Healthy Japanese Male Volunteers Research Articles

Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers.

Male HVs were randomized to receive oral BI 1358894 (n = 18) or placebo (n = 6) after a high-fat, high-calorie meal within three dose groups (50mg, 100mg, 200mg), administered sequentially in dose-ascending order. The primary endpoint was number of HVs with drug-related adverse events (DRAEs). Secondary endpoints were the pharmacokinetic parameters of BI 1358894. Overall, 24 male HVs entered the trial [mean (standard deviation) age: 30.0 (7.6) years]. DRAEs occurred in 3/18 HVs (BI 1358894 100 mg group: one HV experienced dizziness and headache; BI 1358894 200 mg group: one HV experienced headache, another reported sleep disorder). BI 1358894 exposure increased dose dependently and proportionally, peaking 4-6h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group. BI 1358894 was well tolerated with a favorable pharmacokinetic profile in Japanese male HVs, similar to findings from a previous study in Caucasian male HVs. ClinicalTrials.gov (NCT03875001; 08-Mar-2019).

Bioequivalence Study of Ezetimibe Tablets After a Single Oral Dose of 10mg in Healthy Japanese Subjects Under Fasting Conditions.

This study compared the pharmacokinetic and safety profiles between a new generic and a branded reference product of 10-mg ezetimibe (EZE) tablets in 24 healthy Japanese male volunteers under fasting conditions, obtaining sufficient evidence for the marketing approval of the new generic product. The bioequivalence study was conducted with an open-label, 2 × 2, single-dose, crossover design in which the test and reference products were administered to volunteers after fasting for ≥10hours. Blood samples were collected 24 times before to 72hours after the administration of the investigational drug. We evaluated the peak drug concentration and the area under the plasma concentration-time curve up to the last measured concentration of EZE, EZEG, and total EZE (EZE + ezetimibe glucuronide [EZEG]). The 90% confidence intervals of the geometric mean ratios for peak drug concentration and area under the plasma concentration-time curve up to the last measured concentration of the test and reference products fell within the bioequivalence limits of 0.80 to 1.25 for EZE, EZEG, and total EZE. The test and reference products were well tolerated, and no adverse events occurred during the study. The test product was bioequivalent to the reference product.

Beta 1,3-1,6 Glucans Produced by Two Novel Strains of Aureobasidium Pullulans Exert Immune and Metabolic Beneficial Effects in Healthy Middle-aged Japanese Men: Results of an Exploratory Randomized Control Study.

In this pilot study, we have evaluated the specific metabolic and immune-related benefits of the AFO-202 strain and N-163 strain of black yeast Aureobasidium pullulans-produced beta 1,3-1,6 glucan in healthy human subjects. Sixteen healthy Japanese male volunteers (aged 40 to 60 years) took part in this clinical trial. They were divided into four groups (n = 4 each): Group I consumed AFO-202 beta-glucan (2 sachets of 1 g each per day), IA for 35 days and IB for 21 days; Group II consumed a combination of AFO-202 beta-glucan (2 sachets of 1 g each) and N-163 beta-glucan (1 sachet of 15 g gel each per day), IIA for 35 days and IIB for 21 days. Decrease in HbA1C and glycated albumin (GA), significant increase of eosinophils and monocytes and marginal decrease in D-dimer levels, decrease in neutrophil-to-lymphocyte ratio (NLR), with an increase in the lymphocyte-to-CRP ratio (LCR) and leukocyte-to-CRP ratio (LeCR) was observed in Group I between pre- and post-treatment. Decrease in total and LDL cholesterol, a decrease of CD11b, serum ferritin, galectin-3 and fibrinogen were profound in Group II between pre- and post-treatment. However, there was no statistically significant difference between day 21 and day 35 among the groups. This outcome warrants larger clinical trials to explore the potentials of these safe food supplements in the prevention and prophylaxis of diseases due to dysregulated metabolism, such as fatty liver disease, and infections such as COVID-19 in which balanced immunomodulation are of utmost importance, besides their administration as an adjunct to existing therapeutic approaches of both communicable and non-communicable diseases.

Safety and Efficacy of a Novel Dietary Pyrroloquinoline Quinone Disodium Salt on Cognitive Functions in Healthy Volunteers: A Clinical Investigation

Cognitive dysfunctions are increasing alarmingly around the world, and researchers are exploring preventive measures for improving brain performance. Pyrroloquinoline quinone (PQQ), a naturally occurring coenzyme in foods, exhibits potent antioxidant activity, and improves diverse functions which includes mitochondrial activation, growth, repair, protection of nerve cells by increased expression of nerve growth factor (NGF) and NGF receptors; and suppression of fibril formation and aggregation of amyloid β. A randomized, double‐blind, placebo‐controlled, parallel‐group clinical investigation (RCT) was conducted over a period of 12 weeks of supplementation of PQQ disodium salt (mnemoPQQ®; p.o.; 21.5 mg/day) in 64 healthy Japanese male and female volunteers (age 40 ‐ <80 Y) to determine the safety and efficacy on improved cognitive function and performance. In another independent study, mnemoPQQ® exhibited broad spectrum safety in a battery of toxicological assessments. No mutagenic potentials were observed. The efficacy of mnemoPQQ® on cognitive performance (memory, attention, judgment, and cognitive flexibility) was examined using Cognitrax as the primary outcome (endpoint), and forgetfulness questionnaire (DECO: Deterioration Cognitive Observee) and Mini‐Mental State Examination‐Japanese (MMSE‐J) as the secondary outcomes (endpoints). A total of 58 subjects (Placebo group = 31; Age = 70.91 ± 3.06 Y, and mnemoPQQ® group = 27; Age = 72.10 ± 3.77 Y) completed the study over a period of 12 weeks. Significant improvements were observed on the Cognitrax’s cognitive function domain score on “composite memory”, “verbal memory”, “reaction time”, “complex attention”, “cognitive flexibility”, “executive function”, and “motor speed” in the mnemoPQQ® group as compared to the placebo group. The DECO index and the MMSE‐J score were also significantly improved in the mnemoPQQ® group. No adverse events were reported. This investigation demonstrates that supplementation of mnemoPQQ® is safe and efficacious in improving memory, attention, judgment, and cognitive function, in middle‐aged to elderly population.

Safety and tolerability of medicinal parasite ova (Trichuris suis) in healthy Japanese volunteers: A randomized, double-blind, placebo-controlled trial.

Trichuris suis ova (TSO), with the potential to modulate the human immune system, have been tested for therapeutic application in autoimmune and allergic diseases such as inflammatory bowel disease (IBD). Previous clinical studies were limited to European and American participants, whereas Asian populations have not been well documented. In this study, a clinical trial was conducted to examine the safety and tolerability of TSO administration among a healthy Japanese population. The study was a randomized, double-blind, placebo-controlled trial held at Jikei University Hospital, Tokyo. Twelve volunteers were stratified into three groups receiving different doses of TSO (TSO 1000, 2500, and 7500) and another into the control group. These cases were limited to healthy Japanese men aged over 20years old. Single doses of medicinal TSO or placebo were given to three participants of each group. All participants were followed up to 56days after ingestion. During the follow-up period, clinical practitioners checked each participant at the clinic at 7, 14, 28, and 56days post-ingestion (dpi). Clinical symptoms were evaluated using questionnaire-based self-reporting, which participants filled at every visit. Blood samples were drawn at 7, 14, 28, and 56 dpi. Fecal samples were collected at 28 and 56 dpi. During the study period, twelve healthy Japanese male volunteers were enrolled. All participants completed the follow-up period. No severe adverse events were observed during the study period in all groups. Three participants in the TSO 1000, 2500, and 7500 groups had mild to moderate abdominal symptoms, diarrhea, bloating, and appetite loss during the observation period. One participant in the placebo group presented with mild diarrhea. Microscopic examination identified no parasite ova in any fecal samples. Blood sample examination indicated elevated eosinophil count in several cases, especially in the groups with the higher dose of TSO. No extra-abdominal symptoms were present in all cases. Healthy Japanese people tolerated all doses of TSO without any severe adverse events. On the other hand, mild to moderate abdominal symptoms were observed in several participants. This study suggested that the medicinal use of TSO in Japan is relatively safe, and close follow-up is recommended for sustainable usage.

A randomized, single-dose, pharmacokinetic equivalence study comparing MB02 (proposed biosimilar) and reference bevacizumab in healthy Japanese male volunteers

PurposeMB02 is a biosimilar to bevacizumab that has demonstrated similar physicochemical and functional properties in in vitro studies to the reference bevacizumab (Avastin®). This study aims to assess the pharmacokinetic (PK) similarity of MB02 to the reference bevacizumab in Japanese population.MethodsThis double-blind, randomized, parallel-group, single-dose PK study, was performed in healthy Japanese male volunteers. Subjects were equally randomized (1:1) to receive a single (3 mg/kg) IV dose of MB02 or reference bevacizumab. PK assessments were done up to 70 days post-dose. Non-compartmental parameters were calculated. PK similarity was determined using predefined equivalence range (0.80–1.25) for the area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC0–∞). Immunogenicity samples were taken pre-dose and up to day 70. Safety was assessed throughout the study.ResultsIn total, 48 subjects (24 in each treatment group) were dosed. Consequently to the observed similar PK profile, the 90% confidence interval for the geometric means ratio for the primary PK endpoint, AUC0–∞, was within the predefined equivalence range (0.981–1.11). Forty-seven treatment-emergent adverse events (TEAEs) were reported in 20 subjects (41.7%) with comparable incidence among MB02 and reference bevacizumab groups (22 and 25, respectively), none of them was severe or serious. Anti-drug antibodies incidence was low and similar between treatment groups.ConclusionsPharmacokinetic similarity of MB02 to reference bevacizumab was evidenced in Japanese healthy subjects, with comparable safety and immunogenicity profile between treatments. This study supports the biosimilarity of MB02 to reference bevacizumab in Japanese population. ClinicalTrials.gov identifier: NCT04238650.

Effect of food on exposure to napabucasin: Data from two phase I studies.

477 Background: Napabucasin is an orally-administered NAD(P)H quinone dehydrogenase 1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. Methods: Food effects on napabucasin pharmacokinetics were evaluated in two studies: one at two sites in Japan (Study 1; JapicCTI-205447) and the other at two sites in the US and three in Canada (Study 2; NCT01775423). Study 1 enrolled healthy Japanese male volunteers (HJMV) who received napabucasin 480 mg (formula 2) per sequential design — fasting on Day (D) 1 followed by a Japanese diet (JD) on D8 — with a 6-D intervening washout. In Study 2, patients (pts) with advanced malignancies received napabucasin 500 mg (formula 1) on D1 in the fasted state, then napabucasin 500 mg (formula 2) on D4 and D8 with a high-fat breakfast [HFB] or in the fasted state per the randomized sequence per crossover design. Results: In Study 1, mean plasma napabucasin levels 6–10 h after napabucasin 480 mg administration were higher in fed (JD) vs fasted states; in the fed state, Cmax increased by 15% and AUClast by ~60% (Table), while tmax decreased by ~1.4 hours. Adverse events (AEs) in Study 1 occurred in 5/6 (83.3%) HJMVs (fasted, n=3; fed, n=5; all grade [gr] 1). In Study 2, mean concentration profiles were comparable in fasted and fed (HFB) states for napabucasin 500 mg. When comparing fasted and fed states, Cmax increased by 21% and AUClast by 39% in the fed state (Table). Interpatient variability was high: geometric CV% for CL/F was 75.9% (fed) and 141% (fasted). AEs in Study 2 occurred in 68% (17/25) of fasted pts (gr 1: n=7; gr 2: n=8; gr 3, n=2) and 50% (7/14) of pts fed an HFB (gr 1: n=2; gr 2: n=3; gr 3, n=2). Conclusions: In HJMVs, napabucasin 480 mg administered with a JD increased exposure (Cmax; AUClast; AUCinf) and decreased tmax vs the fasted state. In pts with advanced malignancies, napabucasin 500 mg administered with an HFB increased exposure (Cmax; AUClast) vs the fasted state. These exposure increases are not considered to be of clinical relevance. Clinical trial information: JapicCTI-205447; NCT01775423. [Table: see text]

Effects of Milk or Apple Juice Ingestion on the Pharmacokinetics of Elvitegravir and Cobicistat in Healthy Japanese Male Volunteers: A Randomized, Single-Dose, Three-Way Crossover Study.

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF) is specified in its package insert to be taken with food to obtain sufficient exposure of EVG. It has been reported that a nutritional protein-rich drink shows comparable pharmacokinetics (PK) of EVG to those with a standard breakfast. In this study, the PK profiles of EVG and COBI were evaluated by administration of a single dose of EVG/COBI/FTC/TAF, after ingestion of either a nutritional protein-rich drink, milk, or apple juice. The geometric means for Cmax and AUCinf of EVG following milk ingestion slightly decreased by 21% and 14%, respectively, and those following apple juice ingestion decreased by 67% and 61%, respectively, compared with a nutritional protein-rich drink. There were no differences in any PK parameters of COBI. Therefore, taking EVG/COBI/FTC/TAF after milk or apple juice ingestion appeared to be not appropriate. However, for plasma trough concentrations (Ctau ), it is known that Ctau is best correlated with the efficacy of EVG. The mean C24 of EVG after milk ingestion was 620.6 ng/mL, which was more than 10-fold the protein binding-adjusted 95% inhibitory concentration. With all the above considerations, it was concluded that taking EVG/COBI/FTC/TAF with milk could be an option to maintain sufficient plasma concentrations of EVG.

Dietary intake of glucono-δ-lactone attenuates skin inflammation and contributes to maintaining skin condition.

Skin properties are influenced by both external (e.g., ultraviolet [UV], chemicals, and bacteria) and internal factors (e.g., nutrition and hormones). Therefore, some dietary supplements are expected to improve skin conditions. Glucono-δ-lactone (GDL) is widely used as a food additive and is naturally present in wine, honey, and other foods. The aim of this study was to assess whether GDL improves skin condition and inflammation. In a double-blind, placebo-controlled study, 40 healthy Japanese male volunteers were randomly assigned to either the GDL (2000 mg day-1) or placebo group. A significant difference was found in the rates of change in transepidermal water loss (TEWL) from the baseline to 6 months between the placebo and GDL groups (P < 0.05). Facial lightness (L*) significantly increased by 1.6% only in the GDL group at 6 months compared with the baseline. The value of the elasticity parameter, Ua/Uf, of dietary GDL significantly increased (6.2% at 2 months and 5.4% at 6 months). Besides these, dietary GDL suppressed UVB-induced erythema (a*) and pigmentation (L*). Dietary GDL has anti-inflammatory effects on the skin and prevents/improves skin disorders caused by seasonal change.

Evaluation of Bioequivalence Between 0.5-mg Dutasteride Capsules Manufactured by GlaxoSmithKline and an Existing Formulation: A Randomized Study in Healthy Japanese Male Volunteers.

Evaluation of Bioequivalence Between 0.5-mg Dutasteride Capsules Manufactured by GlaxoSmithKline and an Existing Formulation: A Randomized Study in Healthy Japanese Male Volunteers.

Pharmacokinetics and Pharmacodynamics of Azeloprazole Sodium, a Novel Proton Pump Inhibitor, in Healthy Japanese Volunteers.

The pharmacokinetics (PK) and pharmacodynamics (PD) of proton pump inhibitors differ among cytochrome P450 (CYP) 2C19 genotypes. Therefore, we developed azeloprazole sodium (Z-215), a novel proton pump inhibitor, whose metabolism is not affected by CYP2C19 activity in vitro. However, the PK and PD of azeloprazole sodium have not been evaluated in Japanese subjects. We conducted an open-label, crossover study in healthy Japanese male volunteers to evaluate the plasma concentration and intragastric pH with respect to CYP2C19 genotype after repeated administration of 10, 20, and 40mg azeloprazole sodium and 10 and 20 mg rabeprazole sodium (rabeprazole). The plasma concentration profile of azeloprazole sodium was similar among genotypes, whereas that of rabeprazole differed. The 24-hour intragastric pH≥4 holding time ratio (pH≥4 HTR) of azeloprazole sodium was similar among genotypes. The pH≥4 HTR was 52.5%-60.3%, 55.1%-65.8%, and 69.4%-77.1% after administration of 10, 20, and 40mg azeloprazole sodium, respectively, and 59.2%-72.3% and 64.4%-91.2% after administration of 10 and 20mg rabeprazole, respectively, on the fifth day of dosing. The maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC), and pH≥4 HTR of azeloprazole sodium were proportional to dose. The Cmax , AUC, and pH≥4 HTR on day 5 were slightly higher following administration of 20mg azeloprazole sodium before comparison with after a meal. No serious adverse events were observed. These results suggest that azeloprazole sodium is useful for treating gastroesophageal reflux disease in all CYP2C19 genotypes.

Idarucizumab, a Specific Reversal Agent for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran-Induced Anticoagulation in Japanese Healthy Male Volunteers

Background: Specific reversal agents for oral anticoagulants may be necessary to manage life-threatening bleeding or prior to emergency surgical procedures. While many reversal agents are in development, idarucizumab is approved and now available commercially in many countries. Idarucizumab is a humanized antibody fragment that specifically binds to dabigatran with high affinity and has shown immediate, complete and sustained reversal of dabigatran-induced anticoagulation in healthy male Caucasian volunteers. The present study investigated the safety, tolerability and pharmacokinetics of idarucizumab (part 1) and explored the effective dose of idarucizumab to reverse the dabigatran-induced anticoagulant effect (part 2) in healthy male Japanese volunteers.Methods: This was a two-part, phase I, randomized, placebo-controlled, double-blind, single-center, rising dose study. In part 1, subjects (n = 32) were randomized to receive either placebo (n = 2/dose group) or single intravenous doses of idarucizumab, 1, 2, or 4 g as a 5-minute infusion or 8 g as a 1-hour infusion (n = 6/group). In part 2, subjects (n = 48) were treated orally for 3 days with dabigatran etexilate (DE, 220 mg bid). On day 4, subjects received a final DE dose, followed a 3-day wash out period. Subjects were again treated orally for 3 days with DE, 220 mg bid. On Day 11, subjects received a final DE dose followed 2 hours later by placebo (n = 3/group) or idarucizumab (1, 2, 4, or 5 g [2.5 g followed by 2.5 g given 15 minutes apart]) as a 5-minute intravenous infusion, n = 9/group). The number of subjects with adverse events (AEs), emergence of anti-idarucizumab antibodies (ADAs), pharmacokinetics and the impact of idarucizumab on coagulation parameters were assessed (diluted thrombin time, ecarin clotting time, activated partial thromboplastin time, and thrombin time). In addition, potential procoagulant effects were monitored as D-dimer and prothrombin fragment F1.2.Results: Idarucizumab attained a maximum concentration in plasma around the end of each infusion followed by a biphasic decline in plasma concentrations with a rapid initial phase and a longer terminal phase.. Dabigatran treatment prolonged the clotting times of all coagulation parameters. Idarucizumab infusion resulted in immediate and complete reversal of dabigatran-induced anticoagulation, reducing coagulation parameters below the upper limit of normal. The duration was dose-dependent; at 4 and 5 g of idarucizumab, complete reversal was sustained up to 72 hours, at lower doses ≤ 2 g a partial return of the anticoagulation activity of dabigatran was observed 1-2 hours after idarucizumab administration. Concentration of unbound dabigatran decreased to below the limit of quantification immediately after administration of a single dose of idarucizumab. Idarucizumab was safe and well tolerated, and no AEs were reported. There was no elevation of either D-dimer or F1.2 levels post idarucizumab as compared to levels prior to infusion in any of the dose groups. Treatment-emergent ADAs occurred in 6 of 60 patients receiving idarucizumab.Conclusion: Idarucizumab infusion achieved immediate, complete and sustained reversal of dabigatran-associated anticoagulation in healthy male Japanese volunteers. Idarucizumab was safe and well tolerated with no procoagulant effects. Disclosuresvan Ryn:Boehringer Ingelheim: Employment. Yasaka:Sanofi: Research Funding; Nippon Boehringer Ingelheim: Other: received lecture fees (over 1 million Yen); Bristol-Myers Squibb: Other: received lecture fees (over 1 million Yen); Bayer Yakuhin: Other: received lecture fees (over 1 million Yen); Daiichi-Sankyo: Other: received lecture fees (over 1 million Yen). Harada:Boehringer Ingelheim: Employment. Taniguchi:Boehringer Ingelheim: Employment. Imazu:Boehringer Ingelheim: Employment. Norris:Boehringer Ingelheim: Employment. Gansser:Boehringer Ingelheim: Employment. Stangier:Boehringer Ingelheim: Employment.

Population Pharmacokinetic–Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects

PurposeThe goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. MethodsThis multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic–pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method. FindingsA total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration–effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin’s pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An Emax model (E[C]=[Emax⋅C]/[EC50+C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic–pharmacodynamic link model. ImplicationsThe drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316.

Effect of nasal high-flow oxygen therapy on the swallowing reflex: an in vivo volunteer study.

The advantages of nasal high-flow oxygen therapy (NHF) include not only allowing talking, but also eating and drinking, during the therapy. However, the effect of NHF on the swallowing reflex remains unclear. In the present study, we aimed to assess the effects of NHF on the swallowing reflex. Nine healthy adult Japanese male volunteers with no history of dysphagia or diseases that may cause dysphagia, such as stroke or Parkinson's disease, were evaluated. Participants received one of four levels of NHF intervention (0 (control), 15, 30 and 45L/min of oxygen) with the NHF system through the nasal cannula. Swallowing was induced by the administration of a bolus injection of 5mL of distilled water over 3s through a polyethylene catheter at each level of oxygen flow. The primary end-point was the latency period of the swallowing reflex after bolus injection, which was defined as the time from the start of the bolus injection to the onset of the electromyogram (EMG) burst of the first swallow. Mean latency times of the swallowing reflex with 15 (9.8±2.9s), 30 (9.0±2.7s) and 45 (8.5±3.0s)L/min of NHF were significantly shorter than those under control conditions (11.9±3.7s; P<0.05). Our study demonstrates that NHF may enhance swallowing function with increasing levels of NHF by reducing the latency of the reflex. NHF may allow continuation of oral intake without aspiration during oxygen therapy.

Bioequivalence and food effect assessment for vildagliptin/metformin fixed-dose combination tablets relative to free combination of vildagliptin and metformin in Japanese healthy subjects.

To assess the bioequivalence of vildagliptin/metformin fixeddose combination (FDC) tablets (50/250 mg and 50/500 mg) to free combinations of vildagliptin and metformin and the effect of food on the pharmacokinetics (PK) of vildagliptin and metformin following administration of 50/500 mg FDC tablets. Two openlabel, randomized, single-center, singledose, 2-period crossover studies were conducted in Japanese healthy male volunteers. Participants were administered vildagliptin/ metformin FDC tablets (study I: 50/250 mg, study II: 50/500 mg) or their free combinations under fasted condition. Food effect (standard Japanese breakfast: fat, 20 - 30% with ~ 600 kcal in total) was assessed during an additional period in study II (50/500 mg). PK parameters (AUC, C(max), t(max), t(1/2)) were calculated for vildagliptin and metformin. In both studies, vildagliptin/metformin FDC tablets were bioequivalent to their respective free combinations. Administration of FDC tablets after meals had no effect on vildagliptin PK parameters. The rate of absorption of metformin decreased when administered under fed condition, as reflected by a prolonged t(max) (3 hours in fasted state vs. 4 hours in fed state) and decrease in C(max) by 26%, however, the extent of absorption (AUC(last)) was similar to that in the fasted state. Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the C(max) of metformin by 26%, while AUC(last) was unchanged, consistent with previous reports. No food effect was observed on the C(max) or AUC(last) of vildagliptin. Thus, food had no clinically relevant effects on the PK of metformin or vildagliptin.

Histamine H1 receptor occupancy by the new-generation antipsychotics olanzapine and quetiapine: a positron emission tomography study in healthy volunteers.

Histamine H1 antagonists have hypnotic, appetite-promoting, and sedative side effects. Most second-generation antipsychotics have potent antagonistic effects on histamine H1 receptor (H1R). Positron emission tomography (PET) can measure the H1R occupancy (H1RO) in vivo, although there are no reports regarding antipsychotics. We studied the H1RO of olanzapine and quetiapine in vivo with respect to their plasma concentrations and subjective drowsiness by performing human PET imaging studies with [(11)C]doxepin, a potent PET ligand of H1R. Six healthy Japanese male volunteers were enrolled. Cross-randomized PET imaging was performed after a single oral administration of olanzapine (2.5 mg), quetiapine (25 mg), or placebo. PET data were analyzed by region of interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations by liquid chromatography/tandem mass spectrometry and evaluated subjective sleepiness. The binding potential ratios of olanzapine and quetiapine in the cerebral cortex were significantly lower than that of the placebo. The H1RO values of olanzapine and quetiapine in the cortex were approximately 61-80 and 56-81%, respectively. The binding potential ratios of the drugs were significantly lower than that of the placebo in the dorsolateral prefrontal and lateral temporal cortices, and anterior and posterior cingulate gyri. The H1RO values in the cortex were significantly correlated with subjective sleepiness but not plasma drug concentrations. Olanzapine and quetiapine have high H1RO values in the human brain under their clinical minimum doses. This study provides a foundation of the properties by which new-generation antipsychotics block the central histaminergic system in humans.

Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study.

We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different. A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTc F) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQTc F for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model. The concentration-effect slopes of the two populations were also compared. Equivalence was concluded if the two-sided 90% confidence interval of the difference in ΔΔQTc F was contained within -5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2. There were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin Cmax (3.27 ± 0.6 vs. 2.98 ± 0.7 µg ml(-1) ), ΔΔQTc F (9.63 ± 1.15 vs. 11.46 ± 1.19 ms at Cmax of 3.07 µg ml(-1) ) and concentration-response slopes (2.58 ± 0.62 vs. 2.34 ± 0.64 ms per µg ml(-1) ). The difference in the two ΔΔQTc F of -1.8 (90% CI -4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre-specified equivalence limits. Moxifloxacin-induced QTc prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT-prolonging drugs are needed to clarify whether inter-ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study.

Safety, tolerability, and pharmacokinetics of bi409306: A randomized, placebo-controlled, double-blinded phase i study in chinese and japanese healthy male volunteers

Smoking status, n (%) Never smoked 1 (12.5) 1 (20.0) 5 (83.3) 1 (14.3) 3 (50.0) 2 (28.6) 4 (66.7) 4 (80.0) 3 (50.0) 4 (66.7) 4 (66.7) 28 (45.2) Ex-smoker 1 (12.5) 1 (20.0) 1 (16.7) 1 (14.3) 0 (0.0) 2 (28.6) 2 (33.3) 1 (20.0) 2 (33.3) 1 (16.7) 1 (16.7) 12 (19.4) Currently smokes 6 (75.0) 3 (60.0) 0 (0.0) 5 (71.4) 3 (50.0) 3 (42.9) 0 (0.0) 0 (0.0) 1 (16.7) 1 (16.7) 1 (16.7) 22 (35.5) Alcohol status, n (%) Non-drinker 4 (50.0) 3 (60.0) 5 (83.3) 1 (14.3) 4 (66.7) 2 (28.6) 3 (50.0) 2 (40.0) 1 (16.7) 4 (66.7) 4 (66.7) 29 (46.8) Drinks, no interference 4 (50.0) 2 (40.0) 1 (16.7) 6 (85.7) 2 (33.3) 5 (71.4) 3 (50.0) 3 (60.0) 5 (83.3) 2 (33.3) 2 (33.3) 33 (53.2) Drinks, possible interference 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) *Treated set included all randomized subjects who received ≥1 dose of study medication. 1 Identical subjects consecutively received SD and MD treatment. BMI, body mass index; EM, extensive metabolizers; MD, multiple dose; PM, poor metabolizers; SD, single dose

Esomeprazole inhibits the pentagastrin-stimulated secretion of gastric acid in healthy Japanese volunteers.

Gastroesophageal reflux disease (GERD) is a common disease, in which the reflux of gastric acid causes mucosal damage of the esophagus and/or troublesome symptoms. Esomeprazole, a proton pump inhibitor, has been used for treatment of GERD in Japan since 2011; namely, only little is known about its effect on gastric acid secretion in Japanese. We, therefore, assessed the relationship between dose and timing of esomeprazole administration and gastric acid inhibition in 11 healthy male Japanese volunteers by directly examining gastric acid secretion capacity. In this randomized, open-label, three-way crossover study, the subjects were dosed with esomeprazole 10 mg or 20 mg once a day (q.d.), or 20 mg twice a day (b.i.d.) for 14 days, and pentagastrin-stimulated gastric acid secretion was measured by endoscopic gastrin test. At steady states, gastric acid inhibition rates were significantly higher in esomeprazole 20 mg b.i.d. (median 100.0%, interquartile range [IQR] 99.4-100%, P = 0.027) or 20 mg q.d. (100.0%, IQR 99.7-100%, P = 0.016), compared with 10 mg q.d. (98.4%, IQR 84.4-100%). At trough states, esomeprazole 20 mg b.i.d. showed significantly higher gastric acid inhibition (99.6%, IQR 99.0-100%) than did 20 mg q.d. (84.2%, IQR 76.4-88.8%, P = 0.002) or 10 mg q.d. (64.9%, IQR 59.1-76.7%, P = 0.001). Thus, esomeprazole 20 mg b.i.d. was sufficient to inhibit > 99% gastric acid secretion in healthy subjects. We propose that esomeprazole 20 mg b.i.d. is effective for treating Japanese patients with refractory GERD who require long-lasting gastric acid inhibition.

Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin in Japanese healthy male volunteers

Objectives: To investigate the pharmacokinetic/pharmacodynamic interactions of the antidiabetic agents canagliflozin (a sodium-glucose cotransporter-2 inhibitor) and teneligliptin (a dipeptidyl peptidase-4 inhibitor) in Japanese healthy adult men.Methods: Open-label, one-way crossover study used canagliflozin (200 mg/day p.o.) and teneligliptin (40mg/day p.o). A single dose of object drug (either canagliflozin or teneligliptin) was administered on day 1 followed by washout and continuous administration of precipitant drug (days 1 – 9). Both drugs were concomitantly administered on day 7.Results: No changes in AUC0 – 72h and Cmax were observed for canagliflozin+teneligliptin versus monotherapy; geometric mean ratios for AUC0 – 72h and Cmax were 0.982 and 0.982 for the plasma concentration of canagliflozin and 0.983 and 0.976 for the plasma concentration of teneligliptin, respectively. Plasma concentrations of active and total glucagon-like peptide-1 (GLP-1) increased with canagliflozin+teneligliptin versus teneligliptin alone. Mean AUC0.5 – 4h increased post-meal, on combination therapy, from 9.6 to 12.5 pmol·h/l (active GLP-1) and from 21.5 to 32.3 pmol·h/l (total GLP-1). Adverse events developed in four subjects; all were mild and resolved but one subject withdrew due to generalized erythema.Conclusions: GLP-1 levels increased with the canagliflozin+teneligliptin combination, and no PK interaction was observed. This combination may show favorable antidiabetic effects without increasing systemic exposure.