Safety, pharmacokinetics, and pharmacodynamics in healthy Chinese volunteers treated with SC0062, a highly selective endothelin-A receptor antagonist.

This study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effects (FE) of SC0062, a highly active endothelin-A (ETA ) receptor antagonist, in healthy subjects. The primary objectives of this first-in-human phase I study, comprised of single-ascending-dose, multiple-ascending-dose, and FE parts, were to characterize the safety and tolerability of SC0062, and FE. The secondary objectives were to determine the PK behavior of SC0062 and its major active metabolite M18, whereas exploratory objectives focused on PD effects, principally effects on endothelin-1 (ET-1) and total bile acids (TBA). Single doses of 10 to 100 mg and multiple daily doses of 20 and 50 mg for 6 days were well tolerated. SC0062 was rapidly absorbed and plasma exposure of SC0062 and M18 increased disproportionately with dose, achieving steady state by day 3, with accumulation ratios of 1.22 and 1.89 on day 6 for SC0062 and M18, respectively. The geometric mean (geometric standard deviation) terminal elimination half-life (t1/2 ) values of SC0062 and M18 were 7.25 (1.70) h and 13.73 (1.32) h, respectively. Plasma ET-1 concentrations were dose-proportional, whereas plasma TBA concentrations behaved erratically. Following a single 50 mg dose of SC0062 after a high-fat meal, Cmax values for SC0062 and M18 increased by 41% and 32%, respectively, and median Tmax values for SC0062 were 3 h longer than fasting values; exposure was unaffected. These favorable safety, PK, and PD results provide a foundation for further studies of SC0062 in pulmonary arterial hypertension, chronic kidney disease, and other relevant indications.

Alfalfa xenomiR-162 targets G protein subunit gamma 11 to regulate milk protein synthesis in bovine mammary epithelial cells.

OBJECTIVE: It was shown that microRNAs (miRNAs) play an important role in milk protein synthesis. However, the post-transcriptional regulation of casein expression by exogenous miRNA (xeno-miRNAs) in ruminants remains unclear. This study explores the regulatory roles of alfalfa xeno-miR162 on casein synthesis in bovine mammary epithelial cells (bMECs). METHODS: The effects of alfalfa xenomiR-162 and G protein subunit gamma 11 (GNG11) on proliferation and milk protein metabolism of bMECs were detected by 5-Ethynyl-2'-Deoxyuridine (EdU) staining, flow cytometry, cell counting kit-8 (CCK-8), enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot. Dual-luciferase reporter assay was used to verify the targeting relationship between GNG11 and xenomiR-162. RESULTS: Results showed that over-expression of xenomiR-162 inhibited cell proliferation but promoted apoptosis, which also up-regulated the expression of several casein coding genes, including CSN1S1, CSN1S2, and CSN3, while decreasing the expression of CSN2. Furthermore, the targeting relationship between GNG11 and xenomiR-162 was determined, and it was confirmed that GNG11 silencing also inhibited cell proliferation but promoted apoptosis and reduced the expression of casein coding genes and genes related to the mammalian target of rapamycin (mTOR) pathway. CONCLUSION: Alfalfa xenomiR-162 appears to regulate bMECs proliferation and milk protein synthesis via GNG11 in the mTOR pathway, suggesting that this xeno-miRNA could be harnessed to modulate CSN3 expression in dairy cows, and increase κ-casein contents in milk.

A novel automated multi-cycle magnetic solid-phase extraction coupled to LC-MS/MS to study the disorders of six functional B vitamins in patients with gastroenterology and hyperhomocysteinemia.

B vitamins are essential for human life and their disorders can cause a variety of diseases. Solid-phase extraction (SPE) coupled to LC-MS/MS is a preferred technique for determining multiple B vitamins, however, their complexity in real biological matrices makes it hard to achieve satisfactory recovery and accuracy when simultaneous detection. In this study, a novel automated multi-cycle magnetic SPE (MSPE) coupled to the LC-MS/MS method was established using a mixed-mode anion exchange magnetic adsorbent for the simultaneous extraction of six functional B vitamins, including methylmalonic acid, riboflavin, pantothenic acid, 4-pyridoxic acid, folic acid, and 5-methyltetrahydrofolate. After three consecutive MSPE cycles, the recoveries of all analytes were between 51.5% and 89.6%. The method exhibited excellent sensitivity and linearity, with a dynamic range of 200-fold (R > 0.99 for all analytes), exceptional accuracy (ranging between 95.4% and 105.6%) and precision (with RSDs ≤ 6.2%) without significant matrix effects or interferences. Compared to manual SPE method, the automated multi-cycle MSPE method has better feasibility and greater vitamin coverage. It shows a high correlation with the manual method for the detection of 5-methyltetrahydrofolate and folate (R > 0.99). A study of patients from the gastroenterology department showed that those undergoing surgery and those with malignancies may be at risk of folate deficiency. In addition, patients with hyperhomocystinemia had higher levels of methylmalonic acid and lower levels of 5-methyltetrahydrofolate, which correlated with homocysteine levels (R = 0.404 and -0.311, respectively) and showed dose-response relationships. This method is highly automated and cost-effective, with minimal systematic error, making it suitable for the analysis of clinical samples.

A Randomized, Single-Dose, Parallel-Controlled Phase 1 Clinical Comparison of an Omalizumab Biosimilar Candidate with Reference Omalizumab in Healthy Chinese Male Volunteers.

This study evaluated the bioequivalence of omalizumab, a humanized monoclonal antibody against immunoglobulin-E (IgE), with one of its biosimilar candidates. The study was designed as a randomized, double-blind, parallel-controlled trial. A total of subjects who met the inclusion criteria and did not meet the exclusion criteria were dynamically randomly assigned to receive the test drug or the reference drug with a single subcutaneous injection of 150 mg by the minimization method. The test group and the reference group had similar demographic characteristics and baseline characteristics of total IgE. The 90% confidence interval of the geometric average ratio of the area under the serum concentration-time curve from the time 0 to the time of last quantifiable concentration, the area under the serum concentration curve from time 0 to infinity, and the maximum observed serum concentration between the 2 groups were within 80%-125%, showing bioequivalence. The changing trend of total and free IgE in the 2 groups was similar after administration, proving the pharmacodynamic similarity. The 2 groups had no significant difference in the positive rate of antidrug antibodies, and the total positive rate of neutralizing antibodies was 0. The incidence of treatment-emergent adverse events and treatment-related adverse events were similar between the 2 groups, with no serious adverse events. This study shows that the test drug had similar pharmacokinetics, immunogenicity, and safety to the reference omalizumab in healthy male subjects.

A phase I study to evaluate the safety, tolerability, and pharmacokinetics of a novel, potent GABA analog HSK16149 in healthy Chinese subjects.

Purpose: HSK16149 is a novel, potent gamma-aminobutyric acid (GABA) analog for the treatment of neuropathic pain. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of HSK16149 after single and multiple doses in healthy Chinese subjects. Methods: The randomized, double-blind, placebo-controlled study comprised two parts: SAD (single ascending-dose study) and MAD (multiple ascending-dose study). A total of 122 healthy subjects were enrolled in this study. HSK16149 capsule or placebo was administered as the protocol required. The safety of the drug was evaluated through clinical examinations and adverse events. Blood and urine samples were collected at the designated time intervals for pharmacokinetic analysis. Results: Subjects were generally well tolerated after HSK16149 administration and the most common treatment-emergent adverse event (TEAEs) was dizziness, which was expected based on the mechanism of action of HSK16149. In SAD, AUC and Cmax were shown to have a dose-proportional relationship in the dose range of 5-120 mg. The t1/2 of HSK16149 is 3.7-6.4 h. In MAD, after a single and multiple administration of 15-80 mg, AUC and Cmax are proportional to the increased dose of HSK16149, and the accumulative ratios of AUC and Cmax at steady-state were 1.05-1.44 and 1.07-1.36, respectively, indicating that HSK16149 only accumulated slightly after repeated administration. Conclusion: HSK16149 was well tolerated in healthy Chinese subjects. Based on the safety and pharmacokinetic data, 80 mg twice daily (BID) was suggested as the highest target dose for further clinical development. Clinical Trial Registration: http://www.chinadrugtrials.org.cn, identifier CTR20182535 and CTR20191317.

A phase I study comparing the pharmacokinetics and safety of HS628 (tocilizumab biosimilar) and reference tocilizumab in healthy male subjects.

This study aimed to evaluate the pharmacokinetic (PK) similarity of the proposed biosimilar HS628 compared with the reference tocilizumab (Actemra®) and also to demonstrate similar safety and immunogenicity profiles in healthy Chinese male subjects. Eighty eligible subjects were randomized into two treatment groups in a 1:1 ratio to receive a single intravenous infusion of HS628 or tocilizumab at 4 mg/kg over 60 min. Blood samples were collected at the scheduled time points for PK and immunogenicity analysis. PK biosimilarity was determined using the standard bioequivalence criteria 80%-125%. A total of 77 subjects received the study drug and completed the study. The main PK parameters were similar for the test and reference groups. The ratio of geometric least-squares means (GMR) and its 90% CIs for AUC0-t , AUC0-∞ , and Cmax between the test group and reference group were 1.06 (1.00-1.12), 1.07 (1.00-1.14), and 1.04 (0.99-1.10), respectively, which were fully within the predefined bioequivalent range of 80%-125%. The incidence of treatment-emergent adverse events (TEAEs) was similar for HS628 and tocilizumab (p > 0.05). The most common TEAEs were decreased fibrinogen, decreased neutrophils, pharyngalgia, oral ulcer, decreased leukocytes, and increased erythrocyte sedimentation rate. The results of the present study provide strong evidence to support the PK similarity and bioequivalence of HS628 and tocilizumab. The safety and immunogenicity profiles of HS628 were also shown to be similar to those of the reference tocilizumab.

Pharmacokinetics and Bioequivalence of 2 Nifedipine Controlled-Release Tablets: A Randomized, Single-Dose, 2-Period Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

The aim of this study was to evaluate the bioequivalence of generic nifedipine controlled-release tablet compared to branded product under fasting and fed conditions. A randomized, single-dose, 2-period, crossover study with a 7-day washout period was performed in 84 healthy Chinese volunteers (fasting cohort, n = 42; fed cohort, n = 42). In each study period, volunteers were assigned to receive a single oral dose of the generic or reference product (30 mg). Blood samples were collected before dosing and up to 72 hours after administration. The plasma concentration of nifedipine was determined by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained using a noncompartmental model and log-transformed pharmacokinetic parameters (maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, AUC from time 0 to infinity) were used to evaluate bioequivalence. The results showed that the 90% confidence interval for the geometric mean ratio of pharmacokinetic parameters of the test and reference products ranged from 80.0% to 125.0% in both the fasting and fed cohorts, meeting the criteria for bioequivalence. No serious adverse events were reported throughout the study and no adverse events led to withdrawal from the study. Food effects were found in both the test and reference products, with mean maximum plasma concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity increased by 23.7%, 20.7%, and 20.5%, respectively, for the test product and 35.2%, 13.4%, and 14.7% for the reference product after a high-fat and high-calorie breakfast.

Effect of a high-fat and high-calorie food on the pharmacokinetics of a novel, potent GABA analog HSK16149 in healthy subjects.

HSK16149 is a novel, potent gamma-aminobutyric acid (GABA) analog for the treatment of neuropathic pain. The purpose of this study was to assess the effect of a high-fat and high-calorie meal on the pharmacokinetics of HSK16149 in healthy Chinese subjects. An open-label, two-period crossover design was applied in this study. Twenty-six subjects were enrolled and were randomly divided into two groups: a fasted-fed group and a fed-fasted group, with 13 subjects in each group. Subjects took a single oral dose of 45 mg of HSK16149 under fasted or fed conditions on Day 1 and Day 4. A series of blood samples were collected for PK analysis. Safety was evaluated throughout the study by physical examinations, clinical laboratory tests, 12-lead ECGs, vital signs, and adverse events (AEs). The parameters AUC0-∞ , AUC0-t , and Cmax of HSK16149 were compared to assess the bioequivalence of HSK16149 under fasted and fed conditions. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) of AUC0-t and AUC0-∞ under the fed condition compared with the fasted condition were 95.84% (91.94-99.90%) and 95.79% (91.89-99.84%), respectively, which were all within the bioequivalent interval (80.00-125.00%). The GMR (90% CI) of Cmax under the fed condition compared with the fasted condition was 66.04% (59.45-73.36%), which was not within the bioequivalent range (80.00-125.00%). All adverse events were transient and resolved. This study demonstrated that HSK16149 can be administered with or without food.

A single-dose, randomized crossover study in healthy Chinese subjects to evaluate pharmacokinetics and bioequivalence of two capsules of calcium dobesilate 0.5 g under fasting and fed conditions.

OBJECTIVES: To compare the rate and extent of absorption of a launched generic calcium dobesilate capsule versus the branded reference formulation under fasting and fed conditions in healthy Chinese subjects, and to assess their bioequivalence and tolerability. METHODS: This single-dose, open-label, randomized-sequence, 2-period crossover bioequivalence study was conducted on healthy Chinese volunteers aged 18 to 45 years. Subjects received a single 0.5 g dose of calcium dobesilate capsule under fasting or fed conditions, with a 3-day washout period between doses of the test (T) and reference (R) formulations. Blood samples were collected before and up to 24 hours after administration. The plasma concentration of calcium dobesilate was determined by a validated Liquid chromatography-tandem mass spectrometry method. Non-compartmental analysis was applied to identify the pharmacokinetic (PK) properties. The primary PK parameters including the maximal plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC0-t), and the AUC extrapolated to infinity (AUC0-inf) were used for bioequivalence evaluation. RESULTS: The mean of PK parameters for T and R capsules under fasting (fed) condition were: Cmax, 13.57 (6.71) and 12.59 (7.25) µg/mL; AUC0-t, 97.32 (79.74) and 96.97 (80.71) h*µg/mL; AUC0-inf, 101.68 (88.01) and 101.64 (87.81) h*µg/mL. The 90% confidence intervals (CIs) of GMRs under fasting (fed) condition were: Cmax, 97.91%-116.62% (88.63%-96.53%); AUC0-t, 97.15%-104.00% (96.58%-101.39%); and AUC0-inf, 97.19%-102.89% (98.67%-103.99%). These 90% CIs were all within the bioequivalence range of 80%-125%. All adverse events were mild. CONCLUSION: In this study, the T calcium dobesilate 0.5 g capsule was bioequivalent to the reference product under both fasting and fed conditions. Taking food would slow down its rate and reduce its amount of absorption. Both formulations were generally well tolerated.

Association between red blood cell distribution width and ischemic stroke recurrence in patients with acute ischemic stroke: a 10-years retrospective cohort analysis.

Numerous studies have reported that a higher red blood cell distribution width (RDW) level was associated with adverse outcomes in patients with the first stroke. However, no studies have examined the association between RDW and recurrent ischemic stroke. We performed a population-based cohort data analysis from 2007 to 2017. Baseline RDW was measured in 6402 first ischemic stroke participants, who were followed for about five years on average. During 62 months of median follow-up, 205 participants (3.20%) reported a recurrence (self-reported). RDW showed a nonlinear relationship with the risk of ischemic stroke recurrence. When RDW was assessed as quartiles (quartile 1, RDW<12.4; quartile 2, 12.4 to 12.8; quartile 3,12.8 to 13.3, quartile4, RDW>13.3), compared with the reference group (quartile 1), the hazard ratios (HRs) of ischemic stroke recurrence were 1.372 (95% confidence interval [CI]=0.671-2.805, P=0.386) in quartile 2, 1.835 (95% CI=1.222-2.755, P=0.003) in quartile 3, and 1.732 (95% CI=1.114-2.561, P<0.001) in quartile 4. The trend test was significant (P<0.001). When quartiles 3 and 4 were combined, the adjusted HR of ischemic stroke recurrence was 1.439 (95% CI=1.330-1.556, P<0.001) compared with the combined quartiles 1 and 2 subgroups. This study demonstrated that elevated RDW levels were positively associated with an increased risk of recurrent ischemic stroke. RDW can provide a new perspective for initial risk assessment and identify high-risk patients early. Further research is required to confirm our results.

Safety and immunogenicity of a modified COVID-19 mRNA vaccine, SW-BIC-213, as a heterologous booster in healthy adults: an open-labeled, two-centered and multi-arm randomised, phase 1 trial.

BACKGROUND: We assessed the safety and immunogenicity of a core-shell structured lipopolyplex (LPP) based COVID-19 mRNA vaccine, SW-BIC-213, as a heterologous booster in healthy adults. METHODS: We conducted an open-labeled, two-centered, and three-arm randomised phase 1 trial. Healthy adults, who had completed a two-dose of inactivated COVID-19 vaccine for more than six months, were enrolled and randomized to receive a booster dose of COVILO (inactivated vaccine) (n = 20) or SW-BIC-213-25µg (n = 20), or SW-BIC-213-45µg (n = 20). The primary study endpoint was adverse events within 30 days post-boosting. The secondary endpoint was the titers of binding antibodies and neutralizing antibodies against the wild-type (WT) of SARS-CoV-2 as well as variants of concern in serum. The exploratory endpoint was the cellular immune responses. This trial was registered with http://www.chictr.org.cn (ChiCTR2200060355). FINDINGS: Between Jun 6 and Jun 22, 2022, 60 participants were enrolled and randomized to receive a booster dose of SW-BIC-213 (25 µg, n = 20, or 45 µg, n = 20) or COVILO (n = 20). The baseline demographic characteristics of the participants at enrollment were similar among the treatment groups. For the primary outcome, injection site pain and fever were more common in the SW-BIC-213 groups (25 µg and 45 µg). Grade 3 fever was reported in 25% (5/20) of participants in the SW-BIC-213-45µg group but was resolved within 48 h after onset. No fatal events or adverse events leading to study discontinuation were observed. For secondary and exploratory outcomes, SW-BIC-213 elicited higher and longer humoral and cellular immune responses than that in the COVILO group. INTERPRETATION: SW-BIC-213, a core-shell structured lipopolyplex (LPP) based mRNA vaccine, was safe, tolerable, and immunogenic as a heterologous booster in healthy Chinese adults. FUNDING: Shanghai Municipal Government, the Science and Technology and Economic Commission of Shanghai Pudong New Area, and mRNA Innovation and Translation Center of Shanghai.

Alfalfa Xeno-miR168b Target CPT1A to Regulate Milk Fat Synthesis in Bovine Mammary Epithelial Cells.

It was shown that microRNAs (miRNAs) play an important role in the synthesis of milk fat; thus, this manuscript evaluated whether exogenous miRNA (xeno-miRNAs) from alfalfa could influence the milk fat content in dairy cows. At first, mtr-miR168b was screened from dairy cow milk and blood. Then, EdU staining, flow cytometry, Oil Red O staining, qRT-PCR, and WB were applied to explore the effect of xeno-miR168b on the proliferation, apoptosis, and lipid metabolism of bovine mammary epithelial cells (BMECs). Finally, in order to clarify the pathway that regulated the lipid metabolism of BMECs using xeno-miR168b, a double-luciferase reporter assay was used to verify the target gene related to milk fat. These results showed that overexpression of xeno-miR168b inhibited cell proliferation but promoted apoptosis, which also decreased the expression of several lipid metabolism genes, including PPARγ, SCD1, C/EBPß, and SREBP1, significantly inhibited lipid droplet formation, and reduced triglyceride content in BMECs. Furthermore, the targeting relationship between CPT1A and xeno-miR168b was determined and it was confirmed that CPT1A silencing reduced the expression of lipid metabolism genes and inhibited fat accumulation in BMECs. These findings identified xeno-miR168b from alfalfa as a cross-kingdom regulatory element that could influence milk fat content in dairy cows by modulating CPT1A expression.

A Randomized, Single-dose, Phase I Clinical Comparison of a Trastuzumab Biosimilar With a Reference Trastuzumab Formulation in Healthy Chinese Male Volunteers.

The test drug, a recombinant humanized monoclonal antibody, is a biosimilar candidate for the reference drug. The purpose of this study was to evaluate the bioequivalence of these two drugs. The study was divided into two parts, a pre-study and a formal trial. The pre-study included two subjects who were each given a single intravenous infusion of 6 mg/kg test drug. The formal trial was designed to be a randomized, double-blind, parallel controlled trial in which 70 subjects were randomly assigned 1:1 to receive either test or reference drug as a single 6 mg/kg intravenous infusion. In the pre-study, the immunogenicity was negative in both subjects and the safety of the test drug was considered to be good. The two groups in the formal trial had similar demographic characteristics. The 90% confidence interval of geometric mean ratios of area under the serum concentration-time curve from the time 0 to the time of last quantifiable concentration, area under the serum concentration-curve from time 0 to infinity, and maximum observed serum concentration between the test group and the reference group fell between 80% and 125% and the bioequivalence was recognized. There was no significant difference in the positive rate of antidrug antibodies. The treatment-emergent adverse events in the test group were similar to those in the reference group. This study showed that the test drug has similar pharmacokinetics, immunogenicity, and safety to the reference drug in healthy male subjects.

A Randomized, Double-Blind, Parallel Controlled, Single-Dose Phase I Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of the Infliximab Biosimilar CMAB008 and the Reference Product in Healthy Chinese Male Subjects.

This study aimed to evaluate the pharmacokinetics (PK), safety, and immunogenicity of the infliximab biosimilar CMAB008 compared to the reference product (Remicade) in healthy Chinese male subjects to provide the basis for the similarity evaluation of the 2 drugs. In this phase I randomized, double-blind, parallel-controlled, single-dose study, a total of 90 subjects were randomized 1:1 to receive CMAB008 or infliximab reference product with single intravenous injections (5 mg/kg). Blood samples were collected at designed time points for PK and immunogenicity assessment. If the 90%CI of the geometric mean ratio of area under the plasma concentration-time curve from 0 to the time of the last observation, maximum observed plasma concentration, area under the plasma concentration-time curve from 0 to infinity was completely within the range of 80% to 125%, the PK bioequivalence was established. Other PK parameters including time to maximum plasma concentration, half-life time, clearance, apparent volume of distribution, and last measurable concentration time point were also assessed. Adverse events (AEs) were recorded. Serum concentration-time profiles were similar across the 2 groups, and PK parameters were comparable in the 2 groups. The 90%CI of the geometric mean ratio of test to reference was within the predefined bioequivalence range of 80% to 125%. The AEs occurred similarly in 2 groups. One serious AE (rhabdomyolysis, grade 3) occurred in the test group. The total positive rates of antidrug antibody and neutralizing antibodies in the test group (85.7% and 5.6%, respectively) were numerically lower than infliximab reference product group (90.9% and 15%, respectively). The PK profile of the 2 groups is statistically equivalent. The preliminary safety and immunogenicity evaluation of the 2 drugs are comparable.

Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects.

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25-800 mg. T1/2 was within 4.80-6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

Bioequivalence and Safety of Levetiracetam Granules and Oral Solution: A Randomized, Single-Dose, 2-Period Crossover Study in Healthy Chinese Volunteers Under a Fasting Condition.

The bioequivalence and safety of levetiracetam granules (test formulation) and oral solution (reference formulation) were evaluated in Chinese healthy volunteers under a fasting condition. A total of 24 subjects randomly received the test or reference formulation at the rate of 1:1. The alternative formulation was administered after a 7-day washout period. The blood samples were collected at designated time points. Liquid chromatography-tandem mass spectrometry was applied to determine the plasma concentrations of levetiracetam. Adverse events were monitored and recorded. The 90% CIs for the geometric mean ratios of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, and area under the plasma concentration-time curve from time 0 to infinity between test preparation and reference preparation were 95.5% to 110.7%, 100.2% to 105.3%, and 100.3% to 105.7%, respectively, all within an acceptable bioequivalence range of 80.00% 125.00%. Both test and reference preparations were well tolerated. The trial confirmed that a single dose of 500-mg levetiracetam granules was bioequivalent to oral solution under a fasting condition, and may serve as a new dosage form of levetiracetam for clinical practice.

Pharmacokinetics, safety, and simulated efficacy of an influenza treatment, baloxavir marboxil, in Chinese individuals.

Baloxavir marboxil is an endonuclease inhibitor indicated for the treatment of influenza in patients ≥12 years. No data exist for Chinese patients in global studies. This randomized, open-label, phase I study evaluated the pharmacokinetics (PK) and safety of baloxavir marboxil in healthy Chinese volunteers and was used to anticipate efficacy in Chinese patients. Patients received a single oral dose of baloxavir marboxil (40 or 80 mg [1:1]). Serial blood samples were collected predose and at various timepoints up to 14 days postdose. Baloxavir marboxil and acid plasma concentrations were determined by liquid chromatography tandem mass spectrometry. PK parameters of baloxavir acid were estimated by noncompartmental analysis. Adverse events (AEs) were recorded. Time to alleviation of symptoms (TTAS) was simulated for otherwise healthy (OwH) and high-risk (HR) Chinese and Asian patients. Thirty-two male patients received baloxavir marboxil. Baloxavir acid plasma concentration peaked 4 h postdose. Mean maximum concentration (Cmax ) was 107.6 and 206.9 ng/ml, and mean area under the plasma concentration-time curve from zero to infinity (AUC0-inf ) was 6955 and 9643 ng·h/ml in the 40 and 80 mg cohorts, respectively. AEs were mild and transient; no new safety signals were identified. Simulated median TTAS for OwH and HR Chinese patients agreed with simulated values in Asian patients. PK parameters were similar to Asian populations in other studies. The globally adopted baloxavir marboxil dosing strategy was consistent with the established safety profile of baloxavir marboxil in this population. Simulated efficacy indicated Chinese patients could benefit from similar efficacy to Asian patients.

Development and validation of a ligand-binding assay for quantification of the F(ab')2 antivenom of Daboia russelii siamensis in human serum and its application to a phase I clinical study.

Daboia russelii siamensis accounts for most of snakebite mortalities in China, yet, specific treatment against the venom toxins is absent in clinical practice. The F(ab')2 antivenom of Daboia russelii siamensis is manufactured and approved for the clinical trial in China. To satisfy the need for clinical pharmacokinetic research, this study aimed to develop a ligand binding assay (LBA) for the quantification of F(ab')2 antivenom of Daboia russelii siamensis in human serum. A diverse combination of conditions was optimized based on the fitness of the calibration curve and selectivity. The established LBA undergoes thorough method validation according to the guidelines of regulatory authorities. In the calibration range 1.0-64 µg/mL, the correlation coefficient r2 was from 0.9970 to 1.000, indicating good fitness. Accuracy and precision were within ± 20%. Dilution linearity was observed in the ultra-high quality-control (QC) samples (500 µg/mL). In addition, the assay was free from hook effect, the endogenous interferences and exogenous interferences. The QC samples were stable under different handling and storage conditions. The validated assay was successfully applied to a phase I clinical study of the F(ab')2 antivenom of Daboia russelii siamensis in Chinese healthy volunteers. The peak concentrations exhibited dose-proportionality. In conclusion, this study provides a novel and reliable LBA method for the clinical pharmacokinetic research of F(ab')2 antivenom of Daboia russelii siamensis. It will facilitate further clinical trials in treating the snakebite of Daboia russelii siamensis.

Effect of food on the single-dose pharmacokinetics and tolerability of savolitinib in Chinese healthy volunteers.

The aim of this study was to investigate the effect of a high-fat and high-calorie meal on the single-dose pharmacokinetics (PK) and tolerability of savolitinib. The study included two phases: safety run-in phase and food effect assessment phase. In the safety run-in phase, 9 healthy male volunteers were divided into three groups to be administered a single oral dose of savolitinib tablets at 200, 400, and 600 mg. In the food effect assessment phase, 16 healthy male volunteers received a single 600 mg dose of savolitinib tablets following an overnight fast or a high-fat and high-calorie breakfast prior to dosing. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety and tolerability were assessed throughout the study by clinical assessments and adverse events (AEs). A total of 25 healthy male volunteers were enrolled in the study, including 9 in the safety run-in phase and 16 in the food effect assessment phase. In the food effect assessment phase, the geometric mean ratios (90% confidence interval) for savolitinib dosed under the fed condition compared with that dosed under the fasting condition were 102.7% (84.9%, 124.2%) and 117.1% (103.9%, 131.9%) for Cmax and AUC0-inf of savolitinib, respectively. The Tmax was delayed significantly (p = 0.023) under fed condition. The most common AEs possibly related to the study drug were dizziness, nausea, and emesis. The study indicated that a high-fat and high-calorie meal has no clinically relevant impact on the PK and bioavailability of savolitinib in healthy male volunteers.

Association Between Pre-Treatment and Post-Treatment 3-Month Red Cell Distribution Width with Three-Year Prognosis of Prostate Cancer.

PURPOSE: Red cell distribution width (RDW), an inflammation biomarker, has been linked to poor outcomes in patients with different types of cancers. The present study aimed to investigate the relationship between pre-/post-treatment 3-month RDW levels and changes in RDW with 3-year prognosis of prostate cancer. PATIENTS AND METHODS: A total of 348 patients with prostate cancer were recruited between June 1, 2012 and June 1, 2017 and were followed up for at least 3 years. RDW was measured with the Mindray BC-6800Plus automatic blood counting system at pre- and post-treatment 3-month. Demographic and clinical information of the participants were also collected. The overall survival (OS) and cancer-specific survival (CSS) were analyzed using the Kaplan-Meier method. Cox regression and competing risk regression analyses were performed. RESULTS: During the follow-up period, 51 (14.66%) deaths occurred. The levels of pre- and post-treatment RDW levels were significantly higher in the death group than in the survival group (p<0.001). In the death group, the level of RDW continued to rise in most subjects, and the mean level of RDW was significantly higher at post-treatment than pre-treatment, contrary to the results observed in the survival group. Multivariate Cox regression analysis revealed that high pre-treatment RDW, high post-treatment RDW, and persistently higher RDW were independently associated with OS and CSS (p<0.001). Similar results were observed in the competing risk regression analysis. Kaplan-Meier analysis revealed that patients with higher pre-treatment RDW levels, higher post-treatment RDW levels, and persistently higher RDW levels had poorer 3-year OS and CSS rates (p<0.05). CONCLUSION: The levels of and changes in RDW before and after treatment were associated with the 3-year prognosis of prostate cancer, suggesting that RDW might be an efficient prognostic predictor in patients with prostate cancer.