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Background and Objectives: Ilaprazole is a novel proton pump inhibitor that provides effective and long lasting inhibition of intragastric acid secretion. The objectives of this study were to investigate the pharmacokinetics, pharmacodynamics, and safety of intravenous ilaprazole after multiple administrations in healthy Chinese subjects. Methods: This was an open-label and multiple-dose clinical study. Ten healthy Chinese subjects received 10 mg ilaprazole infusion once daily for 5 days. Helicobacter pylori status was examined. Blood samples were collected and intragastric pH was recorded for 24 h. Safety was assessed throughout the study. Results: There was no accumulation after multiple administrations. The mean steady-state half-life and clearance were comparable to those following single administration. Ilaprazole provided sustainable and significant intragastric pH control in terms of percentage time at pH >4, pH >6 within 24 h and mean 24-h pH values. The pH value within 24 h was affected by Helicobacter pylori infection in subjects with continuous infusion. Intravenous ilaprazole was safe and there were no serious adverse events. Conclusion: Intravenous ilaprazole provided stable pharmacokinetics and pharmacodynamics at a dose of 10 mg once daily for 5 days, and was well tolerated in healthy subjects. [ABSTRACT FROM AUTHOR]

Background and Objective: Tylerdipine hydrochloride (KBP-5660) is a novel L/T-type dual calcium channel blocker developed for the treatment of hypertension. We aimed to study the pharmacokinetics, safety and tolerability of tylerdipine in healthy Chinese subjects.Methods: Two double-blind, randomized, dose-escalation studies were conducted that included a total of 88 healthy subjects: (1) a single-ascending dose (SAD) study; and (2) a multiple-ascending dose (MAD) study. In the SAD study, 64 subjects were randomly assigned to receive a single dose of 0.5, 2.5, 5, 10, 15, 20, 25, or 30 mg of tylerdipine or placebo. In the MAD study, 24 subjects were randomly assigned to receive 10 or 20 mg of tylerdipine or placebo once daily for 9 days. Blood samples were collected at the designated time points for pharmacokinetic analyses. Safety assessments were conducted throughout the study.Results: Following a single oral dose of tylerdipine of 5-30 mg, the mean maximum plasma concentration (Cmax) increased from 0.9993 to 10.11 ng/ml; mean area under the plasma-concentration curve (AUC) from time zero to 72 h increased from 4.332 to 73.95 h·ng/ml. AUC increased in a greater than dose-proportional manner, whereas Cmax exhibited a rough but non-typical dose-proportionality increase. In the MAD study, steady-state conditions were achieved after 1 week of daily dosing in both dose groups. Accumulation of tylerdipine was low, with accumulation ratios (RAUC) of less than 1.65. All adverse events were assessed as mild or moderate.Conclusion: Tylerdipine hydrochloride was safe and well tolerated. The exposure (AUC) of tylerdipine over the dose range of 5-30 mg increased in a greater than dose-proportional manner, while Cmax exhibited a rough but non-typical dose proportionality increase. A slight accumulation of tylerdipine was observed following multiple dosing.Study registrations: CTR20140862 and CTR20150660. [ABSTRACT FROM AUTHOR]

Purpose: Fruquintinib (HMPL-013) is a novel, potent, and highly selective tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptors (1, 2 and 3). This study was conducted to investigate the metabolism, excretion, and pharmacokinetics of HMPL-013 after a single oral dose to healthy Chinese men.Methods: Six subjects were administrated an oral suspension containing 5 mg of 14C-labeled HMPL-013 (100 μCi) in a fasted state. Blood and excreta samples were collected at the designated time points or intervals for pharmacokinetics and radiometric analyses. Safety assessments were conducted throughout the study.Results: Over a 336-h post-dose collection period, mean recovery was 90.11% of the radiolabeled dose, with 60.31% in urine and 29.80% in feces. Mean C max, AUC0-∞, and T max for HMPL-013 in plasma were 113 ng/mL, 4797 h ng/mL, and 2 h, respectively. Radioactivity and HMPL-013 were cleared from circulation with terminal half-lives of 41.1 and 33.4 h. HMPL-013 was the predominant circulating radioactive component, representing 72.48% of the total radioactivity. M11 was the major circulating metabolite, accounting for 17.31% of the total radioactivity. An additional seven circulating metabolites were identified, each accounting for less than 5% of the total radioactivity. In urine, HMPL-013 accounted for only 0.50% of the administered dose. Three major metabolites M285, M381, and M409-4 were identified in urine accounting for 10.48, 21.16, and 8.92% of the dose, respectively. In feces, HMPL-013 accounted for 5.34% of the dose. M205, M365-2, and M380 were the major metabolites, accounting for 2.29, 3.30, and 2.59% of the dose, respectively.Conclusion: HMPL-013 was well tolerated and absorbed rapidly, with parent compound being the predominant circulating component. HMPL-013 was extensively metabolized prior to excretion, and urine was the major route of excretion. [ABSTRACT FROM AUTHOR]

Purpose: Ginkgo terpene lactones meglumine injection (GMI) is a novel preparation of traditional Chinese medicine that contains ginkgolides A, B and K (GA, GB, GK, respectively) as its primary components. In this study we evaluated the safety, tolerability and pharmacokinetics of these three ginkgolides after single and multiple intravenous infusions of GMI. We also investigated the effect of GMI on cytochrome P450 3A4 (CYP3A4) in healthy Chinese volunteers. Methods: In this open-label, placebo-controlled study 15 subjects were randomly assigned to receive GMI or matched placebo (4:1 ratio). All subjects first received midazolam (MDZ) on day 1, followed by a 6-day washout. On Day 8, the subjects were started on once-daily dosing of either GMI or placebo for 14 days. Lastly, on Day 22 the subjects were given second dose of MDZ + GMI or MDZ + placebo. Plasma concentrations of ginkgolides, MDZ and its metabolite 1-hydroxy midazolam were quantified. Results: The steady-state conditions of GA, GB and GK were achieved after 6 days of daily dosing. Following a single dose of GMI (Day 8) the area under the concentration-timecurve from zero to 24 h after administration (AUC) of GA, GB and GK (arithmetic ± standard deviation) was 4.10 ± 1.06, 4.61 ± 1.31 and 0.127 ± 0.102 h μg/mL, respectively; the corresponding values following multiple doses of GMI (Day 19) were 3.94 ± 1.16, 5.00 ± 1.55 and 0.118 ± 0.096 h μg/mL, respectively. The mean accumulation ratios were 0.95, 1.08 and 0.89 for GA, GB and GK, respectively. Additionally, the geometric mean [peak concentration (C) and AUC] ratios of MDZ and 1-hydroxy midazolam were all within the specified acceptance ranges in the MDZ + placebo treatment and MDZ + GMI treatment. Conclusions: Our results show that GMI was well tolerated during the entire study. There was no systemic accumulation and no significant effects on the pharmacokinetics of MDZ in healthy Chinese male subjects after repeated dosing of GMI. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the pharmacokinetics and pharmacodynamics of rabeprazole (RPZ) given as successive intravenous infusion to healthy Chinese volunteers. Methods: A total of 63 subjects (33 males and 30 females) were recruited at four research centers and given a 5-day therapeutic course of RPZ (10, 20, or 40 mg) administered as single daily doses during a 30-min period. Plasma concentrations were monitored by sampling at very short intervals for the first 330, 360, or 420 min post-RPZ administration. Intragastric pH was recorded 24 h post-RPZ administration on day 1 and day 5. Results: After receiving a single and repeated doses of RPZ, the area under the plasma concentration-time curve (AUC) was 51.9 ± 22.1, 96.7 ± 27.6, and 188.4 ± 65.8 mg·min/L on day 1 and 59.3 ± 23.9, 106.7 ± 27.8, and 200.3 ± 79.0 mg·min/L on day 5 for the low-, middle-, and high-dose groups, respectively. The corresponding peak concentrations (C) were 0.64 ± 0.11, 1.30 ± 0.26, and 2.6 ± 0.54 μg/mL on day 1 and 0.76 ± 0.15, 1.39 ± 0.25, and 2.91 ± 0.53 μg/mL on day 5, respectively. Although the mean AUC and C values increased from a single dose to repeated doses in the three groups, the difference was not significant. The mean AUC and C ratios of repeated dose to single dose were 1.14, 1.10, and 1.06 on day 1 and 1.19, 1.07, and 1.12 on day 5 for the low-, middle-, and high-dose groups, respectively. After administration of a single dose, the 24-h pH value was significantly higher in the high-dose group than in the low-dose group. After repeated doses, significant increases in pH were observed in the low-, middle-, and high-dose groups; however, the between-group differences were not statistically significant. Conclusions: There is a relationship between the pharmacokinetics and pharmacodynamics of RPZ, with the latter depending in part on the duration of administration, as evidenced by a higher AUC or C and intragastric pH from repeated dosing. [ABSTRACT FROM AUTHOR]

To explore the effect of cytochrome P450 2C19 (CYP2C19) polymorphisms on the relationship between the pharmacokinetics and pharmacodynamics of omeprazole administered by intravenous successive infusions in Chinese healthy volunteers. A total of 21 subjects [7 homozygous extensive metabolizers (homEMs), 9 heterozygous extensive metabolizers (hetEMs), 5 poor metabolizers (PMs)] received a 5-day course of omeprazole (40 mg) administered as a single dose daily during a 30-min period. Plasma concentrations were monitored by sampling at very short intervals for the first 8.5 h post-omeprazole administration and at 24 h post-administration, and intragastric pH was recorded on days 1 and 5. After a single dose, both the area under the plasma concentration–time curve (AUC) and peak concentration (Cmax) were higher in PMs than in EMs. Both the mean half-life (t½) and total clearance in PMs were significantly higher and lower than those in homEMs and EMs, respectively. Mean AUC and Cmax ratios in homEMs, hetEMs, and PMs were 1.0:1.1:1.4 and 1.0:1.0:1.1, respectively. Relative to the values determined after a single dose in EMs, after repeated doses, the intragastric pH, AUC, Cmax, and t½ had increased significantly, while the total clearance had decreased significantly. Mean AUC and Cmax ratios in homEMs, hetEMs, and PMs were 1.4:1.4:1.5 and 1.2:1.2:1.3, respectively, compared to those of a single dose. The mean intragastric pH was significantly higher in PMs than in EMs after the fifth dose. There is a relationship between the pharmacokinetics and pharmacodynamics of omeprazole, with the latter depending in part on the duration of administration as evidenced by a higher AUC or Cmax and intragastric pH resulting from repeated dosing. [ABSTRACT FROM AUTHOR]