黄一玲
中国医学科学院阜外医院 卫生部心血管药物临床研究重点实验室
PURPOSE:The goal of this study was to develop a population pharmacokinetic (PK) and PK/pharmacodynamics (PD) model for ibutilide, to evaluate the time course of its effect on QT interval in Chinese.METHODS:The population PK and PK/PD model were developed using data from 40 Chinese healthy volunteers using nonlinear mixed-effects modeling, and the final population PK/PD model was applied on 100 patients with atrial fibrillation (AF) and/or atrial flutter (AFL).FINDINGS:The PK parameters of ibutilide were best described by a 3-compartment model with first-order elimination. No statistically significant covariate was found for each PK model parameter. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian rhythm of QT intervals was described by 2 mixed-effect cosine functions. The QT interval data of ibutilide was well characterized by a sigmoid Emax model (E(C)=Emaxγ×Cγ/(EC50γ+Cγ)) with an effect compartment. The final PK/PD model was used to estimate individual parameters of patient data and found good predictions compared with healthy volunteers; AF and/or AFL patients had lower Emax and higher EC50.IMPLICATIONS:A population PK and PK/PD model for ibutilide in healthy volunteers was developed and could well capture ibutilide's PK/PD characteristics. The final PK/PD model was applied on patients with AF and/or AFL successfully.
Clinical therapeutics 2017
A liquid chromatography-tandem mass spectrometry (LC-MS) method to quantify tolvaptan and its two main metabolites and applied to human study was first developed and validated as a measure of compliance in clinical research. Because of the structure similarity of tolvaptan and its multiple metabolites, the method was optimized to obtain a chromatographic and MS separation of the endogenous interference and isotope ions as well as high analysis throughput. Tolvaptan, its two main metabolites and the internal standard were extracted from human serum (0.1mL) using solid-phase extraction, separated on a Waters nova-pak C18 column (150×3.9mm, 5μm) using isocratic elution with a mobile phase composed of acetonitrile, water and formic acid (65:35:0.25, v/v/v). The total run-time was shortened to 3.5min. The mass transition ranges under positive electrospray ionisation that were monitored for quantitation included m/z 449-252 for tolvaptan, m/z 479-252 for metabolite DM-4103, m/z 481-252 for metabolite DM-4107 and m/z 463-266 for the internal standard (IS). The limit of quantification in plasma for all three analytes was 1ng/mL. The method was validated over a linear range from 1 to 500ng/mL for all three analytes with acceptable inter- and intra-assay precision and accuracy. The stability of the analytes was determined to be suitable for routine laboratory practices. The method was successfully applied to samples taken from research volunteers who ingested a 15mg tolvaptan tablet.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2016
BACKGROUND:As an acute phase protein, α1-antitrypsin (AAT) has been extensively studied in acute coronary syndrome, but it is unclear whether a relationship exists between AAT and stable angina pectoris (SAP). The purpose of the present study was to investigate the association between AAT plasma levels and SAP.METHODS:Overall, 103 SAP patients diagnosed by coronary angiography and clinical manifestations and 118 control subjects matched for age and gender were enrolled in this case-control study. Plasma levels of AAT, high-sensitivity C-reactive protein (hsCRP), lipid profiles and other clinical parameters were assayed for all participants. The severity of coronary lesions was evaluated based on the Gensini score (GS) assessed by coronary angiography.RESULTS:Positively correlated with the GS (r = 0.564, P < 0.001), the plasma AAT level in the SAP group was significantly higher than that in the control group (142.08 ± 19.61 mg/dl vs. 125.50 ± 19.67 mg/dl, P < 0.001). The plasma AAT level was an independent predictor for both SAP (odds ratio [OR] = 1.037, 95% confidence interval [CI]: 1.020-1.054, P < 0.001) and a high GS (OR = 1.087, 95% CI: 1.051-1.124, P < 0.001) in a multivariate logistic regression model. In the receiver operating characteristic curve analysis, plasma AAT level was found to have a larger area under the curve (AUC) for predicting a high GS (AUC = 0.858, 95% CI: 0.788-0.929, P < 0.001) than that of hsCRP (AUC = 0.665, 95% CI: 0.557-0.773, P = 0.006; Z = 2.9363, P < 0.001), with an optimal cut-off value of 137.85 mg/dl (sensitivity: 94.3%, specificity: 68.2%).CONCLUSIONS:Plasma AAT levels correlate with both the presence and severity of coronary stenosis in patients with SAP, suggesting that it could be a potential predictive marker of severe stenosis in SAP patients.
Chinese medical journal 2015
A liquid chromatography-tandem mass spectrometry method to quantify carvedilol enantiomers in human plasma was developed and validated as a measure of compliance in clinical research. Carvedilol enantiomers were extracted from human serum (0.5 mL) via liquid-liquid extraction with methyl tert-butyl ether (2.5 mL). Carvedilol-related compound C served as the internal standard. The analyte and internal standard were separated on a Sino-Chiral AD column (150 × 4.6mm, 5 μm, amylose tris-3,5-dimethylphenylcarbamate coated on silica-gel) using isocratic elution with mobile phases of methanol, water and diethylamine (94:6:0.01, v/v). The total run-time was 10.5 min. Carvedilol enantiomers were quantified using a triple quadrupole mass spectrometer operated in multiple-reaction-monitoring mode using positive electrospray ionisation. The mass transitions monitored for quantitation were carvedilol (m/z 407→222) and carvedilol-related compound C (m/z 497→222). The limits of quantification for the S- and R-carvedilol enantiomers in plasma were both 0.08 ng/mL. The method was validated in the linear range of 0.08-50 ng/mL with acceptable inter- and intra-assay precision and accuracy and stability suitable for routine laboratory practice. The method was successfully applied to samples taken from research volunteers treated with carvedilol sustained-release tablet 18 mg. Cmax and AUClast were 9.1 ± 5.1 ng/mL and 59.4 ± 39.6 ng h/mL for R-carvedilol, 4.0 ± 2.3 ng/mL and 24.7 ±15.0 ng h/mL for S-carvedilol, respectively. tmax and t1/2 were 4.6 ± 1.9h and 9.6 ± 4.5h for R-carvedilol, and 4.7 ± 1.0 h and 10.7 ± 5.7 h, respectively.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2014
A sensitive, rapid assay method for estimating ivabradine in human plasma has been developed and validated using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The procedure involved extraction of ivabradine and the internal standard (IS) from human plasma by solid-phase extraction. Chromatographic separation was achieved using an isocratic mobile phase (0.1% formic acid-methanol, 60:40, v/v) at a flow rate of 1.0 mL/min on an Aglient Eclipse XDB C8 column (150 × 4.6 mm, 5 µm; maintained at 35 °C) with a total run time of 4.5 min. Detection was achieved using an Applied Biosystems MDS Sciex (Concord, Ontario, Canada) API 3200 triple-quadrupole mass spectrometer. The MS/MS ion transitions monitored were 469-177 for ivabradine and 453-177 for IS. Method validation was performed according to Food and Drug Administration guidelines, and the results met the acceptance criteria. The calibration curve was linear over a concentration range of 0.1-200 ng/mL. The lower limit of quantitation achieved was 0.1 ng/mL. Intra- and inter-day precisions were in the range of 1.23-14.17% and 5.26-8.96%, respectively. Finally, the method was successfully used in a pharmacokinetic study that measured ivabradine levels in healthy volunteers after a single 5 mg oral dose of ivabradine. Copyright © 2013 John Wiley & Sons, Ltd.
Biomedical chromatography : BMC 2013
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 < 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. Trial identifier: ACTRN1261300027741.
Clinical therapeutics 2013
A rapid, selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with electrospray ionization (ESI) was developed and validated for the simultaneous determination of pitavastatin and its lactone in human plasma and urine. Following a liquid-liquid extraction, both the analytes and internal standard racemic i-prolact were separated on a BDS Hypersil C(8) column, using methanol-0.2% acetic acid in water (70: 30, v/v) as the mobile phase. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode using the transition m/z 422.4-->m/z 290.3 for pitavastatin, m/z 404.3-->m/z 290.3 for pitavastatin lactone and m/z 406.3-->m/z 318.3 for the internal standard, respectively. Linear calibration curves of pitavastatin and its lactone were obtained in the concentration range of 1-200 ng/ml, with a lower limit of quantitation of 1 ng/ml. The intra- and inter-day precision values were less than 4.2%, and accuracies were between -8.1 and 3.5% for both analytes. The proposed method was utilized to support clinical pharmacokinetic studies of pitavastatin in healthy subjects following oral administration.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2008
OBJECTIVE:The aim of this study was to explore the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of aranidipine and its active M-1 metabolite in healthy Chinese men.METHODS:This Phase I, randomized, open-label, single- and multiple-dose study included healthy, nons-moking male volunteers aged 18 to 45 years. In the single-dose study, subjects were randomly assigned to receive oral sustained-release, enteric-coated aranidipine tablets 5, 10, or 20 mg. In the multiple-dose study, volunteers who had been assigned to the aranidipine 10-mg group in the single-dose study received this dose for 7 days. In the single-dose study, blood samples for the PK analyses were obtained immediately before dosing and at regular intervals up to 36 hours after dosing. In the multiple-dose study, predose blood samples were collected on days 4 through 7; on the last day of treatment, blood samples were drawn at the same times as in the single-dose study. Plasma concentrations of aranidipine and M-1 were determined using a high-performance liquid chromatography method with tandem mass-spectrometric detection. For the PD analyses, blood pressure (BP) and heart rate were measured before dosing, at regular intervals up to 24 hours after dosing, and after the final dose during repeated administration. Tolerability was assessed throughout the study, based on adverse events, physical examinations, electrocardiography, vital signs, and laboratory tests.RESULTS:The study enrolled 30 healthy Chinese men (mean [SD] age, 23 [2] years; mean body weight, 66 [7] kg; mean height, 174 [6] cm). In the single-dose study, the mean t(1/2) for aranidipine 5, 10, and 20 mg was 3.0 (2.7), 2.7 (1.1), and 3.1 (2.2) hours, respectively; mean T(max) was 4.9 (0.4), 4.4 (1.0), and 4.3 (0.9) hours; mean C(max) was 1.1 (0.6), 2.4 (0.8), and 4.0 (2.0) microg/L; and mean AUC(last) was 4.1 (1.4), 10.3 (2.3), and 20.9 (4.2) microg . h/L. There were no significant differences in any PK parameter between dose groups. For M-1, the corresponding values were 4.6 (1.0), 4.1 (0.5), and 4.1 (0.3) hours for t(1/2); 5.6 (2.0), 5.0 (1.6), and 5.0 (0.8) hours for T(max); 18.4 (0.6), 40.5 (10.0), and 39.2 (11.3) microg/L for C(max); and 143.5 (39.1), 304.5 (108.2), and 403.9 (73.5) microg . h/L for AUC(last). Only dose-normalized Cmax and AUC(last) differed significantly between dose groups (P < 0.001 and P = 0.018, respectively). After multiple doses, the mean values for t(1/2), T(max), C(max), and AUC(0-infinity) for aranidipine 10 mg were 2.3 (0.9) hours, 5.0 (1.2) hours, 3.1 (1.1) microg/L, and 13.8 (3.6) microg . h/L, respectively. Repeated oral administration of aranidipine 10 mg was associated with a significant increase in AUC(last) (P = 0.027). The corresponding values for M-1 were 4.8 (0.9) hours, 5.7 (1.3) hours, 40.0 (11.3) microg/L, and 381.8 (161.2) microg . h/L. There were no significant differences between dose groups in any PK parameter for M-1 after single or multiple doses. In the PD analyses, the mean change from baseline in diastolic BP was statistically significant in all groups (P < 0.01) except the aranidipine 10-mg group in the single-dose study. Three volunteers (10%) reported adverse events after administration of a single dose: headache (10-mg group), palpitations (20-mg group), and dizziness (20-mg group). The headache and palpitations were considered possibly related to study drug.CONCLUSIONS:The results of this small study in healthy Chinese men suggest that the PK properties of aranidipine were linear with respect to dose, whereas the PK properties of the active M-1 metabolite were not fully linear. There was no apparent accumulation of aranidipine or M-1 with administration of single and multiple doses. Aranidipine was generally well tolerated.
Clinical therapeutics 2008
A rapid, selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method with positive electrospray ionization (ESI) was developed for the quantification of ranolazine in human plasma. After liquid-liquid extraction of ranolazine and internal standard (ISTD) phenoprolamine from a 100 microl specimen of plasma, HPLC separation was achieved on a Nova-Pak C(18) column, using acetonitrile-water-formic acid-10% n-butylamine (70:30:0.5:0.08, v/v/v/v) as the mobile phase. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode using the transition m/z 428.5-->m/z 279.1 for ranolazine and m/z 344.3-->m/z 165.1 for the internal standard, respectively. Linear calibration curves were obtained in the concentration range of 5-4000 ng/ml, with a lower limit of quantitation (LLOQ) of 5 ng/ml. The intra- and inter-day precision values were below 3.7% and accuracy was within +/-3.2% at all three quality control (QC) levels. This method was found suitable for the analysis of plasma samples collected during the phase I pharmacokinetic studies of ranolazine performed in 28 healthy volunteers after single oral doses from 200 mg to 800 mg.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2007
BACKGROUND:Atrial flutter is a common sustained atrial tachyarrhythmia whose frequency increases with age. Ibutilide is a class III antiarrhythmic agent used for the cardioversion of atrial flutter or atrial fibrillation.OBJECTIVE:This study assessed the pharmacokinetic (PK) and pharmacodynamic properties and tolerability of a single intravenous dose of ibutilide fumarate in healthy Chinese men.METHODS:This Phase I, randomized, open-label, increasing-dose trial was conducted at the Clinical Pharmacology Center, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing, People's Republic of China. Healthy, nonsmoking men aged 18 to 45 years and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 6 treatment groups: ibutilide 0.005, 0.01, or 0.02 mg/kg, or 0.5, 0.75, or 1.0 mg. Each volunteer received a 10-minute infusion of ibutilide under fasting conditions. For analysis of PK properties, blood samples were obtained at the following times: immediately before administration of study drug; 3, 5, 8, 10, 30, and 60 minutes after administration; and 2, 4, 6, 8, 12, and 24 hours after administration. Plasma ibutilide concentrations were determined using a validated high- performance liquid chromatography method with tandem mass-spectrometric detection. Continuous electrocardiographic monitoring was performed, and 12-lead electrocardiograms were recorded before dosing and at defined times from the start of infusion until 24 hours after dosing. Tolerability was assessed throughout the study based on physical examinations, measurement of vital signs, laboratory analyses, and monitoring of adverse effects.RESULTS:Forty healthy Chinese men were enrolled (mean [SD] age, 24.0 [3.9] years [range, 19-36 years]; mean [SD] body weight, 62.8 [7.9] kg [range, 48- 80 kg]). The plasma ibutilide end-of-infusion concentration and AUC(0-infinity) increased approximately linearly with increasing doses of ibutilide. No statistically significant differences in the principal PK parameters were found among dosage groups; t(1/2) ranged from 7.5 to 9.1 hours, systemic clearance from 68 to 85 mL/min per kg, and Vd from 51 to 60 L/kg. The mean QTc interval was significantly increased during and after ibutilide infusion (baseline range, 406-418 milliseconds; maximum range, 469-683 milliseconds; P < 0.05 vs baseline). The changes in QTc interval were dose dependent, and there was a significant correlation between plasma ibutilide concentrations and changes in the QTc interval (r = 0.7244; P < 0.01). There were no significant changes in blood pressure or the QRS and PR intervals. One volunteer complained of dizziness, but no other apparent adverse effects were observed.CONCLUSIONS:The results of this study in a selected population of healthy Chinese men suggest that the PK properties of ibutilide are linear with respect to dosing. A single intravenous dose of ibutilide prolonged the QTc interval in a dose- and concentration- dependent manner. Ibutilide was generally well tolerated.
Clinical therapeutics 2007
