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Sulcardine sulfate (Sul) is a novel anti-arrhythmic 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 seven-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 ( AE) 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. [ABSTRACT FROM AUTHOR]

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 (C) 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 C, AUC from time zero to time t (AUC), 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. [ABSTRACT FROM AUTHOR]

Aim: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.Methods: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.Results:For the 80, 160, and 320 mg dose groups, the mean Cmax were 4.82, 12.85, and 26.90 mg/L, respectively, and the mean AUC0-12 were 6.18, 16.95, and 40.65 mg·L−1·h, respectively. DAS was rapidly cleared, with a mean Tmax of 0.94-1.0 h and a t1/2 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.Conclusion:This study shows that DAS has nonlinear pharmacokinetic characteristics. To guarantee the effective concentration, mul¬tiple small doses are recommended in clinical regimens. [ABSTRACT FROM AUTHOR]

Background: Losartan is a nonpeptide angiotensin II receptor antagonist used as an antihypertensive agent. The relative bioavailability of a newly developed tablet compared with an established branded formulation has not been reported in a Chinese population. Objective: To meet the requirements for marketing a new generic product, the study was designed to compare the pharmacokinetic parameters and relative bioavailability of a new generic losartan potassium 50-mg tablet (test formulation) with a branded 50-mg tablet (reference formulation) in healthy Chinese male volunteers. Methods: A single-dose, randomized-sequence, openlabel, 2-way crossover study was conducted in healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive a single 50-mg tablet of the test or reference formulation, followed by a 1-week washout period and then administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected over 36 hours. Tolerability was evaluated by recording adverse events (AEs) and monitoring vital signs, ECGs, and laboratory tests at baseline and at completion of the study. Plasma concentrations of losartan and its active metabolite (EXP3174) were analyzed by LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0–36, and AUC0−∞, were calculated. If the 90% CIs for the log-transformed values of AUC were within 80% to 125%, and that of Cmax was within 70% to 143%, the 2 products would be considered bioequivalent according to the guidelines of the US Food and Drug Administration and the State Food and Drug Administration of China. Results: Twenty–seven healthy Chinese male volunteers participated in this study (mean [SD] age, 24.5 [2.3] years [range, 20–29 years]; weight, 64.6 [4.0] kg [range, 60.0-75.0 kg]; height, 172.2 [4.8] cm [range, 165.0183.0 cm]; and body mass index, 21.8 [1.2] kg/m2 [range, 20.0–25.0 kg/m2]). One volunteer (3.7%) experienced an AE (microscopic hematuria) after administration of the test formulation. This resolved spontaneously after 10 days and was considered by the investigator as mild; the relationship with the study drug was uncertain. No serious AEs were reported. Both formulations were associated with significant reductions in systolic and diastolic blood pressure and significant increases in heart rate compared with baseline values (all, P < 0.05). No period, formulation, or sequence effects were observed for any pharmacokinetic parameter, except for a significant subject effect. For parent losartan, the 90% CIs for the ratios (test/reference) of Cmax, AUC0–36, and AUCAUC0−∞ were 83.65% to 113.36%, 89.79% to 98.25%, and 90.95% to 99.55%, respectively. For the metabolite EXP3174, the 90% CIs for the ratios of Cmax, AUC0–36, and AUCAUC0−∞ were 93.49% to 103.61%, 96.79% to 104.09%, and 97.06% to 105.83%. Both Cmax and AUC met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation to the reference formulation was 93.92% for losartan and 100.40% for EXP3174. Conclusions: In this small study in healthy Chinese male volunteers, a single 50-mg oral dose of a losartan potassium tablet (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated. [Copyright &y& Elsevier]

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 Cmax 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 Cmax, AUC0–t, and AUC0−∞ 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. [Copyright &y& Elsevier]

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 Cmax, Tmax, t½, AUC0−t, and AUC0−∞), were calculated. The 2 formulations were to be considered bioequivalent if 90% CIs for the logtransformed ratios of AUC and Cmax of atorvastatin were within the predetermined bioequivalence range (0.80–1.25 for AUC and 0.70–1.43 for Cmax) 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/m2) 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/m2) 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 Cmax, AUC0−t, and AUC0−∞) 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 Cmax, AUC0−t, and AUC0−∞) 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. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]