Xue-Ning Li

Matrine determination and pharmacokinetics in human plasma using LC/MS/MS

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for the determination of matrine in human plasma extracted by isopropanol:ethyl acetate (v/v, 5:95). Rapid chromatographic separation was achieved in the mobile phase composition of 5-mM aqueous ammonium acetate and acetonitrile (v/v, 70:30) with a flow rate of 0.20ml/min. Detection was carried out using positive-ion electrospray tandem mass spectrometry on a Sciex API3000. The method was accurate, specific and sensitive for the analysis of matrine in human plasma in the concentration range of 5-2000ng/ml, when huperzine A was used as internal standard. The method facilitated a clinical pharmacokinetic study after oral administration of a single dose of matrine soft gelatin capsules (100, 200 and 400mg) in a three-period crossover design. Dose-related linear trends were observed for the AUC(0-t) and the C(max) of matrine. The t(1/2) and the T(max) of matrine were independent of the administered doses.

Pharmacokinetics of rosuvastatin in healthy Chinese volunteers living in China: A randomized, open-label, ascending single- and multiple-dose study

BACKGROUND Cross-study comparisons suggest that systemic exposure (AUC) to rosuvastatin calcium, a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor, may be approximately 2-fold higher in Asian subjects living in Asian countries than in white subjects living in Western countries. OBJECTIVE This study was conducted to determine the pharmacokinetic characteristics of rosuvastatin and its metabolites after single and multiple doses of rosuvastatin in healthy Chinese subjects living in China. METHODS This was an open-label, ascending single- and multiple-dose study. Subjects were randomly assigned to receive rosuvastatin 5, 10, or 20 mg. Each subject received 1 tablet of the assigned treatment on day 1 and days 4 through 10. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin lactone were measured through 72 hours after administration of single doses and through 96 hours after administration of multiple doses. Blood samples were obtained within 30 minutes before dosing on days 7, 8, and 9 for the assessment of pharmacokinetic parameters at steady state. Noncompartmental pharmacokinetic analysis was performed to determine the C(max) and AUC(0-t) for rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin lactone after single and multiple doses of rosuvastatin. Tolerability assessments were conducted throughout the study. RESULTS Of the 36 enrolled subjects, only 1 was female. The mean age of subjects in the rosuvastatin 5-, 10-, and 20-mg groups was 22.4, 21.3, and 22.4 years, respectively. Weight and height ranged from 54 to 85 kg and from 161 to 189 cm, respectively. Geometric mean C(max) values for rosuvastatin after administration of single doses of rosuvastatin 5, 10, and 20 mg were 8.33, 10.76, and 19.17 ng/mL, respectively; the corresponding geometric mean AUC(0-t) values were 57.63, 88.89, and 163.87 ng . h/mL. At steady state, values for C(max) were 8.31, 8.41, and 20.73 ng/mL; the corresponding geometric mean AUC values were 64.87, 77.29, and 178.64 ng . h/mL. After administration of multiple doses of rosuvastatin 5, 10, and 20 mg, the accumulation ratios were 1.23, 0.95, and 1.23, respectively, indicating minimal accumulation of rosuvastatin. Circulating concentrations of N-desmethyl rosuvastatin and rosuvastatin lactone were well below those of rosuvastatin after administration of single and multiple doses of rosuvastatin. CONCLUSIONS Increases in C(max), AUC(0-t), C(max,ss), and AUC(ss) were observed with increasing single and multiple doses of rosuvastatin 5, 10, and 20 mg. The increase in exposure with increasing doses was lower than would be expected under conditions of strict proportionality. Rosuvastatin exhibited little accumulation on repeated administration. All rosuvastatin doses were well tolerated in these Chinese subjects.

Pharmacokinetic and bioequivalence comparison between orally disintegrating and conventional tablet formulations of flurbiprofen: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy chinese male volunteers

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 flurbiprofen 50-mg ODT (test) with a conventional flurbiprofen 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 nonstereospecific liquid chromatography/tandem mass spectrometry method. Pharmacokinetic parameters, including C(max), T(max), t(1/2), AUC(0-24), and AUC(0-infinity), were calculated and analyzed statistically. C(max), AUC(0-24), and AUC(0-infinity) 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/m(2) [range, 19-24 kg/m(2)]) completed the study. No period or sequence effect was observed. The 90% CIs for the ln-transformed ratios of Cmax, AUC(0-24), and AUC(0-infinity) 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.

Pharmacokinetics and Tolerability of Tenofovir Disoproxil Fumarate 300 mg Once Daily: An Open-Label, Single- and Multiple-Dose Study in Healthy Chinese Subjects

BACKGROUND Tenofovir disoproxil fumarate (TDF) has been approved worldwide for the treatment of adults with chronic hepatitis B and, in combination with other antiretroviral agents, HIV-1 infection. Although its use for the treatment of HIV has been approved by the Chinese State Food and Drug Administration, there are no data on the pharmacokinetic profile of TDF in Chinese individuals. OBJECTIVES This study aimed to investigate the pharmacokinetic properties and tolerability of TDF in healthy Chinese subjects. METHODS This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. Subjects received TDF 300 mg once daily, administered as a single dose (day 1) and multiple doses (days 4-10). Multiple plasma samples were collected over time, and the concentrations of TDF were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). RESULTS Fourteen volunteers were enrolled (7 men, 7 women; mean age, 24.6 years). TDF was rapidly absorbed; median Tmax was 0.75 hour, and t½ was ~21 hours with single dosing. The mean ratio of AUC0-τ steady state/AUC0-24 single dose was 1.55. The pharmacokinetic properties of TDF were consistent between the single dose and multiple doses, and between men and women. No serious AEs were reported, and there were no discontinuations due to AEs. CONCLUSIONS There was an accumulation of approximately 55% in tenofovir exposure in healthy Chinese between multiple dose and single dose. TDF exhibited a pharmacokinetic profile similar to that of healthy Western subjects in a historical comparison. TDF was generally well tolerated in these healthy Chinese subjects. ClinicalTrials.gov identifier: NCT01480622.

Pharmacokinetics of Orally Administered Single- and Multiple-Dose Olopatadine in Healthy Chinese Subjects

AbstractBackground and objective: Olopatadine is a new selective histamine H1 receptor antagonist with anti-inflammatory and anti-allergic effects. Its pharmacokinetics and safety have not previously been evaluated in Chinese subjects. The aims of this study were to assess the pharmacokinetics and safety of olopatadine after single- and multiple-dose oral administration in healthy Chinese subjects and to identify any differences in pharmacokinetics between males and females. Methods: The pharmacokinetic parameters for olopatadine in 12 healthy Chinese subjects (six males and six females) were assessed by determining olopatadine concentrations with a validated liquid chromatography-tandem mass spectrometry method. Safety and tolerability were evaluated by monitoring adverse events, laboratory assay results, vital signs, physical examination findings and 12-lead ECG results. Results: The pharmacokinetic parameters (mean±SD) for olopatadine following a single dose were: maximum plasma concentration (Cmax) 69.98 ± 20.87 ng/mL, time to reach Cmax (tmax)1.02±0.34 h, elimination half-life (t½) 5.87±4.24h, area under the plasma-concentration curve (AUC) from time zero to the time of last quantifiable concentration (AUClast) 266.00± 143.95 ng · h/mL, AUC from time zero extrapolated to infinity (AUC∞) 283.46±152.96 ng · h/mL, apparent oral clearance (CL/F) 23.45±12.59 L/h and apparent volume of distribution after oral administration (Vd/F) 133.83±43.07 L. The pharmacokinetic parameters of olopatadine after multiple doses were similar to those after a single dose. In both studies, significantly higher AUClast, AUC∞ and Cmax, longer t½ (single-dose only) and lower CL/F were observed in female subjects compared with male subjects after both single and multiple dosing. No serious adverse events occurred. Conclusion: Olopatadine was shown to be safe and well tolerated in healthy Chinese subjects. There were no changes in absorption and elimination of olopatadine following multiple doses and no accumulation was found. Possible sex-related differences in absorption and elimination of olopatadine were observed.

Pharmacokinetics and bioequivalence studies of galantamine hydrobromide dispersible tablet in healthy male Chinese volunteers.

ABSTRACT A randomized, two-way, crossover study was conducted in 18 healthy male Chinese volunteers to compare pharmacokinetics profiles of galantamine hydrobromide dispersible tablet with that of conventional tablet. A single oral dose of 10 mg galantamine was administrated to each volunteer. Plasma concentrations of galantamine were determined by a validated high-performance liquid chromatography (HPLC) method with fluorescence detection, which allowed 1 ng/mL to be assayed as the lowest quantifiable concentration. From plasma concentrations, AUC0→t (the area under the plasma concentration-time curve from time 0 to the last sampling time, 32 hr), AUC0→∞ (the area under the plasma concentration-time curve from time 0 to infinity), t½ (elimination of half-life of the terminal log linear phase), Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were evaluated through noncompartmental pharmacokinetic analysis. AUC0→t and AUC0→∞ were calculated by the linear-log trapezoidal rule method. Cmax and Tmax were obtained directly from the plasma concentration-time curve. Analysis of variance was carried out using logarithmically transformed AUC0→t, AUC0→∞ and Cmax. As far as AUC0→t, AUC0→∞ and Cmax were concerned, there was no statistically significant difference between the test and reference formulations. Ninety percent confidence intervals (90% CI) for the ratio of AUC0→t, AUC0→∞ and Cmax values for the test and reference formulations were 100.4–107.8%, 99.0–107.2% and 87.5–111.3%, respectively. As the 90% CIs of AUC0→t, AUC0→∞ and Cmax were entirely within 80–125%, two formulations were considered bioequivalent.

Pharmacokinetic interaction of finasteride with tamsulosin hydrochloride: an open-label, randomized, 3-period crossover study in healthy Chinese male volunteers.

PURPOSE The primary aim of this study was to evaluate whether there was clinically significant pharmacokinetic (PK) interaction between finasteride and tamsulosin in healthy Chinese male subjects. METHODS This was an open-label, randomized, 3-period, crossover study. Subjects received single and multiple doses of 5 mg finasteride alone, single and multiple doses of 0.2 mg tamsulosin hydrochloride sustained-release capsule alone, and single and multiple doses of 5 mg finasteride with 0.2 mg tamsulosin hydrochloride, in an order determined by a computerized randomization schedule. Blood samples were collected up to 48 hours after dosing on study day 1 and up to 24 hours after dosing on study day 9 for determination of plasma concentrations with a validated LC-MS/MS method. Pharmacokinetic parameters were estimated via noncompartmental methods. Tolerability was evaluated by monitoring adverse events, laboratory assays, vital signs, and 12-lead ECG. FINDINGS Fifteen subjects were enrolled, and 14 completed the study. The geometric mean ratios (GMRs) (90% CIs) of AUC(τ,ss) and C(max,ss) values of finasteride at steady state between coadministration of finasteride and tamsulosin hydrochloride and finasteride alone were 1.14 (1.05-1.23) and 1.06 (0.99-1.14), respectively. The GMRs (90% CIs) for AUC(0-t) and C(max) values of finasteride for a single dose of coadministration of finasteride and tamsulosin hydrochloride and finasteride alone were 1.02 (0.94-1.11) and 1.06 (1.01-1.11), respectively. The GMRs (90% CIs) for AUC(τ,ss) and C(max,ss) values of tamsulosin at steady-state for coadministration of finasteride and tamsulosin hydrochloride and tamsulosin hydrochloride alone were 1.18 (1.05-1.33) and 1.23 (1.06-1.43), respectively. The GMRs (90% CIs) for AUC(0-t) and C(max) values of tamsulosin for a single dose of coadministration of finasteride and tamsulosin hydrochloride and tamsulosin hydrochloride alone were 1.04 (0.97-1.10) and 1.04 (0.98-1.11), respectively. Statistical analyses confirmed that the 90% CIs for these PK parameters were within the predefined not clinically significant PK drug-drug interaction effect boundaries (0.5-2.0) in this study. If comparing the findings with narrower boundaries (0.8-1.25), the conclusion may not be supportive for tamsulosin hydrochloride. During the study, a total of 4 adverse events were reported in 3 subjects including allergic reaction, abnormal findings on an ECG, a slight increase in alanine aminotransferase, and a positive result on glucose urine test. IMPLICATIONS Both finasteride and tamsulosin hydrochloride were well tolerated. Coadministration of finasteride and tamulosin hydrochloride seems unlikely to lead to a clinically significant PK drug-drug interaction, after a single dose and at steady state.

The effect of CYP2C19 activity on pharmacokinetics of lansoprazole and its active metabolites in healthy subjects

Context: Lansoprazole is a gastric proton-pump inhibitor and has been demonstrated to be effective in the treatment of various peptic diseases. The effects of CYP2C19 activity on the pharmacokinetics of lansoprazole and its active metabolites in Chinese subjects have not previously been evaluated. Objective: The study aimed to evaluate the effects of CYP2C19 activity in healthy Chinese volunteers. Materials and methods: Twenty-two healthy volunteers were recruited for an open trial and received a single dose of 30 mg lansoprazole. Using a validated LC-MS/MS method, we measured the plasma concentrations of lansoprazole, 5-hydroxylansoprazole, and lansoprazole sulfone. The genotype of CYP2C19 was identified by polymerase chain reaction (PCR) analysis of single nucleotide polymorphisms (SNPs). Subjects were genotypically classified into the following three groups on the basis of PCR-SNP analysis for CYP2C19: homozygous EM (hmEM) group, heterozygous EM (htEM) group, and PM group. To test differences in pharmacokinetic parameters among the three groups, analysis of variance (ANOVA) after log-transformation of data was used. Results and conclusion: Our results indicated that there were significant differences (p < 0.001) between the hmEM and PM groups, between the htEM and PM groups, and between the hmEM and htEM groups in Cmax, AUC0–t, and AUC0–inf of lansoprazole and lansoprazole sulfone. There were also significant differences (p < 0.001) between the hmEM and PM groups, and between the htEM and PM groups in Cmax of 5-hydroxylansoprazole.

Pharmacokinetics, safety, and tolerability of sulcardine sulfate: an open-label, single-dose, randomized study in healthy Chinese subjects.

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.

Population pharmacokinetic modeling and simulation of huperzine A in elderly Chinese subjects

Aim:Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimers disease (AD) patients in China, exhibits different pharmacokinetic features in elderly and young healthy subjects. However, its pharmacokinetic data in elderly subjects remains unavailable to date. Thus, we developed a population pharmacokinetic (PPK) model of huperzine A in elderly Chinese people, and identified the covariate affecting its pharmacokinetics for optimal individual administration.Methods:A total of 341 serum huperzine A concentration records was obtained from 2 completed clinical trials (14 elderly healthy subjects in a phase I pharmacokinetic study; 35 elderly AD patients in a phase II study). Population pharmacokinetic analysis was performed using the non-linear mixed-effect modeling software Phoenix NLME1.1.1. The effects of age, gender, body weight, height, creatinine, endogenous creatinine clearance rate as well as drugs administered concomitantly were analyzed. Bootstrap and visual predictive checks were used simultaneously to validate the final population pharmacokinetics models.Results:The plasma concentration-time profile of huperzine A was best described by a one-compartment model with first-order absorption and elimination. Age was identified as the covariate having significant influence on huperzine A clearance. The final PPK model of huperzine A was: CL (L/h)=2.4649*(age/86)(−3.3856), Ka=0.6750 h−1, V (L)=104.216. The final PPK model was demonstrated to be suitable and effective by the bootstrap and visual predictive checks.Conclusion:A PPK model of huperzine A in elderly Chinese subjects is established, which can be used to predict PPK parameters of huperzine A in the treatment of elderly AD patients.