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Acarbose and metformin have been recommended both as monotherapy and add-on therapy in type 2 diabetes mellitus. A novel fixed-dose combination (FDC) of acarbose and metformin has been developed to improve compliance and patient adherence to therapy. The current study investigated the bioequivalence (BE) between acarbose/metformin FDC (50 mg/500 mg) with corresponding loose combination of individual components under fasting conditions in healthy Chinese male and female subjects, using a randomized, 2-period, 2-way crossover study design. Pharmacodynamic parameters of serum glucose ratio between treatment day and baseline (ratio of maximum concentration [Cmax ], day 1/Cmax , day -1 and ratio of area under the concentration-time curve [AUC] from time 0 to 4 hours, day 1/AUC from time 0 to 4 hours, day -1) were used as the primary variables to evaluate BE of acarbose. Pharmacokinetic parameters Cmax , AUC from time 0 to the last data point greater than the lower limit of quantification, and AUC were used to evaluate BE of metformin. The results showed that the 90% confidence intervals of the ratios of all primary target variables including ratio of Cmax , day 1/Cmax , day -1 and ratio of AUC from time 0 to 4 hours, day 1/AUC from time 0 to 4 hours, day -1 for acarbose, and Cmax , AUC from time 0 to the last data point greater than the lower limit of quantification, and AUC for metformin all fell within the acceptance limits of 0.8 to 1.25. Thus, BE between 50-mg acarbose and 500-mg metformin as an FDC and loose combination was established. Furthermore, different kinds of exploratory pharmacodynamic parameters (based on either serum glucose or insulin) including several newly proposed parameters were also investigated for acarbose BE evaluation in this study, and inconsistent results were observed.

Lei Sheng,1,* Wei Cao,2,* Pingping Lin,3 Weili Chen,1 Hongrong Xu,1 Chunjiu Zhong,4 Fei Yuan,1 Hanjing Chen,1 Hui Li,1 Chao Liu,1 Mengjie Yang,1 Xuening Li1 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Shanghai Rixin Biotechnology Co., Ltd, Shanghai, 200237, People’s Republic of China; 3Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, Shandong, 266071, People’s Republic of China; 4Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xuening LiDepartment of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 FengLin Road, Shanghai, 200032, People’s Republic of ChinaTel +86 21 3158 7860Fax +86 21 6443 7963Email li.xuening@zs-hospital.sh.cnPurpose: Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials.Methods: Healthy subjects were sequentially enrolled into one of five SAD (150– 1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4– 9, followed by a single morning dose on day 10.Results: In the SAD study, the median time to reach maximum concentration (Tmax) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (Rac, Cmax) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC.Conclusion: Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine.Keywords: Alzheimer’s disease, benfotiamine, thiamine, thiamine diphosphate, pharmacokinetics

Purpose Aprepitant is used to prevent nausea and vomiting associated with moderately and highly emetogenic chemotherapy. In this open-label, 2-period study, the safety, tolerability, and pharmacokinetics (PK) of aprepitant (EMEND®) were evaluated in healthy Chinese and Caucasian subjects. Patients and methods Twelve Chinese and 12 Caucasian subjects were to receive a 125 mg single-dose of aprepitant during period 1; subsequently, after 15 days washout, only Chinese subjects were to receive the 3-day regimen in period 2. In each period, serial blood samples were collected and analyzed by a validated liquid chromatographic and mass spectrometric method to characterize aprepitant PK across both groups. Results In both Chinese and Caucasian subjects, there were no serious adverse events. AUC0-∞, Cmax, Tmax, and t1/2 were largely comparable between the two ethnicities. Comparing the result of period 1 in Chinese and Caucasian subjects, the geometric least-squares mean maximum plasma concentrations (Cmax) were 1482 ng/mL and 1435 ng/mL, and the area under the concentration-time curve (AUC0-∞) 34,035 hr·ng/mL and 34,188 hr·ng/mL. In period 2, the geometric mean AUC0-24 on Day 1 and Day 3 were 19,446 hr·ng/mL and 27,843 hr·ng/mL, and the geometric mean Cmax on Day 1 and Day 3 were 1423 ng/mL and 1757 ng/mL, respectively. Conclusion Aprepitant is generally safe and well tolerated in healthy Chinese and Caucasian subjects. Aprepitant PK is comparable between Chinese and Caucasian subjects following single-dose administration. The PK following a clinical 3-day regimen on healthy Chinese subjects has been characterized.

Chao Liu,1 Hong Lu,2 Fei Yuan,1 Wei-Li Chen,1 Hong-Rong Xu,1 Hui Li,1 Cheng-Pang Hsu,3 Ogo Egbuna,3 Jihua Wu,2 Clapton Dias,3 Bassam Abosaleem,3 Jitesh Rana,3 Maria Laura Monsalvo,3 Xue-Ning Li,1 Zhigang Yu4 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Clinical Pharmacology and Early Development, Amgen China R & D Center, Shanghai, People’s Republic of China; 3Research & Development, Amgen Inc., Thousand Oaks, CA, USA; 4Clinical Development, Amgen China R & D Center, Shanghai, People’s Republic of ChinaCorrespondence: Xue-Ning LiDepartment of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of ChinaTel +86 21 6026 7666Email li.xuening@zs-hospital.sh.cnZhigang YuResearch & Development, Amgen Inc., Thousand Oaks, CA 91320, USATel +1 805 447-9384Email zhigangy@amgen.comPurpose: Evolocumab is a human monoclonal antibody that reduces circulating low-density lipoprotein cholesterol (LDL-C) by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Data on evolocumab pharmacokinetics and pharmacodynamics are derived mostly from Caucasian populations. The objectives of this study were to characterize the single-dose pharmacokinetic and pharmacodynamic parameters, safety, and tolerability of evolocumab in healthy Chinese subjects.Subjects and methods: This was a phase 1, randomized, double-blind, placebo-controlled study (CTR20150465). Two parallel cohorts were randomized 5:1 to receive single subcutaneous injections of either evolocumab (140 mg or 420 mg) or placebo. Pharmacokinetics, pharmacodynamics, and safety were evaluated through day 85. The primary endpoints were maximum concentration (Cmax) and area under the drug concentration–time curve from time 0 to time of last quantifiable concentration (AUClast).Results: Thirty-six men (median age 26) were enrolled to receive evolocumab 140 mg (n=15), evolocumab 420 mg (n=15), or placebo (n=6). After 140 mg and 420 mg evolocumab, mean (SD) Cmax was 13.8 (3.6 μg/mL and 67.6 (15.2) μg/mL, respectively, and mean (SD) AUClast was 166 (55) day·μg/mL and 1110 (274) day·μg/mL, respectively. LDL-C declined reversibly, with reductions of 70% at 140 mg and 71% at 420 mg. Maximum effects on LDL-C and PCSK9 levels were reached by day 15 and 24 hrs, respectively, at 140 mg, and by day 22 and 4 hrs, respectively, at 420 mg. No serious adverse events occurred and the overall incidence of treatment-emergent adverse events was similar for evolocumab and placebo: 26.7% (140 mg) and 33.3% (placebo); 66.7% (420 mg) and 66.7% (placebo).Conclusion: In this population of healthy Chinese subjects, single 140 mg and 420 mg doses of evolocumab exhibited nonlinear kinetics and more than dose-proportional increases in exposure, were associated with up to 71% reduction in LDL-C, and demonstrated a safety profile similar to placebo.Keywords: cardiovascular disease, homozygous familial hypercholesterolemia, PCSK9 inhibitors, monoclonal antibodies, ethnic sensitivity

Anacetrapib is a novel, powerful cholesteryl ester transfer protein (CETP) inhibitor with bidirectional lipid regulation, which was developed for dyslipidemia. The aim of this study is to evaluate the single- and multiple-dose pharmacokinetics (PK), safety and tolerability of anacetrapib in healthy Chinese subjects and assess the PK difference between Chinese and other populations. Forty subjects were enrolled in an open-label study consisting of three panels (50 mg single dose; 100 mg single dose followed by 100 mg once-daily multiple doses for 10 days; a 200 mg single dose). Safety and tolerability were evaluated by monitoring adverse events, laboratory safety tests, ECGs, vital signs and physical examination. PK were evaluated and compared with historical data in black and white subjects. Anacetrapib was absorbed after administration of a single oral dose, with a median Tmax of 3.0–5.0 h and elimination half-life of 105.3–122.3 h. The AUC and Cmax of anacetrapib increased in a slightly less than dose-proportional manner over a dose range of 50–200 mg. Once-daily administration of 100 mg of anacetrapib for 10 days resulted in a median Tmax of 5.0 h with an apparent half-life of 193.7 h on Day 10 of multiple dosing. Anacetrapib accumulation ratios (Day 10 of multiple dosing/Day 1) were 1.39 (AUC0–24 h), 1.11 (Cmax) and 2.57 (C24 h). The PK properties of anacetrapib in Chinese subjects are comparable to those observed in the black population and in white subjects. Single and once-daily administration of anacetrapib was generally well tolerated in healthy Chinese subjects observed in this study. chinadrugtrials.org.cn identifier number CTR20130983.

Purpose Acute pancreatitis in pregnancy (APIP) is a rare condition; however, it markedly affects maternal and fetal health. This study aimed to describe the types, clinical characteristics, mortality, and the safety and necessity of gestation termination of acute pancreatitis in pregnancy (APIP). Methods We retrospectively reviewed 121 APIP cases in the Gastroenterology Department of The First Affiliated Hospital of Nanchang University. APIP diagnosis were based on 2012 Atlanta Criteria. The correlation between APIP types, severity, biochemical parameters and mortality was analyzed. Results The most common symptoms for APIP were abdominal pain (86.8%) and vomiting (73.6%). The most common causes for APIP were gallstone (36.4%) and hypertriglyceridemia (32.2%) and hypertriglyceridemic APIP was correlated with a higher rate for local complication (P = 0.012). Serum calcium level was negatively correlated with the severity of APIP (P

Background The purpose of this study was to clarify whether the current scoring systems and single serum markers used in pancreatitis remain applicable for the early prediction of infected pancreatic necrosis (IPN) and the severity and mortality of acute pancreatitis (AP) in accordance with the revised Atlanta and determinant-based classifications. Methods Demographic, clinical, and laboratory data from 708 consecutive patients with AP were prospectively collected between January 2011 and December 2012. The severity was classified using the revised Atlanta and determinant-based classification systems. The predictive accuracies for moderately severe AP (MSAP), severe AP (SAP), critically severe AP (CAP), IPN, and mortality were measured using area under the receiver operating characteristic curves. Results The receiver operating characteristic analysis showed that the multifactor scoring systems and single serum markers had a low predictive accuracy regarding moderately severe AP. The Acute Physiology and Chronic Health Evaluation (APACHE) II score had the highest accuracy in predicting SAP with area under the curve (AUC) values of 0.75 (95% CI = 0.71–0.79) and 0.77 (95% CI = 0.73–0.81) at 24 and 48 h after admission, respectively. Procalcitonin was the most accurate predictor for CAP and IPN, with respective AUCs of 0.86 (95% CI = 0.82–0.89) and 0.83 (95% CI = 0.78–0.87) at 48 h after admission. In predicting mortality, both the APACHE II score and blood urea nitrogen had the highest accuracy. Conclusions The APACHE II score had the highest predictive accuracy for SAP and mortality as defined by the revised Atlanta classification, whereas procalcitonin was the most accurate predictor for CAP and IPN.

Vicagrel is a new antiplatelet pro-drug based on clopidogrel sulfur lactone metabolites. The purpose of the study was to evaluate the safety, tolerability, and pharmacodynamics (PD) of vicagrel in healthy Chinese subjects. This study was designed as a single-center, randomized, double-blind, placebo-controlled, single oral ascending dose study. Fifty nine subjects were assigned to 6 vicagrel dose cohorts (5, 10, 20, 40, 60, and 75 mg), and 8 subjects were assigned to 75 mg clopidogrel. Within each vicagrel dose cohort, the 10 subjects (9 in the 75 mg cohort) were randomized 4:1 to receive vicagrel or placebo. Platelet function was assessed using VerifyNowTM P2Y12. ΔP2Y12 reaction units (ΔPRU) and percent inhibition platelet aggregation (%IPA) were used to evaluate the PD of vicagrel. Although the number of adverse events (AEs) increased with vicagrel dose, none were considered serious, suggesting that vicagrel is safe and well-tolerated. The ΔPRU and %IPA patterns suggest that inhibition of ADP-induced platelet aggregation increased in a dose-dependent manner across the 10 to 40 mg dose range. The inhibitory effect was nearly complete at 4 hours (mean %IPA 87.9%–93.0%, mean ΔPRU 206.6–240.0) for doses of 40 to 75 mg of vicagrel. In contrast, for 5 mg vicagrel and 75 mg clopidogrel, there were no measurable effects on platelet aggregation throughout the study. The results suggest that vicagrel at 40 to 75 mg inhibits ADP-induced platelet aggregation, with a fast onset of action and significantly greater potency than clopidogrel. These findings indicate that vicagrel may be a highly effective and well-tolerated antiplatelet agent.

Chiglitazar is a novel configuration-restricted non-thiazolidinedione peroxisome proliferator-activated receptor pan-agonist currently in the Phase III clinical development stage for type 2 diabetes mellitus patients. The objective of this Phase I study was to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of chiglitazar tablets taken orally and the effect of food on its pharmacokinetics in healthy Chinese subjects. A single-centre, open-label, randomised, two-stage Phase I study was carried out. In the first-stage study, we evaluated a single dose of 8, 16, or 32 mg, and multiple doses of 16 mg, taken once daily for 9 days. The effect of food consumption was also studied in this stage. In the second-stage study, a greater range of single doses (24, 48 or 72 mg) were further evaluated. Pharmacokinetics, safety and tolerability profiles were assessed at each study stage. After a single oral dose of chiglitazar, at doses ranging from 8 to 72 mg, the maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) were proportionally increased (165–1599 ng/mL for the mean Cmax and 1356–12,584 ng·h/mL for the mean AUC0−t), with low inter-subject variability. There were no significant changes in the mean terminal phase half-life (t1/2), which ranged from 9.0 to 11.9 h, and the clearance and volume of distribution were similar for all evaluated doses. The results from the examination of multiple dose of 16 mg once daily for nine consecutive days showed that a steady-state condition was achieved by Day 6. There was no apparent accumulation of chiglitazar observed at Day 9, as compared with the first administration. While food increased the AUC0−t of chiglitazar by about 13%, there were no effects on other parameters, including Cmax, Tmax and t1/2. There were no serious or severe adverse events observed in the single- or multiple-dose studies. Chiglitazar tablets showed a good dose-dependent linear pharmacokinetic profile in the dose range of 8–72 mg. There was no accumulation after multiple daily administration of chiglitazar at a dose of 16 mg. High-fat/calorie food increased the absorption of the drug, but there were no significant changes in exposure and other pharmacokinetic parameters. Chiglitazar was safe and well tolerated in healthy Chinese subjects at the dose levels and administration regimens evaluated.

Huperzine A (HupA), one of the reversible and selective acetylcholinesterase inhibitors derived from Chinese herb Huperzia Serrata, possesses affirmative action of ameliorating cognitive dysfunction of Alzheimer's disease. Up to now, the effects of HupA on human cytochrome P450s (CYPs) have not been fully elucidated. The purpose of the present study was to clarify the metabolic pathway of HupA in vitro and in vivo, and to evaluate the CYPs inhibition/induction profile of HupA in vitro. The catalytic activity of CYP enzymes (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4) was measured by the quantification of specific enzyme substrates using validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods. The in vivo metabolic pathway evaluation was performed in an open, single-dose pharmacokinetic study of HupA in fourteen elderly subjects, with urine collecting at certain intervals. In human liver microsomes, HupA (10 ng/mL) was not metabolized within 90 min, and it showed negligible inhibition against these CYP isoforms within 0.2-100 ng/mL. In human liver hepatocytes, the activities of CYP1A2 and CYP3A4 were not significantly altered when incubated at 2 or 20 ng/mL of HupA. After oral administration of 0.1 mg HupA, the total proportion of HupA excreted through urine was relatively high, accounting to 35± 9% at the limited time period of 48 h. These results suggest that HupA is substantially excreted by kidney unchanged rather than metabolized by human liver, and is unlikely to cause clinically relevant drug-drug interaction (DDI) when co-administrated with drugs that are metabolized by CYP isoenzyme system.

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 purpose of this study was to clarify whether the current scoring systems and single serum markers used in pancreatitis remain applicable for the early prediction of infected pancreatic necrosis (IPN) and the severity and mortality of acute pancreatitis (AP) in accordance with the revised Atlanta and determinant-based classifications.Demographic, clinical, and laboratory data from 708 consecutive patients with AP were prospectively collected between January 2011 and December 2012. The severity was classified using the revised Atlanta and determinant-based classification systems. The predictive accuracies for moderately severe AP (MSAP), severe AP (SAP), critically severe AP (CAP), IPN, and mortality were measured using area under the receiver operating characteristic curves.The receiver operating characteristic analysis showed that the multifactor scoring systems and single serum markers had a low predictive accuracy regarding moderately severe AP. The Acute Physiology and Chronic Health Evaluation (APACHE) II score had the highest accuracy in predicting SAP with area under the curve (AUC) values of 0.75 (95% CI = 0.71-0.79) and 0.77 (95% CI = 0.73-0.81) at 24 and 48 h after admission, respectively. Procalcitonin was the most accurate predictor for CAP and IPN, with respective AUCs of 0.86 (95% CI = 0.82-0.89) and 0.83 (95% CI = 0.78-0.87) at 48 h after admission. In predicting mortality, both the APACHE II score and blood urea nitrogen had the highest accuracy.The APACHE II score had the highest predictive accuracy for SAP and mortality as defined by the revised Atlanta classification, whereas procalcitonin was the most accurate predictor for CAP and IPN.

Hongrong Xu,1,* Lei Sheng,1,* Weili Chen,1 Fei Yuan,1 Mengjie Yang,1 Hui Li,1 Xuening Li,1 John Choi,2 Guiyu Zhao,2 Tianxin Hu,2 Yongguo Li,2 Yi Zhang,2 Li Chen2 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 2Department of Clinical Research & Development, Hua Medicine, Shanghai, People’s Republic of China *These authors have contributed equally to this work Background: HMS5552, a novel fourth-generation glucokinase (GK) activator, has demonstrated promising effects on glycemic control in preclinical models of type 2 diabetes. This single ascending dose study was conducted to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HMS5552 during its first-in-human exposure.Methods: Sixty healthy subjects were enrolled. In each of six dose-cohorts (5, 10, 15, 25, 35, and 50 mg), ten subjects were randomized with eight subjects receiving the same cohort-dose of HMS5552 and two receiving placebo. Plasma HMS5552 exposure, glucose, and insulin were measured repeatedly during fasting and after a standardized meal. Assessment included safety, PK, and PD endpoints.Results: HMS5552 showed dose-proportional increases in area under the curve 0 to the last quantifiable concentration (AUC0–t) and maximum plasma concentration (Cmax). Slopes estimated by linear regression for AUC0–t and Cmax were ~1.0 (0.932 and 0.933, respectively). Geometric mean elimination half-life ranged from 4.48 to 7.51 hours and apparent clearance ranged from 11.5 to 13.1 L/h across all doses. No significant sex effect was observed in PK parameters. HMS5552 also demonstrated dose-related PD responses in terms of maximum glucose change from baseline (%) and mean glucose area under effect curve 0–4 hours change from baseline (%) (P

Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimer's 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.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.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.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.

Ezetimibe/simvastatin combination tablet has been approved for the treatment of high low-density lipoprotein cholesterol (LDL-C) levels in patients with primary hypercholesterolaemia or mixed hypercholesterolaemia as adjunctive therapy to diet, when diet alone is insufficient in lowering cholesterol. The aims of this study were to assess the pharmacokinetics and safety of an ezetimibe/simvastatin combination tablet after oral single-dose administration in healthy Chinese subjects including sex-related differences in pharmacokinetics.This was an open-label, single-dose study. Twelve healthy subjects (six males and six females) received a single dose of an ezetimibe/simvastatin combination tablet (ezetimibe 10 mg and simvastatin 40 mg). The pharmacokinetic parameters for ezetimibe and simvastatin were assessed by determining total ezetimibe, free ezetimibe, simvastatin and simvastatin acid concentrations using a validated liquid chromatography-tandem mass spectrometry method. Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations and 12-lead electrocardiograms.The pharmacokinetic parameters (mean ± SD) for total ezetimibe and free ezetimibe following a single dose were: maximum plasma drug concentration (C(max)) 81.56 ± 26.62 and 9.40 ± 6.17 ng/mL; time to reach C(max) (t(max)) 0.93 ± 0.30 and 1.25 ± 1.27 h; elimination half-life (t(½)) 24.32 ± 13.27 and 18.90 ± 9.66 h, and mean area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(last)) 579.06 ± 241.45 and 126.01 ± 69.01 ng·h/mL, respectively. The pharmacokinetic parameters (mean ± SD) for simvastatin and simvastatin acid following a single dose were: C(max) 11.92 ± 5.50 and 3.37 ± 1.78 ng/mL, t(max) 0.98 ± 0.28 and 3.73 ± 1.68 h, t(½) 4.19 ± 1.81 and 7.65 ± 7.96 h, and mean AUC(last) 33.63 ± 20.41 and 32.50 ± 18.79 ng·h/mL. Higher AUC(last) and AUC from time zero to infinity (AUC(∞)), and lower apparent total body clearance of drug from plasma after oral administration (CL/F) for total ezetimibe and free ezetimibe were observed in female subjects compared with those in male subjects. There were no differences between the pharmacokinetic parameters of simvastatin and simvastatin acid for female and male subjects in the study.Ezetimibe/simvastatin combination tablet has a generally favourable safety and tolerability profile in healthy Chinese subjects. A statistically significant difference with regard to sex in the pharmacokinetics of ezetimibe was observed. Sex had no effect on the pharmacokinetics of simvastatin and simvastatin acid.

The aim of this study was to evaluate the difference in pharmacokinetics and pharmacodynamics between extended-release (ER) fluvastatin tablet and its immediate-release (IR) capsule in Chinese healthy subjects. This was an open-label, single/multiple-dose, two-period, two-treatment, crossover, randomized trial with a minimum washout period of 7 days. Twenty healthy male adult subjects were given fluvastatin ER tablet 80 mg QD by oral administration or fluvastatin IR capsule 40 mg BID for seven days. Blood samples were collected up to 24 hours after dosing on day 1 and day 7. Serum concentrations of fluvastatin were determined by LC-MS/MS. For fluvastatin ER tablet 80 mg QD, 𝐶 m a x was 61.0 ± 39.0 and 63.9 ± 29.7 ng/mL, and A U C 0 − 2 4 h was 242 ± 156 and 253 ± 91.1 ng·h/mL on day 1 and 7, respectively. For fluvastatin IR capsule 40 mg BID, 𝐶 m a x was 283 ± 271 and 382 ± 255 ng/mL, and A U C 0 − 2 4 h was 720 ± 776 and 917 ± 994 ng·h/mL on day 1 and day 7, respectively. The relative bioavailability of fluvastatin ER tablet 80 mg QD to fluvastatin IR capsule 40 mg BID is (45.3 ± 23.9)% and (43.3 ± 24.1)% on day 1 and day 7, respectively. 𝑇 m a x for fluvastatin ER tablet was 2.50 and 2.60 h and for capsule was 0.78 and 0.88 h on day 1 and day 7, respectively. In the first period, compared to baseline, cholesterol decreased 15.3% in fluvastatin ER tablet 80 mg QD and 16.9% in fluvastatin IR capsule 40 mg BID. Triglyceride decreased 3.7% in fluvastatin ER tablet 80 mg QD and 19.1% in fluvastatin IR capsule 40 mg BID. The difference has no statistical significance at 𝑃 > 0 . 0 5 in reduction percent of cholesterol and triglyceride between the two groups. No adverse events were recorded. The results indicated that 𝐶 m a x of fluvastatin ER tablet is reduced and 𝑇 m a x is prolonged compared with IR capsule. There is no accumulation for ER formulation after multiple doses.

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.The study aimed to evaluate the effects of CYP2C19 activity in healthy Chinese volunteers.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.Our results indicated that there were significant differences (p0.001) between the hmEM and PM groups, between the htEM and PM groups, and between the hmEM and htEM groups in C(max), AUC(0-t), and AUC(0-inf) of lansoprazole and lansoprazole sulfone. There were also significant differences (p0.001) between the hmEM and PM groups, and between the htEM and PM groups in C(max) of 5-hydroxylansoprazole.

Background: Cross-study comparisons suggest that systemic exposure (AUC) to rosuvastatin calcium, a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor, may be ~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 singleand 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.

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.

A rapid and simple liquid chromatographic-tandem mass spectrometric (LC/MS/MS) method was developed and validated for the simultaneous determination of desloratadine and its active metabolite 3-hydroxydesloratadine concentrations in human plasma. After liquid–liquid extraction with ethyl ether for sample preparation, the chromatographic separation was achieved on a CAPCELL PAK C18 column (50 mm × 2.0 mm, 5 μm, Shiseido). [ 2 H 4 ]desloratadine and [ 2 H 4 ]3-OH desloratadine were used as internal standards. A mobile phase consisted of 5 mM ammonium formate in water, methanol and acetonitrile (50:30:20). Detection was by positive ion electrospray tandem mass spectrometry on a Sciex API3000. A quadratic regression (weighted 1/concentration) gave the best fit for calibration curves over the concentration range 0.05–10 ng/mL for both desloratadine and 3-OH desloratadine. The method was shown to be accurate, rapid and sufficiently sensitive to be successfully applied to a pharmacokinetic and bioequivalent study.

A protein precipitation, liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed and validated for the determination of eprosartan in human plasma and urine. The solvent system also served as a protein precipitation reagent. The chromatographic separation was achieved on a CAPCELL PAK C18 column (50 mmx2.0 mm, 5 microm, Shiseido). A mobile phase was consisted of 0.5% formic acid in water and 0.5% formic acid in acetonitrile (72:28). Detection was by positive ion electrospray tandem mass spectrometry on a Sciex API3000. The standard curves, which ranged from 5 to 2000 ng/mL in human plasma and from 0.25 to 50 microg/mL in urine, were fitted to a 1/x weighted quadratic regression model. The method proved to be accurate, specific and sensitive enough to be successfully applied to a pharmacokinetic study.

A protein precipitation, liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed and validated for the simultaneous determination of valganciclovir and its active metabolite ganciclovir in human plasma. The solvent system also served as a protein precipitation reagent. The chromatographic separation was achieved on an Aquasil C18 column (50 mm × 2.1 mm, 5 μm). A linear gradient mobile phase between 0.02% formic acid and methanol was used. Detection was by positive ion electrospray tandem mass spectrometry on a Sciex API3000. The standard curves, which ranged from 4 to 512 ng/mL for valganciclovir and from 0.1 to 12.8 μg/mL for ganciclovir, were fitted to a 1/ x weighted quadratic regression model. The method was proved to be accurate, specific and sensitive enough and was successfully applied to a pharmacokinetic study.