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Uveal melanoma (UM) is an aggressive intraocular malignant tumour that is closely related to autophagic dysfunction. We aimed to identify autophagy-related long noncoding RNAs (lncRNAs) to elucidate the molecular mechanism of UM. Here, we show that LINC01278 is a new potential biomarker with clinical prognostic value in UM through bioinformatics analysis. Application of an autophagy inhibitor (3-MA) and an autophagy agonist (MG-132) indicated that LINC01278 can inhibit UM cell proliferation, migration, and invasion by inducing autophagy. A xenograft nude mouse model was used to examine the tumorigenesis of UM cells in vivo. Mechanistically, LINC01278 can inhibit the mTOR signalling pathway to activate autophagy, as shown by experiments with an mTOR agonist (MHY1485) and mTOR inhibitor (rapamycin) treatment. Our findings indicate that LINC01278 functions as a tumour suppressor by inhibiting the mTOR signalling pathway to induce autophagy. Targeting the LINC01278-mTOR axis might be a novel and promising therapeutic approach for UM.

Aims This study aims to develop and verify a physiologically based pharmacokinetic (PBPK) population model for the Chinese geriatric population in Simcyp. Methods Firstly, physiological information for the Chinese geriatric population was collected and later employed to develop the Chinese geriatric population model by recalibration of corresponding physiological parameters in the Chinese adult population model available in Simcyp (i.e., Chinese healthy volunteer model). Secondly, drug-dependent parameters were collected for six drugs with different elimination pathways (i.e., metabolized by CYP1A2, CYP3A4 or renal excretion). The drug models were then developed and verified by clinical data from Chinese adults, Caucasian adults and Caucasian elderly subjects to ensure that drug-dependent parameters are correctly inputted. Finally, the tested drug models in combination with the newly developed Chinese geriatric population model were applied to simulate drug concentration in Chinese elderly subjects. The predicted results were then compared with the observations to evaluate model prediction performance. Results Ninety-eight per cent of predicted AUC, 95% of predicted Cmax , and 100% of predicted CL values were within two-fold of the observed values, indicating all drug models were properly developed. The drug models, combined with the newly developed population model, were then used to predict pharmacokinetics in Chinese elderly subjects aged 60-93. The predicted AUC, Cmax , and CL values were all within two-fold of the observed values. Conclusion The population model for the Chinese elderly subjects appears to adequately predict the concentration of the drug that was metabolized by CYP1A2, CYP3A4 or eliminated by renal clearance.

To preliminarily develop physiologically based population models for Chinese renal impairment patients and to evaluate the prediction performance of new population models by renally cleared antibacterial drugs. First, demographic data and physiological parameters of Chinese renal impairment patients were collected, and then the coefficients of the relative demographic and physiological equation were recalibrated to construct the new population models. Second, drug‐independent parameters of ceftazidime, cefodizime, vancomycin, and cefuroxime were collected and verified by Chinese healthy volunteers, Caucasian healthy volunteers, and Caucasian renal impairment population models built in Simcyp. Finally, the newly developed population models were applied to predict the plasma concentration of four antibacterial drugs in Chinese renal impairment patients. The new physiologically based pharmacokinetic (PBPK) population models can predict the main pharmacokinetic parameters, including area under the plasma concentration–time curve extrapolated to infinity (AUCinf), renal clearance (CLr), and peak concentration (C max), of ceftazidime, cefodizime, vancomycin, and cefuroxime following intravenous administrations with less than twofold error in mild, moderate, and severe Chinese renal impairment patients. The accuracy and precision of the predictions were improved compared with the Chinese healthy volunteers and Caucasian renal impairment population models. The PBPK population models were preliminarily developed and the first‐step validation results of four antibacterial drugs following intravenous administration showed acceptable accuracy and precision. The population models still need more systematic validation by using more drugs and scenarios in future studies to support their applications on dosage recommendation for Chinese renal impairment patients., The PBPK population models of Chinese renal impaired patients were preliminarily developed by employing demographic and physiological parameters of Chinese patients and results of first steps towards verification by four antibacterial drugs following IV administration showed acceptable accuracy and precision in Chinese patients with mild, moderate, and severe renal impairment.

Aims Chloroquine (CQ) has been repurposed to treat coronavirus disease 2019 (COVID-19). Understanding the pharmacokinetics (PK) in COVID-19 patients is essential to study its exposure–efficacy/safety relationship and provide a basis for a possible dosing regimen optimization. Subject and methods In this study, we used a population-based meta-analysis approach to develop a population PK model to characterize the CQ PK in COVID-19 patients. An open-label, single-center study (ethical review approval number: PJ-NBEY-KY-2020-063-01) was conducted to assess the safety, efficacy, and pharmacokinetics of CQ in patients with COVID-19. The sparse PK data from 50 COVID-19 patients, receiving 500 mg CQ phosphate twice daily for 7 days, were combined with additional CQ PK data from 18 publications. Results A two-compartment model with first-order oral absorption and first-order elimination and an absorption lag best described the data. Absorption rate (ka) was estimated to be 0.559 h−1, and a lag time of absorption (ALAG) was estimated to be 0.149 h. Apparent clearance (CL/F) and apparent central volume of distribution (V2/F) was 33.3 l/h and 3630 l. Apparent distribution clearance (Q/F) and volume of distribution of peripheral compartment (Q3/F) were 58.7 l/h and 5120 l. The simulated CQ concentration under five dosing regimens of CQ phosphate were within the safety margin (400 ng/ml). Conclusion Model-based simulation using PK parameters from the COVID-19 patients shows that the concentrations under the currently recommended dosing regimen are below the safety margin for side-effects, which suggests that these dosing regimens are generally safe. The derived population PK model should allow for the assessment of pharmacokinetics–pharmacodynamics (PK-PD) relationships for CQ when given alone or in combination with other agents to treat COVID-19.

Aim: Dihydroartemisinin (DHA) was also found therapeutic potential for the treatment of systemic lupus erythematosus (SLE). To assess the pharmacokinetic profile of DHA, the concentration of DHA in plasma of SLE patients needed be accurately determined based on a rapid and reliable analytical method. Experimental method & results: Developed method utilizes stable isotope-labeled internal standards and SPE method for sample preparation, applied XBridge C18 column (2.1 × 50 mm, 3.5 μm) for chromatography separation. Detection of the analytes was achieved by an AB Sciex 4000 mass spectrometer under positive electrospray ionization mode. The method was validated in accordance with international guidelines on bioanalytical methods validations. Conclusion: DHA concentrations in human plasma of Chinese SLE patients were quantified by developed LC–MS/MS (no. 2016L02562).

Background PB-201, a partial, pancreas/liver-dual glucokinase activator, showed good tolerance and glycaemic effects in multinational studies. This study determined its optimal dose, safety, pharmacokinetics, and pharmacodynamics in Chinese patients with type 2 diabetes. Methods In this double-blind, randomised, four-period, crossover, phase 1 trial in China, conducted at the Peking University Third Hospital, adult patients with drug-naive type 2 diabetes were randomised (1:1:1:1) to four sequence groups using a computer-generated randomisation table. In each period, they received oral placebo or PB-201 (50+50, 100+50, or 100+100 mg split doses) for 7 days. Investigators and patients were masked to treatment assignment. The primary endpoints were safety and pharmacokinetics. Continuous glucose monitoring was used to delineate the glucose excursion profile. Trial registration number: NCT03973515. Findings Between August 27, 2019 and December 19, 2019, 16 patients were randomised. PB-201 showed a dose-proportional pharmacokinetic profile without apparent accumulation in the body and induced dose-dependent lowering of blood glucose. PB-201 at 50+50, 100+50, and 100+100 mg increased mean time in range (49·210% [standard deviation 27], 56·130% [25], and 63·330% [20] with three doses, respectively) versus placebo (49·380% [27]) and reduced estimated glycated haemoglobin from baseline (-0·5445% [1·654], -1·063% [1·236], and -1·888% [1·381] vs -0·581% [1·200]). Fifteen patients (93·8%) had treatment-emergent adverse events, which were mild. No patients had hypoglycaemia with venous/capillary glucose

Functional dyspepsia (FD) is one of the most common functional gastrointestinal disorders, the therapeutic strategy of which it is limited due to its complex pathogenesis. Oxidative stress-induced damage in gastric mucosal epithelial cells is related to the pathogenesis and development of FD. Quercetin (Que) is one of the active ingredients of Zhishi that showed antioxidant, antiapoptotic, and anti-inflammatory effects. The aim of this study is to investigate the effect of Que on oxidative stress-induced gastric mucosal epithelial cells damage and its underlying molecular mechanism. The gastric mucosal epithelial cell line GES-1 was treated with 200 μM of H2O2 to construct an oxidative stress-induced damage model. The H2O2 cells were then administrated with different concentrations of Que. The results indicated that high concentration of Que (100 μM) showed cytotoxicity in H2O2-induced GES-1 cells. However, appropriate concentration of Que (25 and 50 μM) alleviated the oxidative stress damage induced by H2O2, as demonstrated by the increase of proliferation, decrease of ROS generation, apoptosis, inflammation, and alleviation of mitochondrial function and cell barrier. In addition, Que increased the activation of phosphorylation of PI3K and AKT decreased by H2O2. To investigate whether Que alleviated the oxidative stress damage in GES-1 cells by the PI3K/AKT signaling pathway, the GES-1 cells were treated with Que (25 μM) combined with and without LY294002, the PI3K inhibitor. The results showed that LY294002 suppressed the alleviation effect on Que in H2O2-induced GES-1 cells. In conclusion, the current study demonstrates that Que alleviates oxidative stress damage in GES-1 cells by improving mitochondrial function and mucosal barrier and suppressing inflammation through regulating the PI3K/AKT signaling pathway, indicating the potential therapeutic effects of Que on FD.

Teriflunomide sodium, a novel derivative of leflunomide, was developed to treat systemic lupus erythematosus. The objectives of this trial were to study the safety, pharmacokinetics, and pharmacogenetics of teriflunomide sodium in healthy Chinese subjects in order to support its accelerated development. A clinical study was designed as a single-dose, randomized, parallel, open-label study. Healthy volunteers were randomly assigned to take teriflunomide sodium 10 mg or leflunomide 10 mg. Eligible healthy volunteers were monitored over a 98-day observation period. Blood and urine samples were collected and analyzed for teriflunomide and its metabolite concentrations, and ABCG2 and CYP2C9 genotypes were detected. The safety profile was also collected. All adverse events were mild in intensity, and all subjects completed this trial without any other treatment. After a single administration of teriflunomide sodium and leflunomide, teriflunomide maximal concentrations were 1.32 ± 0.341 mg/L and 0.718 ± 0.169 mg/L, and area under the concentration–time curve from time zero to infinity (AUC∞) was 423 ± 229 mg·h/L and 303 ± 159 mg·h/L, respectively. Overall, teriflunomide AUC∞ in ABCG2 34A/A mutants was 70.4% lower than in wild-type ABCG2 34G/G after administration of teriflunomide sodium. In addition, after administration of leflunomide, teriflunomide AUC∞ in ABCG2 34A/A mutants was 30.0% lower than in subjects carrying ABCG2 34G/G. Teriflunomide sodium was generally safe and well tolerated in healthy Chinese subjects. The relative bioavailability of teriflunomide between teriflunomide sodium and leflunomide after a single dose administration was approximately 150%. Additionally, ABCG2 34G>A was found to significantly affect teriflunomide pharmacokinetics, which suggested ABCG2 34G>A may be a significant influencing factor. This study was registered at the China National Medical Products Administration ( http://www.nmpa.gov.cn ; registration number 2014L01935), and also at the China platform for registry and publicity of drug clinical trials ( http://www.chinadrugtrials.org.cn ; registration number CTR20150314).

Background: PB-201, a partial, pancreas/liver-dual glucokinase activator, showed good tolerance and glycaemic effects in multinational studies. We aimed to determine its optimal dose and to evaluate its safety, pharmacokinetics, and pharmacodynamics in Chinese patients with type 2 diabetes. Methods: In this double-blind, randomised, four-period, crossover, phase 1 trial in China (NCT03973515), adult patients with drug-naive type 2 diabetes were randomised (1:1:1:1) to four sequence groups using a computer-generated randomisation table. In each period, they received oral placebo or PB-201 (50+50, 100+50, or 100+100 mg split doses) for 7 days. Investigators and patients were masked to treatment assignment. The primary endpoints were safety and pharmacokinetics. Continuous glucose monitoring was used to delineate the glucose excursion profile. Findings: Between July 18, 2019 and September 05, 2019, 16 patients were randomised. PB-201 showed a dose-proportional pharmacokinetic profile and dose-dependent lowering of blood glucose, similar to findings in non-Chinese populations. PB-201 at 100+50 and 100+100 mg increased mean time in range (49·210% [standard deviation 27], 56·130% [25], and 63·330% [20] with three doses, respectively) versus placebo (49·380% [27]) and reduced estimated glycated haemoglobin from baseline (−0·5445% [1·654], −1·063% [1·236], and −1·888% [1·381] vs −0·581% [1·200]). All treatment-emergent adverse events were mild. No patients had hypoglycaemia with venous/capillary glucose

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.

Background and Purpose RC18 is a novel recombinant fusion protein targeting on B lymphocyte stimulator (BLyS). We aimed to develop and qualify a population pharmacokinetics (PopPK) model for RC18 in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, taking into account the mechanistic target-mediated drug disposition (TMDD) process. Methods A TMDD model of RC18 was developed using data from two phase I clinical trial (n = 23). The TMDD structural model was developed by simultaneous fitting of the serum free RC18 and serum RC18-BLyS complex. Potential covariates were screened using stepwise method, and predictive performance was qualified using a prediction-corrected visual predictive check (pcVPC) and bootstrap. Results A two compartment TMDD model with first order absorption for subcutaneous administration was built. The final model included a significant relationship between distribution volume of the central compartment and body weight. And the baseline of immunoglobulin IgG had significant effect on the baseline of target BLyS. The plots from goodness-of-fit and pcVPC confirmed good predictive performance of this TMDDmodel. Conclusions This mechanistic TMDD model integrated the interaction of RC18 with its target BLyS and accurately predicts both RC18 and RC18-BLyS complex profiles in RA and SLE patients. Simulated target change profiles can be used to help guide rational dose regimen selection and used as a biomarker for efficacy evaluation.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used in treating COVID-19 patients recently. However, both drugs have some contradictions and rare but severe side effects, such as hypoglycemia, retina and cardiac toxicity. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in 8 cell lines, and further adopted the physiologically-based pharmacokinetic models (PBPK) to predict the tissue risk respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ respectively. The proliferation pattern was monitored in 0-72 hours by IncuCyte S3, which could perform long-term continuous image and video of cells upon CQ or HCQ treatment. CC50 and the ratio of tissue trough concentrations to CC50 (RTTCC) were brought into predicted toxicity profiles. The CC50 at 24 h, 48 h, 72 h of CQ and HCQ decreased in the time-dependent manner, which indicates the accumulative cytotoxic effect. HCQ was found to be less toxic in 7 cell types except cardiomyocytes H9C2 cells (CC50-48 h=29.55 μM; CC50-72 h=15.26 μM). In addition, RTTCC is significant higher in CQ treatment group compared to HCQ group, which indicates that relative safety of HCQ. Both CQ and HCQ have certain cytotoxicity in time dependent manner which indicates the necessity of short period administration clinically. HCQ has the less impact in 7 cell lines proliferation and less toxicity compared to CQ in heart, liver, kidney and lung.

Background: As the number of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infected people is greatly increasing worldwide, the international medical situation becomes very serious. Potential therapeutic drugs, vaccine and stem cell replacement methods are emerging, so it is urgent to find specific therapeutic drugs and the best treatment regimens. After the publications on hydroxychloroquine (HCQ) with anti- SARS-COV-2 activity in vitro, a small, non-randomized, open-label clinical trial showed that HCQ treatment was significantly associated with reduced viral load in patients with coronavirus disease-19 (COVID-19). Meanwhile, a large prophylaxis study of HCQ sulfate for COVID-19 has been initiated in the United States. HCQ offered a promising efficacy in the treatment of COVID-19, but the optimal administration is still being explored. Methods: We used the keyword "hydroxychloroquine" to conduct a literature search in PubMed to collect relevant literature on the mechanism of action of HCQ, its clinical efficacy and safety, pharmacokinetic characteristics, precautions for clinical use and drug interactions to extract and organize information. Results: This paper reviews the mechanism, clinical efficacy and safety, pharmacokinetic characteristics, exposureresponse relationship and precautions and drug interactions of HCQ, and summarizes dosage recommendations for HCQ sulfate. Conclusion: It has been proved that HCQ, which has an established safety profile, is effective against SARS-CoV-2 with sufficient pre-clinical rationale and evidence. Data from high-quality clinical trials are urgently needed worldwide.

Background: Chloroquine has been used to treat malaria for more than 70 years. Its safety profile and cost-effectiveness are well-documented. Scientists have found that chloroquine has in vitro activity against novel coronavirus (SARS-CoV-2). Currently, chloroquine has been adopted in the Protocol for Managing Coronavirus Disease 2019 (COVID-19) (Version 7) issued by the China National Health Commission for clinically managing COVID-19. Objective: This review will focus on the antiviral mechanism, effectiveness and safety, dosage and DDIs of chloroquine, for the purpose of providing evidence-based support for rational use of chloroquine in the treatment of COVID-19. Methods: Use the search terms "chloroquine" linked with "effectiveness", "safety", "mechanism", "drug-drug interaction (DDIs)" or other terms respectively to search relevant literature through PubMed. Results: After searching, we found literature about antivirus mechanism, dosage, DDIs of chloroquine. However, studies on the effectiveness and safety of chloroquine treatment for COVID-19 for the general and geriatric patients are not enough. Conclusion: According to literature reports, chloroquine has been proven to have anti-SARS-CoV-2 effect in vitro and the potential mechanism of chloroquine in vivo. Pharmacokinetic characteristics and DDIs study are helpful in guiding rational drug use in general and geriatric patients. Although there have been reports of successful clinical application of chloroquine in the treatment COVID-19, more clinical test data are still needed to prove its effectiveness and safety.

Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19). To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens, a PBPK model, with parameterization of drug distribution extrapolated from animal data, was developed to predict human tissue distribution of CQ. The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism. Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure–response relationships. The model was finally validated by clinical data from Chinese patients with COVID-19. The novel PBPK model allows in-depth description of the pharmacokinetics of CQ in several key organs (lung, heart, liver, and kidney), and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID, Days 2–5: 500 mg BID, CQ phosphate), patients with moderate COVID-19 (Day 1: 750 mg and 500 mg, Days 2–3: 500 mg BID, Days 4–5250 mg BID, CQ phosphate), and other vulnerable populations (e.g., renal and hepatic impairment and elderly patients, Days 1–5: 250 mg BID, CQ phosphate). A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19., Graphical abstract A PBPK model of chloroquine was developed to understand the drug exposure at the site of action as well as in the tissues of interest where toxicity is of concern, and to predict optimized dosage regimens for patients with COVID-19.Image 1

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in 2019 and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late phase in critically ill patients with SARS-CoV-2. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. Methods The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic (PBPK) models were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen while considering the drug’s safety profile. Results Hydroxychloroquine (EC50 = 0.72 μM) was found to be more potent than chloroquine (EC50 = 5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached 3 times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. Conclusions Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.

Aim: Janagliflozin is a novel, orally selective sodium-glucose co-transporter-2 (SGLT2) inhibitor, which showed good efficacy and safety in preclinical study. The objective of this study is to develop and validate the HPLC–MS/MS method to determine janagliflozin in both of human urine and plasma. Methods: Janagliflozin was separated on Waters Xbridge Phenyl C18 column and detected on API 4000 tandem mass spectrometer with ESI source in negative mode. Results: This method provided good linearity in the range of 5–5000 ng/ml and 5–1000 ng/ml in plasma and urine. The matrix effect and extraction recoveries across three concentration levels were consistent. Conclusion: This validated method is reliable and has been successfully applied to a first-in-human trial of janagliflozin in Chinese subjects.

Aim Janagliflozin is an orally selective SGLT2 inhibitor. To predict human pharmacokinetics/pharmacodynamics (PK/PD) characteristics of janagliflozin. To design optimal starting dose and effective dose for janagliflozin first-in-human (FIH) study. Methods Animal PK/PD properties of janagliflozin were obtained from preclinical in vivo and in vitro study. Pharmacologically effective level of same class SGLT2 inhibitors were assessed through preclinical and clinical efficacy data of dapagliflozin, empagliflozin and canagliflozin. Human PK parameters and profiles of janagliflozin were predicted by various methods such as allometric scaling (AS), dedrick and PK/PD modeling analysis. Mechanistic PK/PD model was developed to describe janagliflozin-mediated impact on urinary glucose excretion (UGE). Human IC50 was scaled from rat model-estimated IC50 by correcting interspecies difference of in vitro IC50 and plasma fu of rat and human. The quantitative PK/PD prediction of janagliflozin was evaluated via observed PK/PD profiles of healthy subjects. Predicted PK/PD characteristics of janagliflozin were applied in FIH dose design. Optimal starting dose was suggested by considering preclinical PD and toxicity data of janagliflozin. Effective dose was suggested by considering pharmacologically effective level of same class drugs. Results PK/PD characteristics of janagliflozin in preclinical species were summarized. Pharmacologically effective level for SGLT2 inhibitors was defined as 25~30% ΔUGE ( Δ UGE = − − ( PG * GFR ) within 24 h ) based on efficacy data of three same class drugs. Human predicted CL, Vss and F were 1.04 L/h, 77.5 L and 0.80. Predicted AUC and Cmax of janagliflozin of 10 and 50 mg were within 0.47~2.08 fold of observed values. Predicted human UGE0-24 h and UGE0-144 h of 10 and 50 mg dose range were within 0.66~1.41 fold of observed values. Optimal starting dose and pharmacologically active dose (PAD) were suggested as 10 mg and 50 mg. Dose range for FIH study was designed as 10–450 mg. Conclusions This study predicted human PK/PD characteristics of janagliflozin based on preclinical data and provide optimal dose design for janagliflozin FIH study based on pharmacologically effective level of same class drugs.

A specific and sensitive method was firstly developed using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC–MS/MS) to simultaneously quantify TPN729 and its metabolites (TPN729-D1, TPN729-D2, TPN729M15-3 and TPN729M3) in human plasma and (TPN729-D1, TPN729-D2, TPN729M15-3 and TPN729M14) in human urine. Protein precipitation and direct dilution were used to extract TPN729 and its metabolites from plasma and urine, respectively. Ionization of TPN729, TPN729-D1, TPN729-D2, TPN729M15-3, TPN729M3, TPN729M14 and sildenafil (internal standard, IS) was performed using an electrospray ionization (ESI) source in positive mode and detection was carried out with multiple reaction monitoring (MRM) mode. This assay method for TPN729 and its five metabolites has been fully validated in terms of sensitivity, linearity, lower limit of quantification (LLOQ), precision, accuracy, stability, matrix effect and recovery. The LLOQ of TPN729/TPN729-D1/TPN729-D2/TPN729M15-3/TPN729M3 in human plasma and TPN729/TPN729-D1/TPN729-D2/TPN729M15-3/TPN729M14 in human urine were 0.200/0.500/2.00/0.500/1.00 ng/mL and 4.00/2.50/10.0/2.50/1.00 ng/mL, respectively. Inter- and intra-batch precision of TPN729 and its metabolites were less than 15% and the accuracy was within ±15% for both plasma and urine. The extraction recoveries of all analytes at three concentration levels were consistent. In conclusion, the validation results showed that this method was robust, specific, and sensitive and it can successfully fulfill the requirement of clinical pharmacokinetic study of TPN729 in Chinese healthy subjects.

Teriflunomide sodium, a novel derivative of leflunomide, was developed to treat systemic lupus erythematosus.The objectives of this trial were to study the safety, pharmacokinetics, and pharmacogenetics of teriflunomide sodium in healthy Chinese subjects in order to support its accelerated development.A clinical study was designed as a single-dose, randomized, parallel, open-label study. Healthy volunteers were randomly assigned to take teriflunomide sodium 10 mg or leflunomide 10 mg. Eligible healthy volunteers were monitored over a 98-day observation period. Blood and urine samples were collected and analyzed for teriflunomide and its metabolite concentrations, and ABCG2 and CYP2C9 genotypes were detected. The safety profile was also collected.All adverse events were mild in intensity, and all subjects completed this trial without any other treatment. After a single administration of teriflunomide sodium and leflunomide, teriflunomide maximal concentrations were 1.32 ± 0.341 mg/L and 0.718 ± 0.169 mg/L, and area under the concentration-time curve from time zero to infinity (AUCTeriflunomide sodium was generally safe and well tolerated in healthy Chinese subjects. The relative bioavailability of teriflunomide between teriflunomide sodium and leflunomide after a single dose administration was approximately 150%. Additionally, ABCG2 34GA was found to significantly affect teriflunomide pharmacokinetics, which suggested ABCG2 34GA may be a significant influencing factor.This study was registered at the China National Medical Products Administration ( http://www.nmpa.gov.cn ; registration number 2014L01935), and also at the China platform for registry and publicity of drug clinical trials ( http://www.chinadrugtrials.org.cn ; registration number CTR20150314).

Lifirafenib (BGB-283), a dual inhibitor trageting BRAF kinase and EGFR, showed favorable efficacy and safety in treating patients with different cancer types harboring mutations in BRAF, KRAS and NRAS. In order to support the clinical pharmacokinetic study, a sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS) method was developed and validated to quantify lifirafenib concentration in human plasma and urine. Plasma samples were purified using protein precipitation. Urine samples were pre-treated by adding tween 80 with the purpose of preventing non-specific adsorption, then extracted by centrifugation. Chromatographic separation was achieved on Phenomenex Luna C18 column with a gradient elution. The mass detection was performed using electrospray ionization (ESI) source under multiple reaction monitoring (MRM) in positive ionization mode. The method was fully validated, and the result of inter-assay and intra-assay precisions were less than 15% and the accuracy within the scope of ±15%. The linear range for plasma and urine covered from 10 to 10,000 ng/mL and 1 to 200 ng/mL, respectively, with correlation coefficients of 0.99. The validation for matrix effect, recovery, stability and carryover were met the acceptance criteria. The method showed robust and sensitive, it successfully fulfilled the requirement of clinical pharmacokinetic study of lifirafenib in Chinese patients with locally advanced or metastatic solid tumors.

A simple high-performance liquid chromatography coupled with tandem mass spectrometry method was developed and fully validated to simultaneously determine teriflunomide (TER) and its metabolite 4-trifluoro-methylaniline oxanilic acid (4-TMOA) in human plasma and urine. Merely 50 μL plasma and 20 μL urine were employed in sample preparation using protein precipitation and direct dilution method, respectively. An Agilent Zorbax eclipse plus C18 column was selected to achieve rapid separation for TER and 4-TMOA within 3 min. Electrospray ionization under multiple reaction monitoring was used to monitor the ion transitions for TER (m/z 269.0 → 159.9), 4-TMOA (m/z 231.9 → 160.0), internal standard teriflunomide-d4 (m/z 273.0 → 164.0) and 2-amino-4-trifluoromethyl benzoic acid (m/z 203.8 → 120.1), operating in the negative ion mode. This method proved to have better accuracy and precision over concentration range of 10-5000 ng/mL in plasma as well as 10-10,000 ng/mL in urine. After a full validation, this method was successfully applied in a pharmacokinetic study of teriflunomide sodium and leflunomide in Chinese healthy volunteers.

Background Foodborne diseases are a worldwide public health problem. However, data regarding epidemiological characteristics are still lacking in China. We aimed to analyze the characteristics of foodborne diseases outbreak from 2010 to 2016 in Guangxi, South China. Methods A foodborne disease outbreak is the occurrence of two or more cases of a similar foodborne disease resulting from the ingestion of a common food. All data are obtained from reports in the Public Health Emergency Report and Management Information System of the China Information System for Disease Control and Prevention, and also from special investigation reports from Guangxi province. Results A total of 138 foodborne diseases outbreak occurred in Guangxi in the past 7 years, leading to 3348 cases and 46 deaths. Foodborne disease outbreaks mainly occurred in the second and fourth quarters, and schools and private homes were the most common sites. Ingesting toxic food by mistake, improper cooking and cross contamination were the main routes of poisoning which caused 2169 (64.78%) cases and 37 (80.43%) deaths. Bacteria (62 outbreaks, 44.93%) and poisonous plants (46 outbreaks, 33.33%) were the main etiologies of foodborne diseases in our study. In particular, poisonous plants were the main cause of deaths involved in the foodborne disease outbreaks (26 outbreaks, 56.52%). Conclusions Bacteria and poisonous plants were the primary causative hazard of foodborne diseases. Some specific measures are needed for ongoing prevention and control against the occurrence of foodborne diseases. Electronic supplementary material The online version of this article (10.1186/s12889-018-5429-2) contains supplementary material, which is available to authorized users.

Imigliptin has been reported as a novel dipeptidyl-peptidase-IV (DPP-4) inhibitor to treat type 2 Diabetes Mellitus (T2DM), and is currently being tested in clinical trials. In the first human clinical study, imigliptin was well tolerated and proved to be a potent DPP-4 inhibitor. Considering its potential therapeutic benefits and promising future, it is of great importance to study the metabolite profiles in the early stage of drug development. In the present study, a robust and reliable analytical method based on the ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF MS) method combined with MassLynx software was established to investigate the characterization of metabolites of imigliptin in human and rat plasma, urine and feces after oral administration. As a result, a total of 9 metabolites were identified in humans, including 6, 9 and 8 metabolites in human plasma, urine, and feces, respectively. A total of 11 metabolites were identified in rats, including 7, 10 and 8 metabolites in rat plasma, urine, and feces, respectively. In addition, 6 of the metabolites detected in humans and rats were phase I metabolites, including demethylation, carboxylation, hydroxylation and dehydrogenation metabolites, and 5 of the metabolites were phase II metabolites, including acetylation and glucuronidation. There was no human metabolite detected compared to those in rats. The major metabolites detected in human plasma (M1 and M2) were products resulting from acetylation, and hydroxylation followed by dehydrogenation. M1 was the major metabolite in rat plasma. M2 and the parent drug were the major drug-related substances in human urine. The parent drug was the major drug-related substances in rat urine. M2, M5 (hydroxylation product) and M6 (2 × hydroxylation and acetylation product) were the predominant metabolites in human feces. M2 and M5 were the major metabolites in rat feces. In addition, renal clearance was the major route of excretion for imigliptin.

Imigliptin is a novel DPP-4 inhibitor, designed to treat type 2 diabetes mellitus (T2DM). A selective and sensitive method was developed using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) to simultaneously quantify imigliptin, its five metabolites, and alogliptin in human plasma and urine. Solid-phase extraction (SPE) and direct dilution were used to extract imigliptin, its five metabolites, alogliptin from plasma and urine, respectively. The extracts were injected onto a SymmetryShield RP8 column with a gradient elution of methanol and water containing 10 mM ammonium formate (pH = 7). Ionization of all analytes was performed using an electrospray ionization (ESI) source in positive mode and detection was carried out with multiple reaction monitoring (MRM) mode. The results revealed that the method had excellent selectivity and linearity. Inter- and intra-batch precisions of all analytes were less than 15% and the accuracies were within 85%-115% for both plasma and urine. The sensitivity, matrix effect, extraction recovery, linearity, and stabilities were validated for all analytes in human plasma and urine. In conclusion, the validation results showed that this method was robust, specific, and sensitive and it can successfully applied to a pharmacokinetic study of Chinese T2DM subjects after oral dose of imigliptin and alogliptin.

Table Number of outbreaks, cases and deaths by month, Guangxi, South China, 2010â 2016. (DOC 42Â kb)