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Purpose Canagliflozin, an orally active sodium-glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of canagliflozin is 100 or 300 mg once daily. This Phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety profile of canagliflozin in healthy Chinese subjects. Methods In this double-blind, single-dose, 3-way crossover study, 15 healthy subjects were randomized (1:1:1) to receive single oral doses of canagliflozin 100 mg, canagliflozin 300 mg, or placebo. Pharmacokinetic, pharmacodynamic, and safety assessments were made at prespecified time points. Findings All participants are healthy Chinese adults. Mean AUC and Cmax of canagliflozin increased in a dose-dependent manner after single-dose administration (AUC0-8, 10,521 ng · h/mL for 100 mg, 33,583 ng · h/mL for 300 mg; Cmax, 1178 ng/mL for 100 mg, 4113 ng/mL for 300 mg). The mean apparent t1/2 and the median Tmax of canagliflozin were independent of dose (t1/2, 16.0 hours for 100 mg, 16.2 hours for 300 mg; Tmax, ~1 hour). Mean CL/F and renal clearance of canagliflozin were comparable between the 2 doses. Mean plasma metabolite to parent molar ratios for Cmax and AUC0-8 were similar with both doses. Canagliflozin decreased the 24-hour mean renal threshold for glucose, calculated by using measured creatinine clearance to estimate the glomerular filtration rate (67.9 and 60.7 mg/dL for canagliflozin 100 and 300 mg, respectively) and 24-hour increased urinary glucose excretion (33.8 and 42.9 g for canagliflozin 100 and 300 mg, respectively) in a dose-dependent manner; the 24-hour plasma glucose profile remained largely unchanged. No deaths, hypoglycemic events, or discontinuations due to adverse events were observed. Implications Pharmacokinetics (AUC and Cmax) of canagliflozin increased in a dose-dependent manner after single oral doses of canagliflozin (100 and 300 mg) in these healthy Chinese subjects. Tmax and t1/2 of canagliflozin were independent of the dose. Canagliflozin decreased the 24-hour mean renal threshold for glucose and increased urinary glucose excretion in a dose-dependent manner; these results are consistent with those observed in other patient populations. Canagliflozin was generally safe and well tolerated in these healthy Chinese subjects. ClinicalTrials. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties and tolerability of the oral once-daily sodium glucose cotransporter 2 inhibitor empagliflozin, given in single and multiple 10 and 25 mg doses in Chinese patients with type 2 diabetes mellitus (T2DM). Methods In a double-blind, placebo-controlled, parallel-group study, Chinese patients with T2DM were randomly assigned to receive a single dose of empagliflozin 10 or 25 mg or placebo on day 1 and once daily on days 3 to 9. Findings A total of 24 patients were enrolled (14 men, 10 women; median age, 53.5 years; empagliflozin 10 mg, n = 9; empagliflozin 25 mg, n = 9; and placebo, n = 6). After both single- and multiple-dose administration, empagliflozin 10 and 25 mg were rapidly absorbed, reaching peak plasma concentrations within 1 to 1.5 hours (median), with plasma levels declining biphasically. Empagliflozin exposure increased roughly dose proportionally between 10 and 25 mg. Mean terminal elimination half-life values at steady state were 13.9 and 12.1 hours with empagliflozin 10 and 25 mg, respectively. Mean (SD) changes from baseline in 24-hour urinary glucose excretion (UGE) on day 1 were +87.7 (22.9) and +82.8 (18.8) g with empagliflozin 10 and 25 mg, respectively, compared with -1.0 (2.8) g with placebo, and on day 9 were +95.8 (24.1), +82.6 (34.8) g with empagliflozin 10 and 25 mg, respectively, compared with -4.1 (6.4) g with placebo. Mean (SD) changes from baseline in fasting plasma glucose (FPG) on day 2 were -18.7 (17.2) mg/dL and -25.8 (19.6) mg/dL with empagliflozin 10 and 25 mg, respectively, compared with -4.2 (15.2) mg/dL with placebo, and on day 9, were -25.6 (20.7) mg/dL and -31.4 (26.9) mg/dL with empagliflozin 10 and 25 mg, respectively, compared to -3.7 (7.5) mg/dL with placebo. On day 10, mean changes in weight were -1.1, -1.6, and +0.5 kg with empagliflozin 10 and 25 mg and placebo, respectively. Overall, empagliflozin 10 and 25 mg had safety profiles similar to that of placebo. There were no reports of hypoglycemia, urinary tract infections, or genital infections. Implications Results with single and multiple doses of empagliflozin 10 and 25 mg suggest linear pharmacokinetic properties in Chinese patients with T2DM, with a safety profile similar to that of placebo. Empagliflozin treatment was associated with increases in UGE and reductions in FPG compared with placebo. [ABSTRACT FROM AUTHOR]

Purpose: Minodronic acid is a third-generation bisphosphonate being developed for the treatment of osteoporosis. The aim of this study was to evaluate the pharmacokinetic profiles and tolerability of minodronic acid in healthy subjects, as well as to assess the effects of food and age on the pharmacokinetics. Methods: This single-center, open-label, Phase I study was conducted in 4 parts. In part 1, minodronic acid tablets were administered to young volunteers at doses of 1, 2, and 4 mg. In part 2, after a single dose, young volunteers in the 1-mg dose group received repeated oral doses of minodronic acid once daily for 7 days. In part 3, a single oral dose of minodronic acid 1 mg was administered to elderly volunteers. In part 4, after a washout period of 8 days, volunteers in the 4-mg group received a single dose of 4-mg minodronic acid under fed conditions (administrated 30 minutes before a high-fat breakfast). Plasma samples were collected, and plasma concentrations of minodronic acid were analyzed by using a LC-MS/MS method. Tolerability was assessed throughout the study by physical examinations, measurement of vital signs, laboratory analyses, and monitoring of adverse events. Findings: Thirty-six young volunteers (mean age, 22.1 years; mean weight, 58.6 kg) and 12 elderly volunteers (mean age, 62.3 years; mean weight, 62.4 kg) were enrolled in the study. After single doses of 1, 2, and 4 mg of minodronic acid, the dose-normalized AUC exhibited dose linearity over the range of 1 to 4 mg in the young subjects. The plasma concentration of minodronic acid reached a steady state on day 7 after oral administration once daily for 7 days, with a mean accumulation ratio of 1.3. After a single dose of minodronic acid 1 mg, plasma Cmax and AUC0-∞ were both 1.8-fold higher compared with those of the young subjects. In the 4-mg dose group, minodronic acid Cmax and AUC0-∞ were reduced by 55% and 72%, respectively, with a high-fat breakfast compared with fasted conditions. No clinically meaningful changes in vital signs, laboratory values, or ECGs were observed. Implications: Single dosing of minodronic acid exhibited linear pharmacokinetics over the range of 1 to 4 mg; there was no accumulation after repeated administration. Food, especially high-fat food, reduced the bioavailability of minodronic acid. In addition, the exposure of the drug was increased with age. Minodronic acid seemed to be well tolerated throughout the study. ClinicalTrials.gov Identifier: NCT02295436. [ABSTRACT FROM AUTHOR]

Purpose: The primary aim of this study was to evaluate whether there was clinically significant pharmacokinetic (PK) interaction between finasteride and tamsulosin in healthy Chinese male subjects. Methods: This was an open-label, randomized, 3- period, crossover study. Subjects received single and multiple doses of 5 mg finasteride alone, single and multiple doses of 0.2 mg tamsulosin hydrochloride sustained-release capsule alone, and single and multiple doses of 5 mg finasteride with 0.2 mg tamsulosin hydrochloride, in an order determined by a computerized randomization schedule. Blood samples were collected up to 48 hours after dosing on study day 1 and up to 24 hours after dosing on study day 9 for determination of plasma concentrations with a validated LC-MS/MS method. Pharmacokinetic parameters were estimated via noncompartmental methods. Tolerability was evaluated by monitoring adverse events, laboratory assays, vital signs, and 12-lead ECG. Findings: Fifteen subjects were enrolled, and 14 completed the study. The geometric mean ratios (GMRs) (90% CIs) of AUCτ,ss and Cmax,ss values of finasteride at steady state between coadministration of finasteride and tamsulosin hydrochloride and finasteride alone were 1.14 (1.05-1.23) and 1.06 (0.99-1.14), respectively. The GMRs (90% CIs) for AUC0-t and Cmax values of finasteride for a single dose of coadministration of finasteride and tamsulosin hydrochloride and finasteride alone were 1.02 (0.94-1.11) and 1.06 (1.01-1.11), respectively. The GMRs (90% CIs) for AUCτ,ss and Cmax,ss values of tamsulosin at steadystate for coadministration of finasteride and tamsulosin hydrochloride and tamsulosin hydrochloride alone were 1.18 (1.05-1.33) and 1.23 (1.06-1.43), respectively. The GMRs (90% CIs) for AUC0-t and Cmax values of tamsulosin for a single dose of coadministration of finasteride and tamsulosin hydrochloride and tamsulosin hydrochloride alone were 1.04 (0.97-1.10) and 1.04 (0.98-1.11), respectively. Statistical analyses confirmed that the 90% CIs for these PK parameters were within the predefined not clinically significant PK drug-drug interaction effect boundaries (0.5-2.0) in this study. If comparing the findings with narrower boundaries (0.8-1.25), the conclusion may not be supportive for tamsulosin hydrochloride. During the study, a total of 4 adverse events were reported in 3 subjects including allergic reaction, abnormal findings on an ECG, a slight increase in alanine aminotransferase, and a positive result on glucose urine test. Implications: Both finasteride and tamsulosin hydrochloride were well tolerated. Coadministration of finasteride and tamulosin hydrochloride seems unlikely to lead to a clinically significant PK drug-drug interaction, after a single dose and at steady state. [ABSTRACT FROM AUTHOR]

Purpose: Insulin glargine is widely used as basal insulin. However, published dose titration regimens for insulin glargine are complex. This study aimed to compare the efficacy and safety profile of a userfriendly, weight-based insulin glargine dose titration regimen with 2 published regimens. Methods: A total of 160 hospitalized patients with hyperglycemia in 3 medical centers were screened. Our inclusion criteria included age 18 to 80 years and being conscious. Exclusion criteria included pregnancy or breast-feeding and hepatic or renal dysfunction. A total of 149 patients were randomly assigned to receive weight-based, glucose level-based, or dose-based insulin glargine dose titration regimen between January 2011 and February 2013. The initial dose of insulin glargine was 0.2 U/kg. In the weight-based regimen (n = 49), the dose was titrated by increments of 0.1 U/kg daily. In the glucose level-based regimen (n = 51), the dose was titrated by 2, 4, 6, or 8 U daily when fasting blood glucose (FBG) was, respectively, between 7.0 and 7.9, 8.0 and 8.9, 9.0 and 9.9, or ⩾10 mmol/L. In the current dose-based regimen (n = 49), titration was by daily increments of 20% of the current dose. The target FBG in all groups was ⩽7.0 mmol/L. The incidence of hypoglycemia was recorded. One-way ANOVA and χ2 test were used to compare data between the 3 groups. Findings: All but 1 patient who required additional oral antidiabetic medication completed the study. The mean (SD) time to achieve target FBG was 3.2 (1.2) days with the weight-based regimen and 3.7 (1.5) days with the glucose level-based regimen (P = 0.266). These times were both shorter than that achieved with the current dose-based regimen (4.8 [2.8] days; P = 0.0001 and P = 0.005, respectively). The daily doses of insulin glargine at the study end point were 0.43 (0.13) U/kg with the weight-based regimen, 0.50 (0.20) U/kg with the glucose level-based regimen, and 0.47 (0.23) U/kg with the current dose-based regimen (P = 0.184). The incidence of hypoglycemia was 4.1%, 2.0%, and 6.3%, respectively (P = 0.557). Implications: The currently proposed weight-based insulin glargine dose titration regimen is effective, tolerable, and user-friendly at achieving FBG target levels in hospitalized patients with hyperglycemia. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study were to determine the efficacy and tolerability of different dosages of, and to identify the best dosage of, tratinterol hydrochloride tablets in the treatment of bronchial asthma. Methods: This multicenter, randomized, doubleblind, dose-finding clinical research study was completed at 3 centers in the People's Republic of China from March 2008 to February 2009. Each center selected patients with bronchial asthma whose forced expiratory volume in 1 second (FEV1) values were <80% of predicted normal (pretreatment). Patients were assigned to 1 of 3 groups, based on daily dosage: low, 50 μg/d; intermediate, 100 μg/d; and high, 150 μg/d. Doses were administered orally twice daily for 10 days. The primary end points were the changes from baseline (0 minutes) in peak expiratory flow (PEF) and FEV1 at 30 minutes and 1, 2, 4, 6, and 12 hours after administration. Secondary end points were changes from baseline in forced vital capacity and asthma scores. Tolerability was monitored throughout the study period using physical examinations, laboratory testing, and spontaneous reporting. Findings: A total of 72 patients were selected in this study (24 per group; 40 men; 32 women; mean age, 43.48 years). The efficacy analysis (per-protocol set) included 20, 20, and 22 patients in the low-, intermediate-, and high-dosage groups, respectively. In terms of the primary and secondary end points, the intermediate dosage was most efficacious, followed by the high and low dosages, respectively. All 3 dosages were well-tolerated. Implications: In these patients with bronchial asthma, 100 μg/d was the dosage of tratinterol hydrochloride tablets most efficacious in terms of improvement in lung function. All 3 dosages were well-tolerated. [ABSTRACT FROM AUTHOR]

Purpose: Evidence on the benefits of combining celecoxib, a cyclooxygenase-2 inhibitor, in treating advanced cancer is still controversial. This study aimed to establish the efficacy and safety profile of celecoxib in treating advanced cancers. Methods: The PubMed, Embase, and Cochrane databases and abstracts from the American Society of Clinical Oncology and European Society for Medical Oncology were searched for reports dated up to January 31, 2014, to find relevant randomized clinical trials. The outcomes included overall response rate (ORR), 1-year mortality, progression-free survival, overall survival, and toxicities. Fixed-effects metaanalytical models were used when indicated, and between-study heterogeneity was assessed. Subgroup analysis was conducted according to cancer type, treatment pattern, and treatment line. Findings: A total of 11 randomized clinical trials consisting of 2570 patients with advanced cancer were included in the final meta-analysis. Addition of celecoxib to the treatment regimen significantly increased the ORR (pooled risk ratio [RR] = 1.20; 95% CI, 1.06-1.36; P = 0.005) but had no effect on 1-year mortality (RR = 1.02; 95% CI, 0.92-1.13; P = 0.68). Subgroup analysis found that the ORR results were significant with non-small cell lung cancer (RR = 1.29; 95% CI, 1.08-1.54; P = 0.005), colorectal cancer (RR = 1.32; 95% CI, 1.02-1.72; P = 0.037), chemotherapy treatment (RR = 1.22; 95% CI, 1.07-1.39; P = 0.003), and first-line treatment (RR = 1.22; 95% CI, 1.07-1.38; P = 0.003). However, celecoxib increased the risk of cardiovascular events (RR = 1.78; 95% CI, 1.30-2.43; P < 0.001) and anemia (RR = 1.88; 95% CI, 0.95-3.74; P = 0.071). Implications: Celecoxib is beneficial in the treatment of advanced cancers but with increased risk of cardiovascular events. Benefit versus harm needs to be carefully considered when celecoxib is recommended in patients with advanced cancers. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies). Methods: In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 g of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, Cmax, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated. Findings: Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70-1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (Cmax in single-dose SC administration) or significantly decreased (Cmin,ss in multiple BID SC doses and first peak Cmax in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentrationdependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after singledose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR. Implications: The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR. [ABSTRACT FROM AUTHOR]

Purpose: Targeted therapy has brought great clinical benefits for patients with multiple solid tumors, but its effects in patients with locally advanced/ metastatic pancreatic cancer (LA/MPC) are disputed. This systematic evaluation compared the efficacy and safety profiles of gemcitabine combined with targeted agents (GEM + TA) versus gemcitabine administered as monotherapy or combined with placebo (GEM ± PLC) in LA/MPC patients. Methods: PubMed and EMBASE were searched for relevant randomized controlled trials published on or before April 30, 2013. The primary end points were overall survival (OS) and progression-free survival (PFS); the secondary end points were 1-year survival rate, objective response rate (ORR), and toxicity rates (TRs), defined as the prevalence of grade 3/4 adverse events. The systematic evaluation was performed by using Review Manager version 5.1.7. Findings: A total of 10 randomized controlled trials involving 3899 patients (2195 males; mean age, 63.6 years) were included in the systematic evaluation. The results reported that there was no significant difference in OS (hazard ratio [HR] = 0.97 [P = 0.85]), PFS (HR = 0.95 [P = 0.14]), or ORR (odds ratio [OR] = 0.95 [P = 0.69]) between GEM + TA and GEM ± PLC. However, a marginal difference in 1-year survival rate (OR = 0.80 [P = 0.05]) between the 2 groups was observed. The grade 3/4 TRs of anemia, diarrhea, nausea, neutropenia, thrombocytopenia, and vomiting were not significantly different between the 2 groups. However, the prevalence of grade 3/4 rash was significantly greater in the GEM + TA group (OR = 8.31 [P < 0.01]). Implications: Based on the results from this analysis, the addition of targeted agents to a regimen of gemcitabine treatment does not bring survival benefits except 1-year survival rate to patients with LA/MPC. [ABSTRACT FROM AUTHOR]

Purpose: A meta-analysis comparing the efficacy and acceptability of selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) in depressed children, adolescents, and young adults was performed. Methods: A comprehensive literature search of the PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to December 2013. Only clinical trials that randomly assigned one SSRI or TCA to patients aged 7 to 25 years who met the diagnostic criteria for unipolar depressive disorder were included. Primary efficacy was determined by the pooling of standardized mean differences (SMDs) calculated from the difference in the reduction in mean depression rating scale scores for the 2 antidepressants. Acceptability was determined by pooling the risk ratios (RRs) of dropouts for all reasons and for adverse effects as well as the suicide-risk outcome. Findings: Five trials with a total of 422 patients were considered to be eligible for inclusion. SSRIs were significantly more effective than TCAs in primary efficacy (SMD = -0.52; 95% CI, - 0 . 8 1 to -0.24; P = 0.0003). Patients taking SSRIs had a significantly greater response to depressive symptoms than patients taking TCAs (RR = 1.55; 95% CI, 1.04 to 2.29; P = 0.03). On an individual SSRI basis, fluoxetine had a significantly greater efficacy than TCAs (SMD = -0.82; 95% CI, - 1 . 3 4 to -0.29; P = 0.003). On an individual TCA basis, only imipramine was not significantly worse than SSRIs (SMD = -0.27; 95% CI, - 0 . 5 6 to 0.02; P = 0.06). Significantly more patients taking TCAs discontinued treatment than patients taking SSRIs (35.8% vs 25.1%; RR = 0.70; 95% CI, 0.52 to 0.93; P = 0.02). Implications: SSRI therapy has a superior efficacy and is better tolerated compared with TCA therapy in young patients. [ABSTRACT FROM AUTHOR]

Background: The recombinant human parathyroid hormone (1--34) (rhPTH[1--34]) teriparatide is the first anabolic agent approved by the US Food and Drug Administration for the treatment of osteoporosis in men and women. This study was conducted to provide support for marketing authorization of an agent biosimilar to teriparatide in China. Objective: The main aim of the present study was to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic parameters of rhPTH(1--34) after single and multiple subcutaneous doses in healthy Chinese subjects. Methods: Two open-label, randomized, single-center, dose-escalation studies were performed. In study 1, subjects were randomized to receive a single dose of rhPTH(1--34) (10, 20, 30, 40, 50, or 60 μg) or a multiple dose of rhPTH(1--34) (10 and 20 μg once daily for 7 consecutive days) to determine the safety profile and tolerability, as reflected by the incidence, intensity, and seriousness of the observed adverse events. In study 2, a single dose of rhPTH(1--34) (10, 20, or 40 μg) and a multiple dose of rhPTH(1--34) (20 μg) were administrated subcutaneously to investigate the pharmacokinetic and pharmacodynamic parameters. Results: Forty-two subjects completed study 1, and 30 subjects completed study 2. rhPTH(1--34) was well tolerated during the investigated single (10--60 μg) and multiple (10--20 μg once daily for 7 consecutive days) dose ranges. The most generally reported adverse events were erythema at the injection site and gastrointestinal reactions. After single and multiple subcutaneous administration of rhPTH(1--34), the drug was rapidly absorbed, with a Tmax of 20 to 30 minutes, and rapidly cleared from the plasma, with a t½ of 47.2 to 60.6 minutes. The mean Cmax, AUC0-t, and AUC0-∞ increased in proportion to the doses, whereas the t½, total clearance, and Tmax values were independent of the administered dose. No significant differences in pharmacokinetic parameters were noted by sex except for Tmax in the 10-μg and 20-μg single-dose groups. Compared with the baseline levels, no significant changes or dose-related significant effects were observed in serum calcium and phosphate levels. Conclusions: All rhPTH(1--34) doses appeared to be well tolerated in the population studied. Linear pharmacokinetic characteristics were displayed in the dose range studied. Chinese ClinicalTrials.gov identifier: ChiCTR-ONC-12002874. [ABSTRACT FROM AUTHOR]

Background: Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias and atrial fibrillation. Objective: The objective of the present study was to determine the pharmacokinetics (PK) of a pilsicainide hydrochloride injection in healthy Chinese adults. The study was conducted to meet China State Food and Drug Administration requirements for the marketing of the new generic formulation of pilsicainide hydrochloride. Methods: This Phase I, randomized, parallel-group, open-label, single-dose PK study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of 0.25-, 0.50-, and 0.75-mg/kg pilsicainide hydrochloride with a 10-minute intravenous infusion. Serial blood and urine samples were collected up to 24 hours after dosing; drug concentrations in plasma and urine were then determined by using LC-MS/MS. The PK parameters of pilsicainide were calculated from the plasma concentration–time data according to noncompartmental methods. Safety profile was evaluated by monitoring adverse events, clinical laboratory parameters, and the results of 12-lead ECGs. Results: Thirty healthy volunteers (mean [SD] age, 28.0 [4.95] years; weight, 59.3 [6.51] kg; height, 165.0 [7.25] cm; body mass index, 21.7 [1.94] kg/m2) were randomly divided into 3 groups, each consisting of 5 men and 5 women. After single-dose intravenous administration of 0.25, 0.50, and 0.75 mg/kg of pilsicainide hydrochloride, mean Cmax was 0.34 (0.11), 0.54 (0.15), and 1.05 (0.19) μg/mL, respectively; AUC0–24 was 0.76 (0.12), 1.61 (0.37), and 2.61 (0.46) h • μg/mL; and AUC0–∞ was 0.79 (0.13), 1.71 (0.46), and 2.72 (0.50) h • μg/mL. The ranges for t½z, CL, and Vz were 5.19 to 5.98 hours, 4.73 to 5.44 mL/min/kg, and 2.23 to 0.58 L/kg, respectively. The mean urinary recovery rate within 24 hours was 75.0% (12.0%), 65.0% (19.2%), and 66.4% (14.1%). Men and women had significantly different AUC0–24 values in the 0.50-mg/kg dose group (P = 0.044), and Vz showed significant differences between men and women in all 3 dose groups (P = 0.001). According to ECG parameters, PR intervals were significantly prolonged after administration at all 3 doses (P = 0.034, P < 0.001, and P = 0.034); no significant changes were seen in QRS width, QTc interval, or other parameters. Conclusions: Pilsicainide hydrochloride demonstrated linear PK, and the increase in the exposure of pilsicainide (AUC0–24 and AUC0–∞) was dose proportional after single doses of 0.25, 0.50, and 0.75 mg/kg. All 3 pilsicainide hydrochloride doses were well tolerated in these Chinese volunteers. ChiCTR-ONC-13003546. [ABSTRACT FROM AUTHOR]

Background: Tenofovir disoproxil fumarate (TDF) has been approved worldwide for the treatment of adults with chronic hepatitis B and, in combination with other antiretroviral agents, HIV-1 infection. Although its use for the treatment of HIV has been approved by the Chinese State Food and Drug Administration, there are no data on the pharmacokinetic profile of TDF in Chinese individuals. Objectives: This study aimed to investigate the pharmacokinetic properties and tolerability of TDF in healthy Chinese subjects. Methods: This open-label, single- and multiple- dose study was conducted in healthy Chinese volunteers. Subjects received TDF 300 mg once daily, administered as a single dose (day 1) and multiple doses (days 4-10). Multiple plasma samples were collected over time, and the concentrations of TDF were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). Results: Fourteen volunteers were enrolled (7 men, 7 women; mean age, 24.6 years). TDF was rapidly absorbed; median Tmax was 0.75 hour, and t½ was ~21 hours with single dosing. The mean ratio of AUC0–&#964; steady state/AUC0–24 single dose was 1.55. The pharmacokinetic properties of TDF were consistent between the single dose and multiple doses, and between men and women. No serious AEs were reported, and there were no discontinuations due to AEs. Conclusions: There was an accumulation of approximately 55% in tenofovir exposure in healthy Chinese between multiple dose and single dose. TDF exhibited a pharmacokinetic profile similar to that of healthy Western subjects in a historical comparison. TDF was generally well tolerated in these healthy Chinese subjects. [ABSTRACT FROM AUTHOR]

Background: Ivabradine is a pure heart rate–lowering agent that acts by inhibiting I(f), an important ionic current involved in pacemaker activity in the cells of the sinoatrial node. In the 2012 European Society of Cardiology Guidelines on Heart Failure, it was recommended that patients with a persistently high heart rate, despite treatment with an evidence- based dose of a β-blocker, should be considered for treatment with ivabradine. Objective: The aim of this study was to explore the pharmacokinetic/pharmacodynamic properties and safety profile of ivabradine in healthy Chinese men. Methods: This Phase I, randomized, open-label, parallel-arm, single- and multiple-dose study was conducted at the Clinical Pharmacology Center of the Cardiovascular Institute and Fu Wai Hospital at the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing, People’s Republic of China. Healthy, nonsmoking volunteers were randomly assigned to 1 of 3 treatment groups based on treatment with 5, 10 or 20 mg of ivabradine. After a single dose, the subjects assigned to the 3 dose groups received repeated oral doses of ivabradine BID for 6 days. The plasma concentrations of ivabradine were determined by using a HPLC-MS/MS method. Systolic and diastolic blood pressure and heart rate measurements were taken, and ECG and Holter monitoring was performed. Tolerability was assessed throughout the study by physical and ophthalmologic examinations, vital signs measurement, laboratory analyses, and monitoring of adverse effects. Results: A total of 36 healthy Chinese men were enrolled in the study. After the single dose, plasma ivabradine Cmax and AUC increased approximately linearly with dosage, no statistically significant differences were found in t½ or Tmax between the dose groups. After multiple doses, there was no significant change in Tmax compared with the results after a single dose. After repeated doses, t½, Cmax, and AUC increased significantly (P o 0.001). After a single dose, a significant reduction in heart rate at 2 hours’ postdose was observed in the highest dose group, whereas after repeated doses, a significant reduction in heart rate was observed from 2 to 4 hours’ postdose for all 3 groups. The mean (SD) heart rate after repeated doses decreased 12.5 (4.8), 12.4 (6.9), and 20.5 (5.8) beats/min for the 5-, 10-, and 20-mg dose groups, respectively. No clear trend in the changes in QTc, systolic and diastolic blood pressures, or respiration rate was observed. Ivabradine was well tolerated in these healthy Chinese men. Conclusions: The results of the study in a small population of healthy Chinese men suggest that the PK properties of ivabradine are linear with respect to dosing. After single and repeated oral administration of ivabradine, a significant decrease in heart rate was observed. Ivabradine appeared well tolerated in the population studied. [ABSTRACT FROM AUTHOR]

Background: Lamivudine is used in the treatment of HIV and chronic hepatitis B (HBV) infections. Since 1999, at least 2 million Chinese HBV patients have been treated with lamivudine, but there are limited studies on the pharmacokinetics and safety of the drug in Chinese populations. Objective: This study was designed to assess the bioequivalence of a newly developed lamivudine tablet (test drug) and a branded lamivudine tablet (reference drug) in healthy Chinese male volunteers. Methods: A single-center, single-dose, randomized, open-label, 2-period crossover study was conducted in 28 healthy Chinese male volunteers. Blood samples were collected up to 24 hours after the administration of oral lamivudine 100 mg in each period. Plasma lamivudine concentrations were analyzed by a validated LC-MS/MS method. Pharmacokinetic and bio-availability parameters were calculated. Adverse events (AEs) were recorded. Results: There were no significant differences in mean (SD) pharmacokinetic parameters between the test and reference drugs, including Cmax (1239 [328.9] ng/mL vs 1176 [341.5] ng/mL), AUC0-t (4096 [599.1] ng · h/mL vs 4064 [678.2] ng · h/ mL), and AUC0-∞ (4200 [607.7] ng · h/mL vs 4162 [672.2] ng · h/mL). The geometric mean test/reference ratios (90% CI) calculated for the log-transformed parameters were Cmax, 1.06 (96.21-116.90); AUC0-t, 1.01 (96.53-105.39); and AUC0-∞, 1.01 (96.81-105.16), all of which were within the acceptance limits for bioequivalence. No serious AEs were reported, and all mild AEs were recovered quickly without treatment. Conclusion: These findings suggest that the test formulation of lamivudine 100 mg meets the FDA regulatory standards for bioequivalence with the reference formulation. Both formulations were well tolerated. [ABSTRACT FROM AUTHOR]

Background: Dapagliflozin, a selective, orally ac-tive, renal sodium glucose cotransporter 2 (SGLT2) 2 inhibitor, is under investigation as a treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin reduces hyperglycemia by inhibiting renal glucose reabsorp- tion and dose-dependently increasing urinary glucose excretion, independent of insulin secretion or action. Objectives: These studies assessed the single- and multiple-dose pharmacokinetic and pharmaco dyna-mic properties of dapagliflozin and its major inactive metabolite, dapagliflozin 3-O-glucuronide (D3OG), in healthy subjects residing in China. Methods: In 2 identically designed, open-label, single- and multiple-dose studies (n = 14 for both studies), healthy Chinese subjects were administered oral dapagliflozin 5 or 10 mg. In both studies, subjects received a single dose on day 1 (single-dose admin-istration period) followed by 6 once-daily doses on days 5 to 10 (multiple-dose administration period). Pharma-cokinetic parameters (plasma and urinary dapagliflozin and D3OG), pharmacodynamic response (urinary glu-cose excretion), and tolerability were assessed. Results: Fourteen subjects completed the dapagli-flozin 5-mg study, and 13 completed the dapagliflozin 10-mg study. Baseline characteristics were balanced across the two studies: 9 versus 10 men; mean age, 27.1 versus 28.9 years; mean weight, 62.8 versus 62.2 kg; and mean body mass index, 23.0 versus 22.2 kg/ m2 in the dapagliflozin 5- and 10-mg studies, respec-tively. In both doses, dapagliflozin was rapidly ab-sorbed (Tmax, ≤1.5 h), accumulation (defined as the geometric mean ratio of AUCT at day 10 to AUCT at day 1) after multiple dosing was minimal (<1.13 fold), and elimination half-life was 10 to 12 h. D3OG showed a slightly longer median Tmax,( ≤2 h) but a similar plasma concentration-time profile and half-life compared with dapagliflozin. The majority of D3OG (up to 69.7% of the dapagliflozin dose) was excreted in urine, while ≤1.9% of dapagliflozin was excreted unchanged in urine. Over a 24-hour period and at steady state (day 10), urinary glucose excretion values were 28.1 and 41.1 g with dapagliflozin 5 and 10 mg, respectively. Dapagliflozin was generally well toler-ated; one dapagliflozin 10 mg-treated subject discon-tinued the study because of a serious adverse event (bronchitis) considered by the investigator as unre-lated to dapagliflozin dosing. Conclusions: Pharmacokinetic and pharmacody-namic characteristics following single- and multiple-dose dapagliflozin 5 and 10 mg oral administration in healthy Chinese subjects were as predicted from previous studies and were similar to findings observed in non-Chinese healthy subjects. Dapagliflozin dosing was well tolerated. The clinically recommended dapa-gliflozin dose of 10 mg once daily is expected to be appropriate in patients of Chinese ethnicity; results from an efficacy and tolerability study in Chinese patients with T2DM are awaited. [ABSTRACT FROM AUTHOR]

Background: Administration of a loading dose of atorvastatin 80 mg/d has been shown to be beneficial in patients with stable coronary artery disease and acute coronary syndromes. However, little is known about the impact and mechanism behind the beneficial effects of loading-dose atorvastatin treatment before percutaneous coronary intervention (PCI), especially for those patients experiencing cardiovascular inflammation in ST-segment elevation myocardial infarction (STEMI). Objective: The goal of this randomized clinical study was to investigate whether, before emergency PCI, administration of loading-dose atorvastatin therapy in STEMI patients inhibits inflammation and improves cardiac function during 24 weeks of follow-up. Methods: A total of 102 STEMI patients were enrolled into 3 groups: group A (n = 32) received 80 mg of atorvastatin before emergency PCI, post-PCI follow- up atorvastatin 40 mg for 4 weeks, and atorvastatin 20 mg for 20 weeks; group B (n = 32) received no pre-PCI loading dose of atorvastatin but did receive atorvastatin 40 mg for 4 weeks and then atorvastatin 20 mg for 20 weeks; and group C (n = 38) received only post-PCI atorvastatin 20 mg for 24 weeks. Results: No differences were found in baseline demographic and angiographic characteristics among the 3 groups. Patients in group A had the lowest plasma levels of high-sensitivity C-reactive protein (hs-CRP), B-type natriuretic peptide (BNP), and matrix metalloproteinase type 9 (MMP-9) (P = 0.05). Patients in group A also showed improvement in heart performance, with significant increases in their left ventricular ejection fraction. To a lesser extent, group B displayed reductions in the plasma levels of hs-CRP, BNP, and MMP-9 at later time points (P = 0.05). Compared with those in group C, patients in group B also exhibited significant improvement in left ventricular ejection fraction (P = 0.05). Conclusions: Loading-dose atorvastatin therapy before emergency PCI reduced the inflammatory response and myocardial dysfunction in these STEMI patients by lowering hs-CRP, BNP, and MMP-9. Pre-PCI loading-dose atorvastatin treatment may help prevent inflammatory response and improve cardiac function in patients with acute coronary syndromes undergoing emergency PCI. ClinicalTrials. gov identifier: NCT01334671. [ABSTRACT FROM AUTHOR]

Background: Insulin is an essential treatment for both type 1 and 2 diabetes. Among the available routes of insulin administration, oral delivery is the most appealing option. Objective: The purpose of this study was to evaluate the pharmacodynamic and pharmacokinetic profiles of orally administered enteric insulin and compare the time-action of these oral insulin capsules with neutral protamine Hagedorn (NPH) insulin. Methods: This was a single-center, randomized, 4-period, crossover study. Twelve healthy volunteers (3 per group) received 1 of 3 doses of oral enteric insulin (50, 100, or 200 U) or 1 subcutaneous injection of NPH insulin (6 U) on 4 separate days. After administration, glucose infusion rates and serum insulin concentrations were monitored for 10 hours. Results: Glucose infusion rates increased after administration of either NPH or oral enteric insulin. The mean times for maximal metabolic effects for 50, 100, and 200 U of oral enteric insulin were 250 (118), 170 (58), and 236 (132) minutes, respectively, compared with 243 (79) minutes for NPH insulin. The onset of action was slower for oral enteric insulin at 50 U (38 [10] minutes), 100 U (41 [18] minutes), and 200 U (65 [58] minutes) compared with NPH insulin (35 [8] minutes). The maximum glucose infusion rates for oral enteric insulin treatment (1.66 [0.50], 1.61 [1.00], and 1.80 [0.60] mg/kg/min for 50, 100, and 200 U, respectively) were lower compared with NPH insulin (2.06 [0.82] mg/kg/min), although these differences were not statistically significant. Conclusions: Oral enteric insulin capsules induced significant glucodynamic effects and exhibited a time- action profile similar to that of NPH insulin in these healthy volunteers. No detectable increases in serum insulin concentration were observed in any treatment group. [ABSTRACT FROM AUTHOR]

Abstract: Background: Nateglinide, N-(trans-4-isopropylcyclohexyl-carbonyl)-d-phenylalanine, is a potent insulin secretagogue designed to restore early-phase insulin secretion. It increases pancreatic insulin secretion by competitively binding to sulfonylurea receptors inhibiting adenosine triphosphate–sensitive potassium channels and thus reducing blood glucose levels. The drug has a rapid onset (causing immediate insulin release) and a short duration (allowing insulin to return to baseline levels between meals) of insulinotropic action. Objective: To meet the requirements for marketing a new generic product, this study was designed to compare the pharmacokinetic parameters and relative fasting bioavailability of new generic (test) formulation of nateglinide with the reference formulation of nateglinide in healthy Chinese male volunteers. Methods: This open-label, single-dose, randomized-sequence, 2-way crossover study was performed at Nanjing First Hospital of Nanjing Medical University. Eligible subjects were healthy male volunteers who were randomly assigned in a 1:1 ratio to receive a single 60-mg (0.88 mg/kg) dose of the 2 formulations, followed by a 1-week washout period and then administration of the alternate formulation. Study drugs were administered after a 10-hour overnight fast. Concentrations of nateglinide were determined by using a validated LC-MS method. For analysis of pharmacokinetic properties, including Cmax, AUC0–10, and AUC0–∞, blood samples were obtained at intervals over the 10-hour period after study drug administration. As established by the State Food and Drug Administration, the formulations were assumed bioequivalent if 90% CIs for the test/reference ratios of ln-transformed values of Cmax and AUC (obtained by using ANOVA) were within the predetermined equivalence range (80%–125%). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) and by questioning subjects about adverse events. Results: The 90% CIs for nateglinide were as follows: Cmax, 98.4% to 118.6%; AUC0–10, 99.5% to 110.3%. Both Cmax and AUC0–10 met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation was estimated to be 102.1% (13.5%). One volunteer (5%) experienced a headache after administration of the test formulation. This resolved spontaneously within 1 hour and was considered by the investigators to be mild. No serious adverse events were reported. No period or sequence effects were observed. Conclusions: In this study of healthy Chinese male volunteers, a single 60-mg dose of nateglinide (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TRC-11001754. [Copyright &y& Elsevier]

Abstract: Background: Risperidone (RIS), an atypical antipsychotic drug, is used for the treatment of psychoses associated with schizophrenia and other psychiatric disorders in adult and pediatric populations. An oral dispersible tablet formulation of risperidone has been developed. This study was conducted to provide support for marketing authorization of this drug in China. Objective: This study was designed to compare the pharmacokinetic (PK) properties and bioavailability of 2 RIS formulations—the dispersible formulation (test) and a branded formulation (reference) in healthy male Chinese volunteers. Methods: This single-dose, randomized-sequence, open-label, 2-period crossover study involved 22 healthy male Chinese volunteers. Equal numbers of eligible participants were randomly assigned to receive either the test drug (2 mg) or the same dose of the reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Blood samples were collected before dosing and at 0.33, 0.67, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72, and 96 hours after dosing. Plasma concentrations of RIS and its active metabolite, 9-hydroxyrisperidone (9-OH-RIS), were measured using LC-MS/MS. The safety profile was evaluated by recording adverse events (AEs), assessed using physical examination including vital signs, spontaneous reporting, and clinical laboratory results. The 2 formulations were considered to have met the requirements for bioequivalence if the 90% CIs for the log-transformed Cmax and AUC values were within the predetermined ranges of 75% to 133% and 80% to 125%, respectively, according to the guidelines of the State Food and Drug Administration (SFDA) of China. Results: All 22 volunteers (mean [SD] age, 22.2 [1.98] years; weight, 64.07 [5.93] kg; height, 173 [5] cm; and body mass index, 21.2 [1.67] kg/m2) that were enrolled completed the study. For RIS, the 90% CIs for the ratios of Cmax, AUC0–t, and AUC0−∞ were 93.2% to 116.7%, 97.9% to 111.3%, and 98.0% to 111.6%, respectively. For 9-OH-RIS, the 90% CIs were 95.8% to 113.9%, 100.2% to 109.7%, and 100.5% to 110.3%, respectively. All values were within the predetermined bioequivalence range. Seven AEs were reported somnolence (4 subjects [9.1%]) and dizziness (3 subjects [6.8%]). All AEs were transient and considered mild by physicians. Conclusions: The test (dispersible) and reference tablets met the regulatory criteria for bioequivalence as defined by the SFDA. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TRC-12001996. [Copyright &y& Elsevier]

Purpose: SY-004, a dual-acting full glucokinase activator, is under development to provide a dose-dependent improvement of glucose control. This study aimed to assess the tolerability, safety, and pharmacokinetic and pharmacodynamic properties of SY-004 in healthy Chinese adults., Methods: Two study participants were administered 2 mg of SY-004 in the 2-mg cohort, whereas 6 study participants were randomized with 4 study participants receiving SY-004 and 2 receiving placebo in the 20-mg cohort. In each of other 3 dose cohorts (40, 80, and 120 mg), 12 participants were randomized in a 10:2 ratio to receive single oral SY-004 capsules or placebos. Drug concentrations, glucose and insulin levels, and safety data were assessed and analyzed. Noncompartmental analysis was used to determine SY-004 pharmacokinetic parameters., Findings: SY-004 was generally well tolerated. Nine of the 44 study participants reported 17 treatment-related adverse events, and most treatment-related adverse events were mild. SY-004 had approximately dose-proportional increases in systemic exposure. The mean t ½ ranged from 37.6 to 49.9 hours, and CL/F values ranged from 67.1 to 110 L/h across all doses. The cumulative amounts of the unchanged drug excreted in urine were very low, accounting for no more than 1.53% of the given doses. No significant difference in sex was observed in pharmacokinetic parameters. The pharmacodynamic response appeared to slightly correlate with dose., Implications: SY-004, a new potential glucokinase activator, had favorable safety profiles and good PK characteristics. The glucose-lowering effects were slightly dose related. The SY-004 data in healthy Chinese adults supports further development., Clinicaltrials: gov identifier: NCT03171623., Competing Interests: Disclosures The authors have indicated that they have no conflicts of interest regarding the content of this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Tedizolid phosphate is a new antibacterial agent under investigation for the treatment of Gram-positive infections in China. This study was conducted to assess the pharmacokinetic (PK) properties, oral bioavailability, and safety of once daily tedizolid phosphate 200 mg in Chinese subjects to support its further clinical development in China., Methods: This Phase I single-center study, conducted in 16 healthy Chinese male subjects, consisted of a single-dose administration, 1:1 randomized, two-way, intravenous (IV)/oral (PO) crossover of tedizolid phosphate 200 mg (Part 1) and, after a 7-day washout, a nonrandomized, multiple-dose, 7-day tedizolid phosphate 200 mg once daily administration (IV for 3 days, PO for 4 days; Part 2). Blood samples were collected for up to 72 hours after single dosing and for up to 2 hours on Day 3 and 72 hours on Day 7 of multiple dosing to determine PK parameters. Adverse events (AEs) were recorded throughout the entire study., Findings: The Cmax and AUC of tedizolid (the active moiety of tedizolid phosphate) were 3.02 µg/mL and 30.50 µg • h/mL after single IV dosing of tedizolid phosphate, and 2.25 µg/mL and 26.10 µg • h/mL after single PO dosing, respectively, and the mean half-life was 10.1 hours for both administration routes. The oral bioavailability of tedizolid was 85.5%. PK parameters of tedizolid were similar after single and multiple dosing of tedizolid phosphate, indicating no time dependency. Only minor accumulation of tedizolid was observed after multiple dosing (expressed as accumulation ratios RAAUC: 1.18 for PO dosing, and RACmax: 1.16 and 1.05 for IV and PO dosing, respectively). Steady state of tedizolid was reached after about 3 days, and trough concentrations remained constant when switching from IV to PO dosing. Tedizolid phosphate was well tolerated with 6 subjects (37.5%) in Part 1 and 5 subjects (31.3%) in Part 2 experiencing an AE; all AEs but one were related to the study drug assessed by the investigator. All AEs were of mild intensity and had recovered or resolved by the end of the study. No serious AEs were observed, and no subjects prematurely discontinued the study due to an AE., Implications: The results of this Phase I study conducted in Chinese male subjects indicate that no dosage adjustment of tedizolid phosphate 200 mg would be required when switching administration routes in this population. Tedizolid phosphate was well tolerated in healthy Chinese subjects. China Food and Drug Administration clinical trial permission numbers 2014L00360 and 2014L00361., (Copyright © 2016. Published by Elsevier Inc.)

Purpose: Histamine dihydrochloride (HDC) injection has been approved in Europe for the treatment of adults with acute myeloid leukemia, used in combination therapy with the T-cell-derived cytokine interleukin-2. Despite years of clinical applications of HDC in Europe, no data are available on its tolerability and pharmacokinetic properties in Chinese patients. The objective of this study was to determine the safety profile and pharmacokinetic properties of HDC in Chinese healthy volunteers (HVs)., Methods: In this Phase I, single-center, open-label, randomized study, 20 Chinese HVs were randomized to receive a single dose of 0.5 or 1.0 mg HDC via a 10-minute subcutaneous injection. Whole-blood and urine samples were collected at designated time points after dosing. Plasma and urine concentrations of histamine and metabolite N-methyl histamine were measured using a validated HPLC-MS/MS method. Pharmacokinetic parameters were estimated through noncompartmental procedures based on concentration-time data. Adverse events and evaluation of clinical laboratory tests were used to assess the safety profile. The pharmacokinetic profile for a single-dose of 1.0 mg HDC in Chinese HVs was compared with that in Western HVs., Findings: No severe adverse events occurred in this study, and the severity of all adverse events was grade I according to the Common Terminology Criteria for Adverse Events, version 4.0. For the pharmacokinetic parameters of histamine at the 0.5-mg and 1.0-mg dose levels, t½ was 0.50 and 1.02 hours; Tmax was 0.15 and 0.14 hours; mean Cmax was 26.59 and 71.01 nmol/L; AUC0-t was 8.35 and 20.43 nmol/h/L; AUC0-∞ was 9.61 and 22.69 nmol/h/L; accumulated amount excreted in urine within 24 hours was 125.93 and 145.52 nmol; and maximum urine excretion rates were 21.85 and 38.94 nmol/h, respectively. For N-methyl histamine at the 0.5-mg and 1.0-mg dose levels, t½ was 0.58 and 0.66 hours; Tmax was 0.28 and 0.26 hours; mean Cmax was 17.01 and 23.54 nmol/L; AUC0-t was 7.72 and 17.08 nmol/h/L; AUC0-∞ was 9.01 and 19.62 nmol/h/L; accumulated amount excreted in urine within 24 hours was 331.7 and 583.21 nmol; and maximum urine excretion rates were 53.29 and 133.53 nmol/h, respectively., Implications: Both single-dose 0.5 mg and 1.0 mg HDC were well tolerated in Chinese HVs, and the pharmacokinetic profile of HDC in Chinese HVs was characterized in this study. A single dose of 1.0 mg HDC had a more rapid but similar extent of absorption, a wider distribution, and a little more rapid elimination in Chinese HVs compared with Western HVs. Findings from this study support additional clinical trials for HDC using in Chinese patients. Chinese Clinical Trial Registry identifier: ChiCTR-ONC-13003954., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)