Effect of food on the pharmacokinetics and safety profiles of a new PARP inhibitor fuzuloparib capsules in healthy volunteers.

PURPOSE: This study assessed effect of food on pharmacokinetics (PK) and safety of fuzuloparib capsules. METHODS: A randomized, open-label, two-cycle, two-sequence, crossover clinical trial was conducted. 20 subjects were randomly assigned to 2 groups at a 1:1 ratio. The first group subjects were orally administered 150 mg fuzuloparib capsules under fasting condition in first dosing cycle. The same dose of fuzuloparib capsules were taken under postprandial state after a 7-day washout period. The second group was reversed. 3 ml whole blood was collected at each blood collection point until 72 h post dose. PK parameters were calculated. Furthermore, safety assessment was performed. RESULTS: The time to maximum concentration (Tmax) was prolonged to 3 h and maximum concentration (Cmax) decreased by 18.6% on high-fat diets. 90% confidence intervals (CIs) of geometric mean ratios (GMRs) for Cmax, area under the concentration-time curve from time zero to time t (AUC0-t), and area under the concentration-time curve extrapolated to infinity (AUC0-∞) after high-fat meal were 71.6-92.6%, 81.7-102.7% and 81.6-102.5%, respectively. All treatment-emergent adverse events (TEAEs) were grade 1; No serious adverse events (SAEs), serious unexpected suspected adverse reaction (SUSAR) or deaths were reported. CONCLUSION: Food decreased the absorption rate and slowed time to peak exposure of fuzuloparib capsules, without impact on absorption extent. Dosing with food was found to be safe for fuzuloparib capsules in this study. CLINICAL TRIAL REGISTRATION: This study was registered with chinadrugtrials.org.cn (identifier: CTR20221498).

LC-MS/MS method for quick detection of vonoprazan fumarate in human plasma: Development, validation and its application to a bioequivalence study.

A liquid chromatography-tandem mass spectrometry method with vonoprazan fumarate-d4 as a stable isotope-labeled internal standard was developed and validated aiming at quantification of vonoprazan fumarate in human plasma for a bioequivalence study. Chromatographic separation was achieved by acetonitrile one-step protein precipitation using a gradient elution of 0.1% formic acid aqueous solution and acetonitrile with a run time of 3.65 min. Detection was carried out on a tandem mass spectrometer in multiple reaction monitoring mode via a positive electrospray ionization interface. The multiple reaction monitoring mode of precursor-product ion transitions for vonoprazan fumarate and vonoprazan fumarate-d4 were m/z 346.0 → 315.1 and 350.0 → 316.0, respectively. The linear range was 0.150-60.000 ng/ml. This method was fully validated with acceptable results in terms of selectivity, carryover, lower limit of quantification, calibration curve, accuracy, precision, dilution effect, matrix effect, stability, recovery and incurred sample reanalysis. A successful application of this method was realized in the bioequivalence study of vonoprazan fumarate tablet (20 mg) among healthy Chinese volunteers.

Age-related pharmacokinetics differences were observed between young and elderly populations of a novel PDE5 inhibitor, youkenafil, and its metabolite M459.

PURPOSE: Youkenafil is a novel oral selective PDE5 inhibitor for treating Erectile Dysfunction. This investigation assessed pharmacokinetics (PK), safety, and tolerability of youkenafil and its main metabolite (M459) after taking 100 mg youkenafil hydrochloride tablets in elderly and young subjects. METHODS: This Phase I, single-center, open-label, parallel-group, single-dose study was conducted on 24 individuals (12 elders and 12 youngsters). Each subject received a single oral 100 mg youkenafil hydrochloride tablets. Blood samples were collected before medication and up to 48 h after medication for PK analysis. Safety and tolerability were also assessed, including treatment-emergent adverse events (TEAEs), laboratory tests, 12-lead ECG, vital sign inspections, color vision examinations, and physical examinations. RESULTS: Plasma concentrations of youkenafil and M459 were quantified. PK parameters were determined by non-compartmental analysis. Median Tmax of elderly and young groups were both 0.733 h. However, Cmax, AUC0-t, and AUC0-∞ of youkenafil were separately 16.8 %, 37.2 %, and 37.5 % higher in elders and t1/2 of youkenafil was 2.1 h longer in elders. More great differences were observed for M459. T1/2 values were 4.05 h longer in elders, with Cmax, AUC0-t and AUC0-∞ 73.7 %, 81.1 %, and 81.4 % higher in elders. Two (8.3 %) elderly subjects reported TEAEs (all grade Ⅰ in severity) and both recovered without any treatment. No serious adverse reactions (SAEs) or serious unexpected suspected adverse reactions (SUSARs) occurred in this study. CONCLUSIONS: This was the first PK research of youkenafil and M459 in elderly men. PK parameters differences between youkenafil and M459 were comparable between elderly and young groups. Moreover, safety and tolerability of youkenafil were favorable in both groups.

CYP3A inhibitor itraconazole affect pharmacokinetic behavior of famitinib and its active metabolite: results of a single-center, single-arm, open-label and fixed sequence study.

BACKGROUND: Famitinib, the novel oral multitargeting tyrosine kinase inhibitor, was developed for treatment of patients with advanced solid cancer. This investigation assessed the pharmacokinetic (PK) effects of itraconazole, an officially recommended CYP3A4 strong inhibitor, on famitinib and its metabolite (SHR116637). METHODS: A single-center, single-arm, open-label, and fixed sequence study was conducted in 22 healthy subjects. Famitinib was administered as a single oral 15 mg on Day1. Itraconazole 200 mg once daily was given from Day12 to Day24, concomitantly with famitinib on Day15 and for follow-up during Day30 to Day32. Blood sampling followed each famitinib dosage for PK analysis of famitinib and SHR116637. Safety and tolerability were also assessed throughout the treatment. RESULTS: Cmax, AUC0-t and AUC0-∞ were raised by 40.6%, 77.7% and 81.6%, respectively, and t1/2 was prolonged from 36.08 hours to 48.24 hours for famitinib. In contrast, Cmax, AUC0-t and AUC0-∞ were reduced by 63.5%, 42.6%, and 39.0%, respectively, for SHR116637. Eight (36.4%) subjects reported seventeen treatments that emerged adverse events (all grade 1-2 in severity) all recovered at follow-up period. CONCLUSIONS: Single oral dose of 15 mg famitinib and co-therapy with 200 mg intraconazole were safe and well tolerated in healthy subjects. Famitinib should be avoided in conjunction with strong CYP3A inhibitors if possible. TRIAL REGISTRATION: This trial was registered at http://www.chinadrugtrials.org.cn/index.html. (Registration number: CTR20201824.).

Schisandrin protects against ulcerative colitis by inhibiting the SGK1/NLRP3 signaling pathway and reshaping gut microbiota in mice.

BACKGROUND: According to the Chinese Pharmacopoeia, the fruit of Schisandra chinensis (Turcz.) Baill. (SC) is an important traditional Chinese medicine that can be used to treat diarrhea. Despite the increasing research on the anti-inflammatory and anti-oxidant aspects of SC, the studies on the anti-ulcerative colitis of Schisandrin (SCH), the main constituent of SC, are relatively few. METHODS: The mice used in the study were randomly distributed into 6 groups: control, model, 5-ASA, and SCH (20, 40, 80 mg/kg/d). The mice in the model group were administered 3% (w/v) dextran sulfate sodium (DSS) through drinking water for 7 days, and the various parameters of disease activity index (DAI) such as body weight loss, stool consistency, and gross blood were measured. ELISA was used to detect inflammatory factors, and bioinformatics combined with transcriptome analysis was done to screen and verify relevant targets. 16S rDNA high-throughput sequencing was used to analyze the composition of the gut microbiota(GM), while mass spectrometry was done to analyze the changes in the content of bile acids (BAs) in the intestine. RESULTS: Mice treated with SCH experienced significant weight gain, effectively alleviating the severity of colitis, and decreasing the levels of inflammatory factors such as TNF-α, IL-1ß, IL-18, IL-6, and other related proteins (NLRP3, Caspase-1, SGK1) in UC mice. Furthermore, the analysis of GM and BAs in mice revealed that SCH increased the relative abundance of Lactobacilli spp, reduced the relative abundance of Bacteroides, and promoted the conversion of primary BAs to secondary BAs. These effects contributed to a significant improvement in the DSS-induced GM imbalance and the maintenance of intestinal homeostasis. CONCLUSION: It seems that there is a close relationship between the SCH mechanism and the regulation of SGK1/NLRP3 pathway and the restoration of GM balance. Therefore, it can be concluded that SCH could be a potential drug for the treatment of UC.

Pharmacokinetic and Pharmacodynamic Interactions Between Henagliflozin, a Novel Selective SGLT-2 Inhibitor, and Warfarin in Healthy Chinese Subjects.

PURPOSE: While controlling blood glucose, patients with diabetes and abnormal coagulation should be treated with positive anticoagulation because the hypercoagulable state of their blood is the primary cause of macroangiopathy. The goal of this study was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) interactions between henagliflozin, a novel selective sodium-glucose cotransporter 2 inhibitor, and warfarin in healthy subjects. METHODS: This single-center, open-label, single-arm clinical study was conducted in 16 healthy male Chinese subjects. According to the study protocol, the PK properties of henagliflozin 10 mg/d and warfarin 5 mg/d were collected and tabulated in accordance with sampling time. All study drugs were given with once-daily administration. Subjects were monitored for adverse reactions and their severity, outcomes, and relationship to study drug. This influences of warfarin on the PK properties of henagliflozin (Cmax,ss and AUCτ,ss), the effects of henagliflozin on the PK properties of warfarin (Cmax, AUC0-t, and AUC0-∞), and the influences of henagliflozin on the PD properties of warfarin (PTmax, PTAUC, INRmax, and INRAUC) were evaluated. FINDINGS: The geometric mean ratios (GMRs; 90% CIs) of henagliflozin Cmax,ss and AUCτ,ss were 101.75% (96.11%-107.72%) and 102.21% (100.04%-104.42%), respectively. The GMRs (90% CIs) of S- and R-warfarin Cmax, AUC0-t, and AUC0-∞ were as follows: Cmax, 114.31% (106.30%-122.91%) and 115.09% (109.46%-121.01%), respectively; AUC0-t, 120.15% (116.71%-123.69%) and 119.01% (116.32%-121.76%); and AUC0-∞, 120.81% (117.17%-124.58%) and 121.94% (118.90%-125.05%). The GMRs (90% CIs) of warfarin PTmax and PTAUC were 92.73% (91.25%-94.22%) and 97.42% (96.61%-98.24%). The GMRs (90% CIs) of warfarin INRmax and INRAUC were 92.66% (91.17%-94.17%) and 97.36% (96.52%-98.21%). A total of 32 cases of mild adverse events were reported, and were recovered/resolved. There were no serious adverse events reported. IMPLICATIONS: No significant clinically relevant effects on the PK/PD properties of henagliflozin or warfarin were found with coadministration of the two drugs in these healthy male Chinese subjects. Based on these findings, it is expected that henagliflozin and warfarin can be used in combination without dose adjustment. Chinadrugtrials.org.cn identifier: CTR20190240.

Quantification of cefaclor in human plasma using SIL-IS LC-ESI-MS/MS for pharmacokinetics study in healthy Chinese volunteers.

A steady, high-efficiency, and precise liquid chromatography-electrospray ionization-tandem mass spectrometry method was established and validated using cefaclor-d5 as the stable isotope-labeled internal standard for quantification of cefaclor in human plasma. One-step protein precipitation was applied to extract human plasma samples using methanol as precipitant. An Ultimate XB C18 column (2.1 × 50.0 mm, 5.0 µm) was used to achieve chromatographic separation. Mobile phases of gradient elution were an aqueous solution containing 0.1% formic acid (mobile phase A) and an acetonitrile solution containing 0.1% formic acid (mobile phase B). Electrospray ionization in positive-ion mode was applied to detect under multiple reaction monitoring mode. Target fragment ion pairs of cefaclor and stable isotope-labeled internal standard, respectively, were m/z 368.2 → 191.1 and m/z 373.2 → 196.1. Linear range of this method was between 20.0 and 10,000.0 ng/ml, with coefficient of determination (R2 ) >0.9900. Seven concentrations of quality control samples were used: 20.0 ng/ml (lower limit of quantitation), 60.0 ng/ml (low quality control), 650 ng/ml (middle quality control), 5000 ng/ml (arithmetic average middle quality control [AMQC]), 7500 ng/ml (high quality control), 10,000 ng/ml (upper limit of quantification), and 40,000 ng/ml (dilution quality control [DQC]). The method was validated for selectivity, lower limit of quantitation, linearity, accuracy, precision, recovery, matrix effect, dilution reliability, stability, carryover, and incurred sample reanalysis. This stable isotope-labeled internal standard liquid chromatography-electrospray ionization-tandem mass spectrometry approach has been successfully applied to study the pharmacokinetics of cefaclor dry suspension among healthy Chinese volunteers.

Three-Period Bioequivalence Study of Sodium Levofolinate Injection With Calcium Levofolinate for Injection and Sodium Folinate for Injection in Healthy Chinese Subjects.

The aim of this study was to compare the bioequivalence and safety of test preparation sodium levofolinate injection with reference preparations of calcium levofolinate for injection and sodium folinate for injection in China. A single-center, randomized, open-label, 3-period, crossover test was conducted on 24 healthy subjects. Plasma concentration of levofolinate, dextrofolinate, and their metabolites l-5-methyltetrahydrofolate and d-5-methyltetrahydrofolate were quantified by a validated chiral-liquid chromatography-tandem mass spectrometry method. All adverse events (AEs) were documented to evaluate safety as they occurred and evaluated descriptively. Pharmacokinetic parameters (maximum plasma concentration, time to maximum concentration, area under the plasma concentration-time curve over the dosing interval, area under the plasma concentration-time curve from time 0 to infinity, terminal elimination half-life, and terminal rate constant) of 3 preparations were calculated. A total of 8 subjects (10 cases) of AEs occurred in this trial. No serious AEs or unexpected serious adverse reactions were observed. Sodium levofolinate was bioequivalent to calcium levofolinate and sodium folinate in Chinese subjects, and the 3 preparations were all well tolerated.

Evaluation of Pharmacokinetic Interactions Between the New SGLT2 Inhibitor SHR3824 and Valsartan in Healthy Chinese Volunteers.

PURPOSE: Hypertension is often observed in patients with diabetes, and the progression of diabetic nephropathy is closely related to blood pressure elevation. Thus, the effects of hypoglycemic drugs on kidney function and pharmacokinetic interactions in combination with antihypertensive and hypoglycemic drugs are of great clinical value. The purpose of this study was to evaluate the pharmacokinetic interactions between henagliflozin (SHR3824), a new sodium-dependent glucose transporter 2 (SGLT2) inhibitor class drug, and valsartan, an angiotensin II receptor blocker. METHODS: A single-center, single-arm, open-label, self-controlled study was conducted in healthy Chinese volunteers. The pharmacokinetic parameters were calculated with Phoenix WinNonlin version 7.0, and the statistical analysis was performed with SAS version 9.4. Data on pharmacokinetic parameters (single and/or steady-state) were collected and tabulated for different analytes (valsartan and SHR3824) according to the sampling time specified in the protocol. Continuous attention was paid to the safety of all subjects. The aim of the study was to evaluate the effect of a single dose of valsartan on the pharmacokinetic behavior of SHR3824 after multiple doses of SHR3824 (Cmax,ss and AUCτ,ss) and the effect of multiple doses of SHR3824 on the pharmacokinetic behavior of valsartan (Cmax, AUC0-24h, and AUC0-∞). A mixed effect model was used to estimate the point estimation and 90% CI of the geometric mean ratio of the corresponding pharmacokinetic indices at the combined-medication stage (SHR3824 + valsartan) and the single-medication stage (SHR3824 or valsartan). FINDINGS: Twelve volunteers were screened into this experiment and underwent blood sampling. The pharmacokinetic properties of SHR3824 were evaluated after its administration alone or in combination with valsartan. Point estimates and 90% CIs of the geometric mean ratio of SHR3824 Cmax,ss and AUCτ,ss were within the conventional bioequivalence range of 80% to 125%. The pharmacokinetic properties of valsartan were evaluated after its administration alone or in combination with SHR3824. The geometric mean ratios and 90% CIs of the valsartan Cmax, AUC0-24h, and AUC0-∞ were also within the range of 80% to 125%. Thirty-four mild adverse events were reported, with no serious adverse events or suspected unexpected serious adverse reactions. IMPLICATIONS: This study provides basis for the clinical co-administration of SHR3824 with angiotensin II receptor blockers represented by valsartan. Based on these findings, co-administration of SHR3824 and valsartan seemed to have no effect on the pharmacokinetic properties of either drug. Chinadrugtrials.org.cn Identifier: CTR20180002.

Analysis of Trend and Associated Factors of Neuropsychological Development of Infants and Toddlers Based on Longitudinal Data.

OBJECTIVE: To explore the trend and associated factors of neuropsychological development of infants and toddlers in China. METHODS: A longitudinal study was conducted among 619 infants and toddlers (2914 person-times) aged 0 to 36 months from different provinces or cities in China from January 2013 to December 2019. RESULTS: The development age of each area increased with the extension of follow-up time, but this upward trend slowed down with physiological age at first measurement increasing. Among a low age group and each area, most of the development qualification rates in different follow-up periods were higher than that in the baseline (p < 0.05); however, many of them were not higher than that in the baseline among the medium or high age group (p > 0.05). For the areas of gross motor and self-care, the growth of qualification rate with the extension of follow-up was not obvious in the medium and high age group (both p trend > 0.05). Some impact factors of development in all areas were identified. CONCLUSIONS: The neuropsychological development delay of various areas of infants and toddlers, especially that of gross motor and self-care, should be paid early (within 1 years old) and constant attention. The impact of gender and maternal age on the development of young children has been further confirmed in the present study.

Predictive Model Construction for Social-Emotional Competence of Toddlers in Shanghai, China: A Population-Based Study.

OBJECTIVE: To construct a simple model containing predictors derived from Chinese Learning Accomplishment Profile (C-LAP) to better the evaluation of the social-emotional development of toddlers aged 24-36 months. METHOD: The test results by C-LAP system and demographic information of toddlers aged 24-36 months were collected between 2013 and 2019 in Shanghai, China, whose guardians were voluntary to accept the investigation. We developed a norm with the dataset based on the study population. With the norm, stepwise regression and best subset analysis were applied to select predictors. RESULTS: Relying on the norm established and stepwise regression and also the best subset analysis, an optimal model containing only 6 indicators was finally determined and the nomogram of the model was constructed. In the training and validation dataset, the AUCs of the optimal model were 0.95 (95% CI: 0.94-0.96) and 0.88 (95% CI: 0.85-0.90), respectively. When the cutoff point of the model was set at 0.04, its sensitivity in training and validation dataset was 0.969 and 0.949, respectively, and the specificity in training and validation dataset is 0.802 and 0.736, respectively. CONCLUSION: A simplified predictive model which includes only 6 items derived from C-LAP is developed to evaluate the probabilities of being at risk of developmental problem in social-emotional development for toddlers aged 24-36 months. Meanwhile, specificity and sensitivity of the model may be high enough for future fast screening.