BackgroundTAK-438 (vonoprazan) is a potassium-competitive acid blocker that reversibly inhibits gastric H+, K+-ATPase.AimTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-438 in healthy Japanese and non-Japanese men.MethodsIn two Phase I, randomised, double-blind, placebo-controlled studies, healthy men (Japan N = 60; UK N = 48) received TAK-438 10–40 mg once daily at a fixed dose level for 7 consecutive days. Assessments included safety, tolerability, pharmacokinetics and pharmacodynamics (intragastric pH).ResultsPlasma concentration–time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax ≤2 h). Mean elimination half-life was up to 9 h. Exposure was slightly greater than dose proportional, with no apparent time-dependent inhibition of metabolism. There was no important difference between the two studies in AUC0-tau on Day 7. TAK-438 caused dose-dependent acid suppression. On Day 7, mean 24-h intragastric pH>4 holding time ratio (HTR) with 40 mg TAK-438 was 100% (Japan) and 93.2% (UK), and mean night-time pH>4 HTR was 100% (Japan) and 90.4% (UK). TAK-438 was well tolerated. The frequency of adverse events was similar at all dose levels and there were no serious adverse events. There were no important increases in serum alanine transaminase activity. Serum gastrin and pepsinogen I and II concentrations increased with TAK-438 dose.ConclusionsTAK-438 in multiple rising oral dose levels of 10–40 mg once daily for 7 days was safe and well tolerated in healthy men and caused rapid, profound and sustained suppression of gastric acid secretion throughout each 24-h dosing interval. Clinicaltrials.gov identifiers: NCT02123953 and NCT02141711.
Loss or down-regulation of human leukocyte antigen (HLA) class I expression has been demonstrated in a variety of solid tumors. To date, such altered HLA expression has not been studied extensively in freshly isolated leukemic blasts. If it occurs, leukemic cells could escape T-cell surveillance as a consequence. Genotypes of nine leukemic cell lines were determined using a polymerase chain reaction for HLA classes I and II. Cells were also examined for HLA β β β β2-microglobulin, and allele-specific HLA protein expression using flow cytometry. Next, 44 samples of freshly isolated leukemic blasts from 43 patients with malignant hematological diseases were examined for allele-specific HLA expression using flow cytometry.
We report interim safety and immunogenicity findings from an ongoing phase 1/2 study of BNT162b2 in healthy Japanese adults. Participants were randomized 3:1 to receive 2 intramuscular injections of 30 μg BNT162b2 or placebo 21 days apart. Overall, 160 individuals were randomized: 119 received BNT162b2, and 41 received placebo. Participants were stratified by age: 20–64 years (n = 130) and 65–85 years (n = 30). More than 97% of BNT162b2 recipients received 2 doses. Local reactions and systemic events were generally transient and mild to moderate. Severe adverse events were uncommon; there were no serious adverse events. One month after dose 2, SARS-CoV-2 50% serum neutralizing geometric mean titers were 571 and 366, and geometric mean fold rises were 55.8 and 36.6, in the younger and older age groups, respectively. In summary, BNT162b2 has an acceptable safety profile and produces a robust immune response, regardless of age, in Japanese adults. (ClinicalTrials.gov, NCT04588480).
Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects. Three studies were conducted: single-ascending dose study (10-640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5-80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20-40 mg) in 30 Japanese subjects. Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t of 5-6 h. Exposure increased dose-proportionally up to 320 mg. Body weight-corrected exposure was similar between Japanese and Caucasian subjects. Urinary excretion of tofogliflozin ranged from 17.1 to 27.4% of dose. Tofogliflozin did not accumulate with once daily administration. Food intake decreased C by approximately 30% but did not change AUC. Tofogliflozin caused dose-dependent daily urinary glucose excretion (UGE), but food intake condition at administration did not affect it. The exposure-response relationship between plasma average concentration of tofogliflozin (C) and UGE fitted E model well. There were no serious adverse events leading to discontinuation or episodes of hypoglycemia. Single and multiple administration of tofogliflozin were generally well tolerated. Exposure to tofogliflozin was dose-proportional up to 320 mg and did not accumulate with multiple once-a-day administration. The model suggests more than 100 ng/mL C corresponding to the dose of between 20 and 40 mg leads to almost maximum effect of tofogliflozin.
Naf1 (Nef-associated factor 1)/TNIP1/ABIN-1 (A20-binding inhibitor of NF-κB activation) is a cellular protein that interacts and cooperates with the NFκB inhibiting protein A20. It is reported that Naf1 attenuates epidermal growth factor (EGF)/extracellular-signal-regulated kinase2 (ERK2) nuclear signaling. Naf1 also binds to Nef, which plays a key role in acquired immunodeficiency syndrome pathogenesis and HIV-1 virus replication. Naf1 mRNA consists of 18 exons and multiple splice variants have been reported; two isoforms for exon 1, deletion of exon 2 and isoforms • and ß for exon 18. Using specimens from 29 acute myeloid leukemia (AML) patients, we detected a high frequency of allelic loss on DNA at STS marker D5S2014 near the Naf1 gene. We therefore performed mutation and expression analyses using leukemia-lymphoma lines and 6 pairs of clinical AML samples. There was no mutation in the Naf1 coding region of any sample. As a result of expression analysis, we identified novel splice variants of the Naf1 gene; deletion of exon 16 (Naf1 •2, Naf1 ß2), deletion of exon 16 with an insertion (Naf1 •3, Naf1 ß3) and deletion of exons 16 and 17 (Naf1 •4). Naf1 •3 and ß3 showed premature termination. In peripheral blood mononucleocytes (PBMNCs) from healthy adults, almost no expression of full-length Naf1 (Naf1 FL), Naf1 •3 and ß3 were observed. In contrast, their expression was clear in AML blasts and in the majority of leukemia-lymphoma lines investigated. Naf1 •2 was widely expressed in PBMNCs from healthy adults, AML blasts and cell lines, suggesting it is the main transcript of the Naf1 gene. Luciferase assay revealed that Naf1 •2 had equal NF-κB inhibitory effect to that of Naf1 FL , while Naf1 •4 was less effective. In clinical AML patients, the expression of Naf1 •3 was much higher at diagnosis than on remission after chemotherapy, suggesting the possible dominant negative effect of Naf1 •3.
Ruxolitinib (INC424), a potent and selective oral Janus kinase 1 and 2 inhibitor, was recently approved by the US food and drug administration for the treatment of intermediate or high-risk myelofibrosis. The safety, tolerability, and pharmacokinetics (PK) of ruxolitinib have been extensively evaluated in healthy subjects and patients. The present study is the first to investigate the PK and tolerability of ruxolitinib in the Japanese population. Forty subjects were randomized to receive single (10-100 mg) and multiple (10 and 25 mg every 12 h) doses of ruxolitinib or placebo. Cohorts were sequentially enrolled based on the outcome of safety assessments. Ruxolitinib was rapidly absorbed, and its exposure increased dose proportionally up to 100 mg. The half-life of ruxolitinib was approximately 3 h, and drug accumulation was not observed after repeated dosing at a 12-h dosing interval. Decreasing absolute neutrophil counts were observed in five Japanese subjects treated once (100 mg, n = 1) or twice (10 mg, n = 3; 25 mg, n = 1) daily. These events were manageable and reversible upon drug discontinuation. Orally administered ruxolitinib was well tolerated in healthy Japanese volunteers. There were no apparent differences in the safety or PK of ruxolitinib between Japanese and non-Japanese subjects.
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