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Qingqing Wu,1,2 Xiaodong Wang,3 Qian Chen,1,2 Yang Zou,1,2 Xiaoyan Xu,1,2 Tingting Li,1,2 Chen Yu,1,2 Fu Zhu,1,2 Kanyin E Zhang,4 Jingying Jia,1,2 Yanmei Liu1,2 1Center Laboratory, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China; 2Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, People’s Republic of China; 3Changzhou Siyao Pharmaceuticals Co., Ltd, Jiangsu, People’s Republic of China; 4ViaClinical Ltd, Shanghai, People’s Republic of ChinaCorrespondence: Yanmei LiuCenter Laboratory, Shanghai Xuhui Central Hospital, No. 966, Huaihai Road(M), Shanghai, People’s Republic of ChinaTel/Fax +86-21-54030254Email ymliu@shxh-centerlab.comPurpose: To compare the bioequivalence of two formulations of valsartan (80 mg capsules) under fasting and fed conditions in healthy Chinese volunteers using a full-replicate study design.Methods: A total of 78 Subjects were randomly assigned to fasting cohort (n = 48) or fed cohort (n = 30). Each cohort includes 4 single-dose observation periods and 3-day washout periods. Blood samples were collected at designed time point. Plasma concentration of valsartan was analyzed by a validated LC-MS/MS method. Noncompartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation (SWR) of the reference formulation, either reference-scaled average bioequivalence (RSABE) or average bioequivalence (ABE) method was used to evaluate the bioequivalence of the two formulations.Results: Under fasting conditions, the RSABE method was used to evaluate the bioequivalence of Cmax (SWR> 0.294), while ABE method was used to evaluate the bioequivalence of AUC0-t and AUC0-∞. The geometric mean ratio (GMR) of the test/reference for Cmax was 99.52%, and the 95% upper confidence bound was < 0. For AUC0-t and AUC0-∞ comparisons, GMRs were 102.07% and 101.92%, and the 90% CIs of the test/reference were 96.28%– 108.21%, 96.28%– 107.88%, respectively. Under fed conditions, the SWR value of Cmax, AUC0-t and AUC0-∞ all exceeded the cutoff value of 0.294 and therefore, the RSABE method was used. The GMRs for Cmax, AUC0-t and AUC0-∞ were 98.78%, 103.33% and 103.08%, respectively, while the 95% upper confidence bound values were all < 0. These results all met the bioequivalence criteria for highly variable drugs. All adverse events were mild and transient.Conclusion: In this study, the generic formulation of valsartan 80 mg capsule was considered to be bioequivalent to the reference product under both fasting and fed conditions, and satisfied the requirements for marketing in China.NMPA Registration No: CTR20181422.Keywords: valsartan, bioequivalence, replicate, pharmacokinetics, safety

Purpose Surufatinib is a potent and orally active small-molecule tyrosine kinase inhibitor targeting VEGFRs 1 to 3, FGFR-1, and CSF-1R, and thus may exert antitumor and antiangiogenic effects. The objective of this study was to determine the tolerability and effects of food intake on the pharmacokinetic properties of surufatinib in healthy Chinese subjects. Methods A total of 24 healthy Chinese male subjects aged between 18 and 55 years were enrolled. Subjects were administered a single dose of surufatinib 250–mg capsules in the fasted and fed states in succession. Pharmacokinetic analysis was performed through the collection of blood samples at predose and at several time points after surufatinib administration. Tolerability assessments comprised physical examination including vital sign measurements, laboratory testing, and ECG to determine adverse events (AEs). Findings The 90% CIs of the geometric mean ratios of AUC0–t and AUC0–∞ in the fasted and fed states was within 0.80 to 1.25; and for Cmax, within 0.70 to 1.43, indicating that food had no effect on the bioavailability of surufatinib in these healthy Chinese male subjects. Food intake delayed the time to peak absorption of surufatinib, as the median Tmax in the fed state was longer than that in the fasted state (4.0 vs 2.0 h). Surufatinib was marginally excreted from urine (mean [SD] cumulative excretion fraction, 1.2% [0.4%]). AEs occurred in 7 of the 24 subjects (29.2%) and included upper respiratory tract infection, dizziness, merycism, intervertebral disc protrusion, influenza-like disease, hematuria, prostatitis, and elevated blood urea nitrogen. All AEs were grade 1 or 2. Implications The bioavailability of surufatinib was not affected by food intake prior to dosing. However, food intake led to delated Tmax of surufatinib. The tolerability of a single oral dose of surufatinib 250 mg in the fasted and fed states was favorable in these healthy Chinese male subjects. These results indicate that surufatinib capsules could be administered before or after meals. ClinicalTrials.gov identifier: NCT02320409.

Hongjie Qian,1,2 Qian Chen,1,2 Liyu Liang,1,2 Yang Zou,1,2 Huahua Pu,1,2 Liang Xin,1,2 Rong Song,1,2 Tingting Li,1,2 Huijuan Zhu,1,2 Yu Wang,3 Guanghui Tian,4 Jingshan Shen,2,3 Hualiang Jiang,2,3 Chen Yu,1,2 Zhen Wang,2,3 Jingying Jia1,2 1Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, 200031, People’s Republic of China; 2Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, 200031, People’s Republic of China; 3CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China; 4Vigonvita Life Science Co., Ltd., Suzhou, 215123, People’s Republic of ChinaCorrespondence: Jingying JiaShanghai Xuhui Central Hospital, No. 966, Huaihai Road(M), Shanghai, 200031, People’s Republic of ChinaTel/Fax +86 21 54030254Email jyjia@shxh-centerlab.comZhen WangShanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Pudong, Shanghai, 201203, People’s Republic of ChinaTel +86 21 20231000Fax +86 21 20231962Email wangzhen@simm.ac.cnPurpose: TPN171H is a novel, potent and selective phosphodiesterase type 5 (PDE5) inhibitor for the treatment of pulmonary arterial hypertension (PAH). The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of TPN171H in healthy subjects after single and multiple dosing, in addition, to investigate the food effect on pharmacokinetics and safety of TPN171H.Methods: The entire study was comprised of three parts: Part I (single ascending-dose study), Part II (food effect study), and Part III (multiple ascending-dose study). A total of 63 healthy subjects were enrolled in the study. TPN171H tablet or placebo was administered per protocol requirements. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events.Results: In Part I, AUC and Cmax were proved to be linear within the 5– 30 mg dose range. T1/2 of TPN171H was 8.02– 10.88 h. In Part II, we figured out that TPN171H administration under fed condition could decrease Cmax, prolong Tmax, but had no effect on AUC. In Part III, the accumulation ratio at steady-state for AUC and Cmax indicated that TPN171H has a slight accumulation upon repeated dosing. Subjects were generally tolerable after TPN171H administration. Compared with other PDE5 inhibitors, TPN171H was found to have no impact on blood pressure and color discrimination.Conclusion: TPN171H was safe and generally tolerated in healthy subjects. Based on the half-life, food effect, and safety profile of TPN171H, we recommend a once-daily, post-meal administration of TPN171H in subsequent clinical studies in healthy subjects and patients with PAH.Keywords: TPN171H, PDE5 inhibitor, safety, pharmacokinetics, food effect, healthy subjects

Background Henagliflozin, a novel selective inhibitor of sodium–glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus. Purpose To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers. Methods Two clinical studies were conducted. One was a single ascending dose (SAD) study (2.5–200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25–100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies. Findings No serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a Tmax of 1.5–3 h, and then eliminated from plasma with a half-life of 11–15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5–200 mg (SAD) and 1.25–100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%–5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration. Implications Henagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132.

Sulcardine sulfate (Sul) is a novel antiarrhythmic agent as a potential treatment for atrial fibrillation and ventricular arrhythmias. This study was conducted to investigate the pharmacokinetic profile, safety, and tolerability of Sul in healthy Chinese subjects. In this open-label, single-dose, randomized study, 10 healthy subjects were assigned to receive Sul doses of 200, 400, and 800 mg under fasting conditions (Cohorts A, B, and C, respectively) or 400 mg under fed conditions (Cohort D). The study incorporated a crossover design, separated by a 7-day washout period. Blood samples were collected before treatment and at successive time intervals up to 48 h after treatment. Sul concentrations in plasma samples were determined using a validated LC-MS/MS method. Tolerability was determined by clinical evaluation and adverse-event monitoring. Pharmacokinetic results demonstrated that Cmax and AUC(0-t) of Sul increased with an increasing dose. The mean t1/2 values for Cohorts A, B, and C were 16.85, 17.66, and 11.87 h, respectively. No statistically significant differences were observed between men and women for the main pharmacokinetic parameters, with the exception of t1/2 in Cohorts B and C. No significant differences were observed in the absorption and bioavailability of Sul between the fed and fasted states (P > 0.05). Four subjects reported mild AEs during the study. No serious AEs were reported. Sul was shown to be safe and well tolerated in healthy Chinese subjects. Pharmacokinetics studies demonstrated that Sul has adequate oral absorption and bioavailability properties. This article is protected by copyright. All rights reserved.

Sulcardine sulfate is a novel antiarrhythmic agent with mechanism of action as a multi-ion channel blocker. Preclinical studies in animal models have demonstrated that sulcardine sulfate is efficacious in atrial and ventricular arrhythmias, and consequently, leads to the prevention of sudden cardiac death.This study was conducted in healthy Chinese male subjects to investigate the pharmacokinetic profile and safety of sulcardine sulfate after repeated oral dose administration at 200, 400, and 800 mg for 5 days.Thirty-three male subjects were enrolled in this study. In the multiple dose phase, sulcardine sulfate was administered orally twice at the interval of q12 h since day 3. Sulcardine sulfate plasma concentration was determined using a validated LC-MS/MS method. Safety was assessed using clinical evaluation and AE monitoring.In this repeated dose study, pharmacokinetic parameters (CPharmacokinetic characteristics of sulcardine sulfate were shown to be non-linear, with the modest accumulation upon repeated dosing, and sulcardine sulfate was safe and well tolerated.

Only sporadic data are available on hair concentrations of diazepam and some of its metabolites (nordazepam, oxazepam, and temazepam) following a single controlled dose. The aim of this study was to investigate the deposition of diazepam and its metabolites in human hair after eight healthy volunteers (four women and four men, ages 24-26, East Asian) consumed 10 mg of diazepam. Hair was collected from all volunteers 1 month after exposure, and also 2 months post-exposure from men and 10 months post-exposure from women. Diazepam and the complete metabolite profile, including oxazepam glucuronide and temazepam glucuronide, were measured by ultra-high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) with limits of quantifications (LOQs) of 0.5-2.5 pg/mg for diazepam, nordazepam, oxazepam, and temazepam, and of 10 pg/mg for oxazepam glucuronide and temazepam glucuronide. There were no differences by gender in the amounts of diazepam or metabolites found. The concentration of the main metabolite nordazepam was consistently higher than that of diazepam at both 1 and 2 months after consumption. Oxazepam and temazepam traces were found in some volunteers' hair, but the glucuronides were not detected. Diazepam and nordazepam levels at 10 months post-exposure were extremely low (near the LOQ), indicating drug loss by personal hygiene and physical handling. To our knowledge, this is the first single-dose diazepam study using black hair and the first study to include measurements of oxazepam glucuronide and temazepam glucuronide in human hair.

Purpose Fruquintinib is a potent and highly selective oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and demonstrates promising activity against a broad spectrum of cancer types. The objective of the study was to investigate the tolerability and effect of high-fat food on the pharmacokinetic profile of a fruquintinib capsule in healthy Chinese subjects. Methods Healthy Chinese male subjects aged between 18 and 45 years were enrolled in the study. The study included 2 phases: a dose-escalation phase and a food effect–assessment phase. In the dose-escalation phase, subjects were administered a single dose of fruquintinib (2, 3, or 4 mg) in the fasted state. In the food effect–assessment phase, subjects were administered a 4-mg fruquintinib capsule in the fasted and fed states, respectively, in 2 cycles. Blood samples for pharmacokinetic analysis were collected at the designated time points. Tolerability was assessed throughout the study by physical examination including vital sign measurements, clinical laboratory tests, 12-lead ECG, clinical assessments, and monitoring for and spontaneous reporting of adverse events. Findings Twenty-nine eligible male subjects were enrolled in the study, including 9 in the dose-escalation phase and 20 in the food effect–assessment phase. In the food effect–assessment phase, the ratios (90% CI) of the geometric mean AUC0-∞ and Cmax values for fruquintinib in the fed state to those observed in the fasted state were 97.2% (94.0%–100.4%) and 82.9% (76.7%–89.5%), respectively. The mean (SD) Tmax values of fruquintinib were 3.0 (1.0) and 5.6 (4.5) hours in the fasted and fed states, respectively. The most common adverse events possibly related to the study drug were elevated blood uric acid, diarrhea, and decreased white blood cell count. Implications The overall bioavailability of the evaluated formulation of fruquintinib was not affected by the consumption of a high-fat, high-calorie meal prior to dosing. However, the consumption of a high-fat, high-calorie meal prior to dosing prolonged the Tmax. These results indicate that the fruquintinib capsule can be administered with or without food. ClinicalTrials.gov identifier: NCT01955304.

To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers. This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin. The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects. Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers.

The pharmacokinetics of lurasidone have been studied in healthy Japanese and Caucasian subjects, but not in Chinese subjects. The objective of this study was to evaluate the pharmacokinetics, safety, and tolerability of oral lurasidone in healthy Chinese subjects. This single-center, randomized, parallel-group, placebo-controlled, and double-blind study evaluated the pharmacokinetics, safety, and tolerability of oral lurasidone administered as a single dose (20, 40, and 80 mg) and multiple doses for 5 days (40 mg administered once daily) in healthy Chinese subjects. Serum lurasidone and its metabolites were quantified using high-performance liquid chromatography–mass spectrometry. Pharmacokinetic parameters for lurasidone and its metabolites were calculated using non-compartmental analysis of WinNonlin® version 6.2. Safety analyses were recorded using physical examinations, vital signs, electrocardiogram, and clinical laboratory tests. Serum concentrations of lurasidone reached maximum concentration (C max) within 1.0–3.0 h after each single dose, and then decreased biphasically, with a mean half-life (t ½) from 18.1 to 25.5 h over the dose range of 20–80 mg. The area under the concentration–time curve (AUC) and C max values increased approximately dose proportionally. Lurasidone steady state was achieved after 5 days of daily dosing and the accumulation index of the AUC during a dosage interval (AUCτ) was 1.25, smaller than theoretical cumulative coefficient (1.76). Similar results were observed for the metabolites (ID-14283, ID-14326, and ID-11614). No severe adverse events (AEs) were observed in the single- or multiple-dose studies and no subject discontinued from the study due to AEs. The most common reported AEs were somnolence, increased blood prolactin, and restlessness, with a higher rate as dose increased. Lurasidone was safe and well-tolerated in healthy Chinese subjects, following single doses in the range of 20 to 80 mg and multiple doses of 40 mg/day for 5 days. Linear increase in lurasidone C max and AUC values were seen following single doses from 20 to 80 mg. There was no unexpected accumulation after multiple administrations of lurasidone at 40 mg/day, and the pharmacokinetic characteristics were consistent with the conclusion obtained in the previous studies. Trial Registration: Clinicaltrials.gov identifiers NCT02174510 and NCT02174523.

Ulinastatin, is a broad-spectrum protease inhibitor purified from human urine, inhibits endogenous proteases such as trypsin, α-chymotrypsin, hyaluronidase, and plasmin. It is widely being used at increasingly higher doses for the treatment of acute or chronic pancreatitis, severe infection, and acute organ failure. We aimed to evaluate the safety and tolerability of high-dose ulinastatin in healthy volunteers in our single center, randomized, double-blind, placebo-controlled, single-dose escalation study. Fifty-one healthy Chinese subjects were enrolled in 9 dose cohorts (3×105 U, 6×105 U, 12×105 U, 20×105 U, 30×105 U, 45×105 U, 60×105 U, 70×105 U, or 80×105 U of ulinastatin) and randomized to UTI or matching placebo (n = 1). Each dose cohort was composed of 3–7 subjects. All subjects were required to have 2 h of intravenous infusion. Safety and tolerability were assessed throughout the study via monitoring of vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and interviews with the subjects about adverse events. Fifty-one subjects (35 men and 16 women) completed the study. A total of 13 AEs were reported by 10 subjects: 11 adverse events in the ulinastatin groups and 2 adverse events in the placebo group. Twelve of the adverse events were possibly related to the study drug. The most common drug-related adverse events included dizziness, pain at injection site, and a decrease in white blood cell count. All adverse events were of mild severity; none were serious. In conclusion, 2 hours of intravenous infusion of ulinastatin (3×105 to 80×105 U) was well tolerated by healthy Chinese subjects.

Dehydroandrographolide succinate (DAS) is extracted from herbal medicine Andrographis paniculata (Burm f) Nees. DAS injection is used in China for the treatment of viral pneumonia and upper respiratory tract infections. The aim of this study is to investigate the pharmacokinetics and tolerance of DAS injection in healthy Chinese volunteers.This was a single-center, randomized, single-dose, three-way crossover design study. Nine eligible subjects were randomly divided into 3 groups, and each group sequentially received 80, 160, or 320 mg of DAS infusion according to a three-way Latin square design. Plasma and urine samples were collected and determined using an LC-MS/MS method. Safety and tolerability were determined via clinical evaluation and adverse event monitoring.For the 80, 160, and 320 mg dose groups, the mean C(max) were 4.82, 12.85, and 26.90 mg/L, respectively, and the mean AUC(0-12) were 6.18, 16.95, and 40.65 mg·L(-1)·h, respectively. DAS was rapidly cleared, with a mean T(max) of 0.94-1.0 h and a t(1/2) of approximately 1.51-1.89 h. Approximately 10.1%-15.5% of the intravenous DAS dose was excreted unchanged in urine within 24 h in the 3 groups, and more than 90% of unchanged DAS was excreted between 0 and 4 h. The pharmacokinetic profile was similar between male and female subjects. No serious or unexpected adverse events were found during the study, but one mild adverse event (stomachache) was reported.This study shows that DAS has nonlinear pharmacokinetic characteristics. To guarantee the effective concentration, mul¬tiple small doses are recommended in clinical regimens.

Background: Atorvastatin calcium is a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor indicated for the prevention of cardiovascular disease and for the treatment of dyslipidemia. Information on the pharmacokinetics of atorvastatin in a Chinese population is lacking, and regulatory requirements necessitate a bioequivalence study for the marketing of a generic product in China. Objective: The aim of the present study was to assess the pharmacokinetics and bioequivalence of a test and branded reference formulation of atorvastatin calcium 10-mg tablets in healthy fasted Chinese male volunteers. Methods: This was a single-dose, randomized-sequence, open-label, 2-period crossover study with a 2-week washout period between doses. Healthy Chinese males were randomly assigned to receive 20 mg of either the test or reference formulation, and 13 blood samples were obtained over a 48-hour interval. Plasma concentrations of parent atorvastatin and ortho-hydroxy-atorvastatin (primary active metabolite) were simultaneously determined using a validated liquid chromatography-isotopic dilution mass spectrometry method. Pharmacokinetic parameters, including C max , T max , t ½ , AUC 0−t , and AUC 0−∞ ), were calculated. The 2 formulations were to be considered bioequivalent if 90% CIs for the logtransformed ratios of AUC and C max of atorvastatin were within the predetermined bioequivalence range (0.80–1.25 for AUC and 0.70–1.43 for C max ) as established by the State Food and Drug Administration of China. Tolerability was evaluated throughout the study by vital signs monitoring, physical examinations, 12-lead ECGs, and subject interviews on adverse events (AEs). Results: A total of 66 subjects were assessed for inclusion; 20 were excluded prior to study initiation. Of the 46 healthy subjects (mean [SD] age, 24.1 [2.5] years; height, 170.8 [5.1] cm; weight, 64.6 [6.4] kg; body mass index (BMI), 22.1 [1.7] kg/m 2 ) who completed the study, 45 subjects (mean [SD] age, 24.1 [2.5] years; height, 171.1 [4.9] cm; weight, 64.8 [6.3] kg; BMI, 22.1 [1.7] kg/m 2 ) were included in the pharmacokinetic and bioequivalence analyses; 1 subject was excluded from these analyses because he mistakenly received the same formulation in both periods. No period or sequence effect was observed. The mean values of C max , AUC 0−t , and AUC 0−∞ ) for the test and reference formulations of atorvastatin (8.78 and 10.76 ng/mL, 38.22 and 40.02 ng/mL/h, 42.73 and 44.51 ng/mL/h, respectively) and ortho-hydroxy-atorvastatin (5.78 and 5.77 ng/mL, 47.32 and 48.47 ng/mL/h, 52.36 and 53.14 ng/mL/h) were not significantly different. The 90% CIs for natural log-transformed ratios of C max , AUC 0−t , and AUC 0−∞ ) of both atorvastatin (0.73–0.91, 0.92–1.02, and 0.91–1.01, respectively) and ortho-hydroxy-atorvastatin (0.83–1.05, 0.92–1.02, and 0.93–1.02) were within the bioequivalence acceptance limits. Three subjects (6.5%) reported a total of 4 mild AEs (1 abdominal discomfort and 3 venipuncture syncope), which were not considered to be associated with administration of the study drug. Conclusions: This single-dose (20 mg) study found that the test and reference formulations of atorvastatin calcium 10-mg tablet met the regulatory definition for assuming bioequivalence in these healthy fasted Chinese male volunteers. Both formulations were generally well tolerated in the population studied. Chinese National Registry Code: 2007L02512.

Background: Glimepiride is an oral sulfonylurea antihyperglycemic agent indicated for the treatment of type 2 diabetes mellitus. Although there are reports in the literature regarding the pharmacokinetic (PK) characteristics of glimepiride, few data of PK parameters are available in a Chinese population; none are available regarding a recently developed generic formulation. Objective: To meet the requirements for marketing a new generic product in China, the study was designed to compare the PK properties and bioequivalence of 2-mg tablets of glimepiride: the newly developed generic formulation (test) and a branded formulation (reference) in healthy Chinese male volunteers. Methods: A single-dose, randomized-sequence, open-label, 2-way crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 1 tablet (2 mg each) of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected before study drug administration (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours after study drug administration. Concentrations in plasma of the parent glimepiride and its M1 metabolite were analyzed with a LC-MS/MS method. The formulations were considered bioequivalent if the 90% CIs for the log-transformed values were within the predetermined equivalence range (70%–143% for C max and 80%–125% for AUC), according to the guidelines of the State Food and Drug Administration (SFDA) of China. Tolerability was based on the recording of adverse events (AEs), monitoring vital signs, ECGs, and laboratory tests at baseline and completion of the study. Results: A total of 24 healthy Chinese male volunteers were enrolled and completed the study; however, only the data from 23 subjects were included (mean [SD] age, 23.6 [2.2] years [range, 18.6–26.9 years]; weight, 64.0 [8.4] kg [range, 52.0–82.0 kg]; and height, 172.3 [5.6] cm [range, 164.0–185.0 cm) in the PK and toler-ability assessments due to a violation of the protocol. For parent glimepiride, the 90% CIs for the ratios of C max , AUC 0–t , and AUC 0−∞ were 93.83% to 115.19%, 90.82% to 102.29%, and 92.22% to 103.78%, respectively. For the M1 metabolite, the 90% CIs were 91.71% to 110.79%, 91.33% to 101.76%, and 89.99% to 99.85%. Both met the predetermined criteria for bioequivalence. Four AEs (17.4%) were reported: hypertriglyceridemia (2 subjects [8.7%]; 1 each receiving the test and reference formulations); increase of red blood cells in urine (1 subject [4.3%] receiving the reference formulation); and hypoglycemia (1 subject [4.3%] receiving the test formulation). The incidence of hypo-glycemia was the only AE considered probably related to study drug administration; all others were considered probably not related. All AEs were transient and considered by the investigators to be mild. Conclusions: In this small study in fasted healthy Chinese male volunteers, a single 2-mg dose of the test formulation met the regulatory criteria to assume bioequivalence to the reference formulation based on the rate and extent of absorption. Both formulations were well tolerated. SFDA Registration No.: 2009L01033.

Melamine was found to be the etiological factor for the urinary stones epidemic in infants and young children in China in 2008. Urine level of melamine and its analog cyanuric acid may be useful markers for the evaluation of toxic effects. Liquid chromatography tandem mass spectrometry methods for the individual determination of melamine and cyanuric acid in human urine are described. Using isotope labeled internal standards during liquid-liquid extraction, the method was fully validated by verifying specificity, linearity, LLOQ, intra- and inter-assay precision and accuracy, matrix effect, recovery and stability. Calibration curves with good linearity (r=0.9999) over the concentration range from 10 to 5000 ng/ml, intra-assay precision10% and inter-assay precision15%, accuracy between 93.0 and 111.6% were obtained with multiple reaction monitoring mode for melamine and cyanuric acid in human urine. The methods were successfully applied to the analysis of urine samples collected from 86 infants and 110 adults.

Background: Amlodipine is a third-generation dihydropyridine calcium antagonist for the treatment of angina and hypertension. The relative bioavailability of a newly developed dispersible tablet as compared with an established branded formulation has not been reported in a Chinese population. Objective: The aim of this study was to assess and compare the pharmacokinetic properties, bioavailabili-ty, and bioequivalence of a newly developed dispersi-ble tablet formulation of amlodipine besylate with those of an established branded formulation in healthy Chinese adult male volunteers. Methods: An open-label, single-dose, randomized, 2-way crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 2 tablets (5 mg each) of the test or 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. Serum samples were collected over 120 hours. Amlodipine concentrations in the serum were analyzed by liquid chromatography tandem mass spectrometry with positive ion electrospray ionization using the multiple reaction monitoring mode. The visible detection of the method was in the range of 0.2 to 32.0 ng/mL, and the lower limit of quantification for amlodipine was 0.2 ng/mL. The amlodipine serum concentration-time curves were used to obtain pharmacokinetic parameters including AUC 0−t , AUC 0−∞ ), and C max . The criteria for bioequivalence were 90% CIs of 80% to 125% for AUC and 70% to 143% for C max , according to guidelines of the State Food and Drug Administration of the People's Republic of China. Tolerability was based on the recording of adverse events (AEs), monitoring vital signs, electrocardiograms, and clinical laboratory tests at baseline and completion of the study. Results: A total of 20 healthy Chinese male volunteers (mean [SD] age, 21.4 [2.6] years [range, 1926 years]; weight, 61.3 [5.4] kg [range, 54.0–75.0 kg]; and height, 171.2 [3.6] cm [range, 162.0–177.0 cm) were included in the study. The mean (SD) C max , T max , AUC 0−t , and AUC 0−∞ ) values after administration of the test and reference formulations, respectively, were as follows: 5.46 (1.13) versus 5.88 (1.24) ng/mL, 7.70 (2.08) versus 9.20 (4.18) hours, 284.56 (77.59) versus 311.34 (75.97) ng/mL/h, and 331.37 (111.03) versus 358.74 (101.10) ng/mL/h. The mean (SD) t 1/2 was 38.52 (10.51) hours for the test formulation and 38.75 (7.07) hours for the reference formulation. On analysis of variance, no period or sequence effects were observed for any pharmacokinetic property; however, a significant formulation effect was observed for C max , AUC 0−t , and AUC 0−∞ ). The relative bioavaila-bility of the test formulation was 90.9% by mean AUC 0−t and 91.2% by mean AUC 0−∞ . The 90% CIs for the ratios of C max , AUC 0−t , and AUC 0−∞ were 88.4% to 97.5%, 86.4% to 95.7%, and 85.8% to 97.0%, respectively, meeting the predetermined criteria for bioequivalence. One subject (5%) reported 2 AEs. The AEs were mild, possibly associated with study drug, and resolved spontaneously by the next evaluation. No serious AEs were reported. Conclusions: In this small study in healthy Chinese adult male volunteers, a single 10-mg dose of the dispersible tablet formulation (test) of amlodipine besy-late met the regulatory criteria for bioequivalence to the established tablet formulation (reference) based on the rate and extent of absorption. Both formulations were well tolerated.

A simple, rapid and sensitive liquid chromatography–tandem mass spectrometry method was developed for quantification of deglymidodrine in human plasma. The plasma samples were pretreated by protein precipitation with trichloroacetate. The chromatographic separation was performed on reversed phase Aquasil C 18 column, and the plasma extraction was eluted with a mobile phase solution consisting of acetonitrile (containing 0.02% formic acid) and water (containing 0.02% formic acid). The molecular ion of analyte was detected in positive ionization by multiple reaction monitoring. The mass transitions of m / z 198.4 → 148.1 and m / z 212.4 → 162.3 were used for detection of deglymidodrine and its internal standard, respectively. The assay exhibited linear ranges from 0.25 to 32 ng/ml for the analyte in human plasma. Acceptable precision and accuracy were obtained for concentrations of quality control (QC) samples. The proposed method has been successfully used to analyze human plasma samples for application in oral pharmacokinetic study.

UNLABELLED Inhaled umeclidinium (UMEC) and the combination of inhaled UMEC with vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. This was a randomized, open-label, three-period crossover, single- and repeat-dose study to assess the pharmacokinetics (PK), safety, and tolerability of inhaled UMEC/VI 62.5/25 μg (delivering 55/22 μg) and UMEC/VI 125/25 μg (delivering 113/22 μg) compared with their monotherapy components (UMEC 62.5 μg, UMEC 125 μg and, VI 25 μg [delivering 55, 113, and 22 μg, respectively]) in healthy Chinese subjects (n=20). UMEC and VI were rapidly absorbed following single and repeat dosing (time to maximum plasma concentration [tmax]: UMEC = 5 min; VI = 5 min). The median tlast was 2–4 h for UMEC and 1–2 h for VI following single doses of UMEC/VI and UMEC monotherapy (both doses). UMEC reached steady-state prior to Day 10; steady-state for VI could not be assessed. UMEC accumulation following repeat dosing was 11–34% based on Cmax and 19–59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25–66% based on Cmax and 17–43% based on AUC(0-2). The evidence was not sufficient to suggest that systemic exposure was substantially different between UMEC/VI combination therapy and the constituent monotherapies following single or repeat dosing. Following both single- and repeat-dose administration, the inter-subject coefficient of variation for all UMEC PK parameter estimates ranged from 12% to 165% for all treatments, indicating a wide range of variability in inhaled PK parameters. Twelve subjects experienced ≥1 adverse event (AE). Six subjects experienced ≥1 treatment-related AE; the most commonly reported treatment-related AE was chest discomfort (n=3 [15%]). No clinically important changes in vital signs or electrocardiogram parameters were reported. These data suggest that single- and repeat-dose administration of UMEC/VI combination therapy in healthy Chinese subjects did not result in substantial differences in systemic exposure compared with UMEC and VI as monotherapies. TRIAL REGISTRATION Clinicaltrials.gov NCT01899638 NCT01899638.

Artesun-Plus is a fixed-dose combination antimalarial agent containing artesunate and amodiaquine. The current study was conducted to compare the pharmacokinetic and safety profiles of Artesun-Plus and the WHO-designated comparator product Artesunate Amodiaquine Winthrop. To overcome the high intrasubject variability of artesunate, the study applied a two-sequence and four-period crossover (2 by 4), replicate study design to assess bioequivalence between the two products in 31 healthy male Chinese volunteers under fasting conditions. The results showed that the values of the geometric mean ratios of maximum concentration of drug in plasma ( C max ) and area under the concentration-time curve from time zero to the last blood sample collection (AUC 0-last ) for the artesunate component in the test and reference products were 95.9% and 93.9%, respectively, and that the corresponding 90% confidence intervals were 84.5% to 108.7% and 87.2% to 101.1%, while the geometric mean ratios for the amodiaquine component in the test and reference products were 95.0% and 100.0%, respectively, and the corresponding 90% confidence intervals were 86.7% to 104.1% and 93.5% to 107.0%. In conclusion, bioequivalence between the two artesunate and amodiaquine fixed-dose combination products was demonstrated for both components. The study also confirmed high intrasubject variability, especially for artesunate: the coefficients of variation (CV) of C max values for the test and reference products were 39.2% and 43.7%, respectively, while those for amodiaquine were 30.6% and 30.2%, respectively.

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 T max was 0.75 hour, and t ½ was ~21 hours with single dosing. The mean ratio of AUC 0–τ steady state/AUC 0–24 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. ClinicalTrials.gov identifier: NCT01480622.

Background Risperidone is a benzisoxazole derivate and is effective in the treatment of schizophrenia and other psychiatric illnesses in adults and children. Although there are a few reports in the literature regarding the pharmacokinetic characteristics of risperidone, insufficient data on its pharmacokinetic properties in a Chinese population are available. Objective To meet the requirements for marketing a new generic product, this study was designed to compare the pharmacokinetic properties and bioequivalence of two 2 mg tablet formulations of risperidone: a newly developed generic formulation (test) and a branded formulation (reference) in healthy adult male Chinese volunteers. Methods A single-dose, open-label, randomized-sequence, 2 × 2 crossover study was conducted in fasted healthy male Chinese volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 1 tablet (2 mg each) of the test formulation (Risperidone tablet; Dr. Reddy’s Laboratories Ltd., Hyderabad, India) or the reference formulation (Risperdal® tablet; Xian-Janssen Pharmaceutical Ltd., Xi-an, China), followed by a 2-week washout period and subsequent administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected over 96 hours. Plasma concentrations of the parent drug, risperidone, and its active metabolite, 9-hydroxy-risperidone, were analyzed by a liquid chromatography–tandem mass spectrometry method. The formulations would be considered bioequivalent if the 90% confidence intervals (CIs) of the natural log-transformed values were within the predetermined 80–125% equivalence range for the maximum plasma drug concentration (Cmax) and the area under the plasma concentration–time curve (AUC), in accordance with guidelines issued by the US Food and Drug Administration. Assessment of tolerability was based on recording of adverse events (AEs), monitoring of vital signs, electrocardiograms, and laboratory tests at baseline and at completion of the study. Results A total of 24 healthy male Chinese volunteers (mean age 22.9 years [standard deviation (SD) 2.7, range 19.2–27.1]; weight 63.2 kg [SD 7.0, range 52.0–78.0]; and height 171.3 cm [SD 6.1, range 162.0–187.0]) were enrolled, and all completed the study. For the parent drug, risperidone, the 90% CIs of the relative values (test vs. reference) of the Cmax, AUC from time zero to time t (AUCt), and AUC from time zero to infinity (AUC∞) were 97.0–124.0%, 92.7–115.1%, and 92.8–114.2%, respectively. For the active metabolite, 9-hydroxy-risperidone, the values were 104.4–117.7%, 101.0–113.7%, and 100.4–113.4%, respectively. The two formulations met the predetermined criteria for bioequivalence. A total of 73 AEs were observed in 24 subjects during the study. The most common AE was sedation (48 events), followed by nasal reactions (14 events), postural hypotension (3 events), hypertriglyceridemia (2 events), dizziness (4 events), nausea (1 event), and anorexia (1 event). Their severity was as follows: 16 were mild, 57 were moderate, and none were severe. The majority of the AEs were considered to be related (48 events) or probably related (23 events) to the study medication. No clinically significant abnormalities on physical examination, vital sign measurements, or electrocardiographic recordings were reported. No serious AEs were reported. Conclusions The data from this study in healthy adult male Chinese subjects suggest that the test formulation met the regulatory criteria for bioequivalence to the reference formulation, on the basis of the rate and extent of absorption. Both formulations were well tolerated.

Background: Acetylcysteine may be used as a muco- lytic agent for the treatment of chronic bronchitis, chronic obstructive pulmonary disease, and other pul- monary diseases complicated by the production of viscous mucus. However, little is known of its pharma- cokinetic properties when given orally in healthy vol- unteers, particularly in a Chinese Han population. This study was conducted to provide support for the market- ing of a generic product in China. Objective: The purpose of this study was to compare the pharmacokinetics and relative bioavailability of a generic test formulation and a branded reference formulation of acetylcysteine in fasting healthy Chinese male volunteers. Methods: A single-dose, open-label, randomizedsequence, 2-period crossover design with a 7-day washout period between doses was used in this study. Healthy Chinese male nonsmokers aged 18 to 40 years with a body mass index (BMI) of 19 to 25 kg/m 2 were selected. Eligible volunteers were randomly assigned to receive acetylcysteine 600 mg PO as either the test formulation (3 tablets of 200 mg each) or reference formulation (1 tablet of 600 mg) under fasting conditions. A total of 15 serial blood samples were collected over a 24-hour interval, and total plasma acetylcysteine concentrations were analyzed by a validated liquid chromatographyisotopic dilution mass spectrometry method. Pharmacokinetic parameters (C max , T max , t ½ AUC 0-t , and AUC 0-∞ were calculated and analyzed statistically. The 2 formulations were considered bioequivalent if the 90% CIs of the log-transformed ratios (test/reference) of C max and AUC were within the predetermined bioequivalence ranges (70%–143% for C max ; 80%–125% for AUC), as established by the State Food and Drug Administration of China. Tolerability was determined by vital signs, clinical laboratory tests, 12-lead ECGs, physical examinations, and interviews with the subjects about adverse events (AEs). Results: A total of 24 healthy Chinese Han male volunteers were enrolled in and completed the study (mean [SD] age, 25.0 [2.4] years; height, 173.0 [5.6] cm; weight, 65.9 [6.4] kg; BMI, 22.0 [1.7] kg/m 2 ). No formulation, period, or sequence effects were observed. The 90% CIs for the log-transformed C max , AUC 0-t , and AUC 0-∞ were 89.7% to 103.8%, 86.7% to 101.7%, and 87.7% to 102.4%, respectively, which met the predetermined criteria for assuming bioequivalence. Two subjects (8.3%) experienced 2 mild AEs (increase in total bile acid and prolongation of the QT interval), which were not considered to be related to study drug administration. Conclusions: This single-dose study of acetylcysteine 600 mg PO found that the 3 tablets of the generic test formulation and 1 tablet of the branded reference formulation met the regulatory criteria for assuming bioequivalence in these fasting healthy Chinese male volunteers. Both formulations were generally well tolerated

Background: Flurbiprofen, an NSAID, is used for the treatment of inflammation and pain caused by rheumatoid arthritis and osteoarthritis as well as soft-tissue injuries. A new orally disintegrating tablet (ODT) of flurbiprofen has recently been developed; this study was conducted to provide support for this drug to obtain marketing authorization in China. Objective: The aim of the study was to compare the pharmacokinetic properties and bioequivalence of flur-biprofen 50-mg ODT (test) with a conventional flur-biprofen 50-mg tablet (reference) under fasting conditions in healthy volunteers. Methods: This was a single-dose, randomized-sequence, open-label, 2-period crossover study. Healthy, nonsmoking Chinese male volunteers were randomly assigned to receive 150 mg (administered as three 50-mg tablets) of either the test or reference formulation of flurbiprofen, followed by a 7-day washout period and administration of the alternate formulation. Study drugs were administered after a 12-hour overnight fast. Blood samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. Serum flurbiprofen concentrations were analyzed using a validated nonstereospe-cific liquid chromatography/tandem mass spectrome-try method. Pharmacokinetic parameters, including Cmax, Tmax, t1/2, AUC0–24, and AUC0-∞, were calculated and analyzed statistically. Cmax, AUC0–24, and AUC0-∞ were used to test for bioequivalence after natural logarithm (ln)-transformation. Tolerability was evaluated throughout the study by clinical assessments, vital sign monitoring, physical examinations, 12-lead ECG, clinical laboratory tests, and questioning subjects about adverse events (AEs). Results: A total of 20 Chinese males (mean [SD] age, 21.4 [2.5] years [range, 19–28 years]; height, 174.4 [4.2] cm [range, 169–183 cm]; weight, 63.2 [5.1] kg [range, 56–78 kg]; body mass index, 20.8 [1.4] kg/m2 [range, 19–24 kg/m2]) completed the study. No period or sequence effect was observed. The 90% CIs for the ln-transformed ratios of Cmax, AUC0–24, and AUC0-∞ were 99.9% to 115.9%, 97.8% to 107.9%, and 100.3% to 110.9%, respectively, meeting the predetermined criteria for bioequivalence. Two subjects (10.0%) experienced 1 of 2 mild AEs (increase in total bilirubin and dizziness), which were not considered to be associated with study drug administration. Conclusions: This single-dose 150-mg (three 50-mg tablets) study of each formulation of flurbiprofen found that the test and reference products met the regulatory criteria for bioequivalence in these fasting healthy Chinese male volunteers. Both formulations were generally well tolerated. State Food and Drug Administration of China study registration number: 2005L04356.

A liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for the determination of human plasma homocysteine (Hcy), an important independent risk factor for cardiovascular disease, with a simplified sample pretreatment procedure and a zero blank free of endogenous Hcy for calibrator/QC preparation. Following protein precipitation, chromatographic separation was performed on Hypersil Aquasil C18 column (50 mm x 2.1mm, 5 microm, Thermo) using mobile phase of aqueous 10% methanol containing 0.02% formic acid at 0.25 mL/min. Hcy and deuterated internal standard were detected in the multiple reaction monitoring mode with precursor to product ion transitions of m/z 136.1/90.0 and 140.1/94.0, respectively. The retention time was 1.2 min, and the total run time was 2 min per injection. A streamlined three-point calibration curve and one-point QC was used. Excellent linearity was observed with correlation coefficient (r)>0.99. The intra- and inter-batch were < or =3.24% and < or =4.04%, and accuracy was within +/-10%. Method comparison between the proposed method (y) and FPIA assay (x) demonstrated a correlation equation of y=1.003x + 0.4318 (r=0.9589). The developed method, improved for automation with cost-effective reagents, was proven to be suitable for high-throughput quantitative determination of Hcy in clinical practice by successfully applying it to the cardiovascular disease study.