicals were classified as negative, positive or equivocal. Mannitol and clofibrate were judged as negative in all treatment schedules. Bleomycin was positive in all the treatment schedules, with an increase in the number of micronucleated cells in both mononucleate and binucleate cells when using cytochalasin B. This was also shown for the aneugens colchicine, diethylstilboestrol and griseofulvin, as expected. Urethane was judged as equivocal only after long treatment with cytochalasin B, and negative in all other treatment schedules. In any case, no genotoxic compound would have been missed with schedules including a short and a long treatment time, whether the treatment was followed by a recovery period or not and whether cytochalasin B was used or not. Thus, these results show that CHL cells were suitable for accurately detecting clastogenic and aneugenic compounds of various types in the in vitro micronucleus test.