Pharmacokinetics, Safety, and Immunogenicity of Intravenous and Subcutaneous Single-Dose QX002N Injection in Healthy Subjects: A Randomized, Open, Parallel, Single-Center, Phase I Study.

INTRODUCTION: Interleukin-17A (IL-17A) plays a crucial role in the pathogenesis of ankylosing spondylitis (AS), although not all patients respond to traditional IL-17A antibody treatments. QX002N injection, as a new monoclonal antibody targeting IL-17A, has shown potential in treating AS, offering a new treatment option for patients who do not respond well to existing therapies. METHODS: A randomized, open, parallel, single-center, phase I study was conducted to assess the pharmacokinetics, safety, and immunogenicity of single doses of QX002N injection administered intravenously (IV) or subcutaneously (SC) to healthy Chinese volunteers. Blood samples were collected at specified time intervals, and then serum concentrations of QX002N were analyzed by enzyme-linked immunosorbent assay. RESULTS: Pharmacokinetic analysis of the drug concentration-time data showed that the mean maximum observed serum QX002N concentration (Cmax) was 110 and 33.9 µg/ml, respectively. The average area under the drug concentration-time curves from 0 to the time of the last quantifiable concentration (AUClast) were 52,656 and 36,269 µg·h/ml, respectively and the average area under the drug concentration-time curves from 0 to infinity (AUCinf) were 54,867 and 38,194 µg·h/ml, respectively. The absolute bioavailability of QX002N after SC injection was 69.6%. CONCLUSIONS: Immunogenicity was assessed and all the subjects in this study were Anti-drug antibody (ADA)-negative, which means no subjects appeared to develop immunogenicity to QX002N. All the results testify to the safety of QX002N injection, which is satisfactory after IV or SC dosing in healthy subjects. TRIAL REGISTRATION: www.chinadrugtirals.org.cn , CTR20220430.

Ivosidenib in Chinese patients with relapsed or refractory isocitrate dehydrogenase 1 mutated acute myeloid leukemia: a registry study.

Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with IDH1-mutated (mIDH1) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) mIDH1 AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration (T max) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%-53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

Efficacy and safety of pralsetinib in Chinese advanced RET-mutant medullary thyroid cancer patients.

Pralsetinib has demonstrated efficacious activity in various solid tumors, including medullary thyroid cancer (MTC), as observed in the phase 1/2 global ARROW study (BLU-667-1101; NCT03037385). We evaluated the safety and efficacy of pralsetinib in Chinese patients with advanced RET-mutant MTC. In the extension cohort of ARROW, adult patients with advanced MTC, who had not received systemic therapy (except for cytotoxic chemotherapy), were treated with pralsetinib (400 mg once daily, orally). The primary endpoints were blinded independent central-reviewed (BICR) objective response rate (ORR) and safety. Between October 9, 2019, and April 29, 2020, 34 patients were enrolled at 12 centers across China. Among them, 28 patients tested positive for RET mutations in the central laboratory, and 26 of these, with measurable disease at baseline per BICR, were included in the analysis set for tumor response. As of April 12, 2021 (data cutoff), the ORR was 73.1% (95% CI: 52.2-88.4), and the median duration of response was not reached. The most common (≥15%) grade ≥3 treatment-related adverse events (TRAEs) in the 28 patients with RET-mutant MTC were neutrophil count decreased (8/28, 28.6%), blood creatine phosphokinase increased (6/28, 21.4%), and lymphocyte count decreased (5/28, 17.9%). Serious TRAEs were reported by six patients (21.4%), with the most common event being pneumonia (3/28, 10.7%). No patient discontinued treatment or died from pralsetinib-related adverse events. Pralsetinib demonstrated broad, deep, and durable efficacy, as well as a manageable and acceptable safety profile in Chinese patients with advanced RET-mutant MTC.

Phase I study of a non-S2P SARS-CoV-2 mRNA vaccine LVRNA009 in Chinese adults.

BACKGROUND: COVID-19 caused by SARS-CoV-2 is a great threat to public health. We present the safety and immunogenicity data from a phase I trial in China of an mRNA vaccine (LVRNA009). METHODS: In the single-centre, double-blind, placebo-controlled and dose-escalation study, 72 healthy unvaccinated adults aged 18-59 years were randomized (3:1) to receive LVRNA009 with one of three vaccine dosage (25, 50 and 100 µg) or placebo, to evaluate for the safety, tolerability and immunogenicity of LVRNA009. RESULTS: All these participants received two injections 28 days apart. No adverse events higher than grade 2 were reported during the study. A total of 30 participants (42 %) reported solicited adverse reactions during the first 14 days after vaccinations. Of the events reported, fever (n = 11, 15 %) was the most common systemic adverse reaction, and pain at the injection site (n = 17, 24 %) was the most frequent solicited local adverse reaction. Anti-S-protein IgG and neutralising antibodies were observed to have been induced 14 days after the first dose, significantly increased 7 days after the second dose, and remained at a high level 28 days after the second dose. Specific T-cell responses peaked 7 days and persisted 28 days after second vaccination. CONCLUSION: LVRNA009 has demonstrated promising results in safety and tolerability at all three dose levels among Chinese adults. LVRNA009 at three dose levels could rapidly induce strong humoral and cellular immune responses, including binding and neutralising antibody production and IFN- γ secretion, which showed good immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT05364047; Chictr.org.cn ChiCTR2100049349.

Efficacy and safety of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer.

BACKGROUND: Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations. As part of the global, phase 1/2 ARROW trial (NCT03037385), the efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC) were evaluated. METHODS: Adult patients with advanced, RET fusion-positive NSCLC with or without prior platinum-based chemotherapy were enrolled into two cohorts receiving 400-mg once-daily oral pralsetinib. Primary end points were objective response rates assessed by blinded independent central review and safety. RESULTS: Of 68 patients enrolled, 37 had received prior platinum-based chemotherapy (48.6% with ≥3 prior systemic regimens) and 31 were treatment-naïve. As of March 4, 2022 (data cutoff), of the patients with measurable lesions at baseline, a confirmed objective response was observed in 22 (66.7%; 95% confidence interval [CI], 48.2-82.0) of 33 pretreated patients, including 1 (3.0%) complete response and 21 (63.6%) partial responses; and in 25 (83.3%; 95% CI, 65.3-94.4) of 30 treatment-naïve patients, including two (6.7%) complete responses and 23 (76.7%) partial responses. Median progression-free survival was 11.7 months (95% CI, 8.7-not estimable) in pretreated patients and 12.7 months (95% CI, 8.9-not estimable) in treatment-naïve patients. The most common grade 3/4 treatment-related adverse events in 68 patients were anemia (35.3%) and decreased neutrophil count (33.8%). Eight (11.8%) patients discontinued pralsetinib because of treatment-related adverse events. CONCLUSION: Pralsetinib showed robust and durable clinical activity with a well-tolerated safety profile in Chinese patients with RET fusion-positive NSCLC. CLINICAL TRIAL REGISTRATION: NCT03037385.

Safety, tolerability, pharmacokinetics, and immunogenicity of JMB2002-an antibody against COVID-19: a phase 1 clinical trial in healthy Chinese adults.

BACKGROUND: The emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and subsequent Coronavirus Disease 2019 (COVID-19) pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. Monoclonal antibodies (mAbs) are a potentially effective therapeutic option. We identified a potent antibody JMB2002 against the SARS-CoV-2 receptor binding domain. JMB2002 has demonstrated therapeutic efficacy in a SARS-CoV-2 infected rhesus macaque model. METHODS: We conducted a randomized, double-blind, phase 1 trial to evaluate the JMB2002's safety, tolerability, pharmacokinetics, and immunogenicity in healthy Chinese adults. Participants were randomly assigned to one of four cohorts with sequential dose, administrated intravenously with JMB2002 or placebo, and followed up for 85 ± 5 days. RESULTS: 40 participants were recruited and completed in the study. Eight (25.0%) participants experienced 13 treatment emergent adverse events (TEAEs) that were drug-related. No serious adverse events (SAEs), dose limiting events (DLTs), or adverse events of special interest (AESIs), such as infusion related/allergic reactions, were observed, and no drop out due to adverse events (AEs) occurred. There was no significant safety difference observed between JMB2002 and the placebo, suggesting it was well tolerated. The AUC0-∞, AUC0 - t of JMB2002 infusion increased dose-dependently from 5 mg/kg to 50 mg/kg while there is also a linear trend between doses and Cmax. CONCLUSION: Therefore, JMB2002 was well tolerated after administration of a single dose in the range of 5 mg/kg to 50 mg/kg in healthy Chinese adults. TRIAL REGISTRATION: ChiCTR2100042150 at https://www.chictr.org.cn/searchproj.aspx (14/01/2021).

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Anti-C5a Antibody BDB-001 for Severe COVID-19: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Clinical Trial in Healthy Chinese Adults.

INTRODUCTION: Severe Coronavirus Disease 2019 (COVID-19) progresses with inflammation and coagulation, due to an overactive complement system. Complement component 5a (C5a) plays a key role in the complement system to trigger a powerful "cytokine and chemokine storm" in viral infection. BDB-001, a recombinant human immunoglobulin G4 (IgG4) that specially binds to C5a, has the potential to inhibit the C5a-triggered cytokine storm in treating COVID-19 patients and other inflammation diseases. Here, we have explored its safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adults. This trial is registered with http://www.chinadrugtrials.org.cn/(CTR20200429 ). METHODS: Thirty-two enrolled participants were randomized into three single-dose cohorts (2, 4, and 8 mg/kg) and 1 multi-dose cohort (4 mg/kg), and received either BDB-001 or placebo (3:1) double-blindly. The safety and tolerability after administration were evaluated for 21 days for single-dose cohorts and 28 days for the multi-dose cohort. The pharmacokinetics of BDB-001 in plasma and pharmacodynamics as free C5a in plasma were analyzed. RESULTS: The incidence of drug-related adverse events (AEs) was low, and all AEs were mild or moderate: neither AEs ≥ 3 (NCI-Common Terminology Criteria For Adverse Events, CTCAE 5.0) nor serious adverse events (SAEs) were found. The area under the concentration-time curve from time zero to 480 h (AUC0-480h), that from time zero to infinity (AUCinf), and peak plasma concentration ©max) increased dose-dependently from 2 to 8 mg/kg in the single-dose cohorts and were characterized by a nonlinear pharmacokinetics of target-mediated drug disposal (TMDD). The accumulation index by AUC0-tau after five administrations (4 mg/kg) from the multi-dose cohort was 6.42, suggesting an accumulation effect. Furthermore, inhibition of C5a at the plasma level was observed. CONCLUSION: The results of this phase I study supported that BDB-001 is a potent anti-C5a inhibitor with safety, tolerability, and no immunogenicity. TRIAL REGISTRATION NUMBER: CTR20200429.

Recent Advances on the Function and Purification of Milk Exosomes: A Review.

Exosomes are nano-scale extracellular vesicles, which can be used as drug carriers, tumor treatment, intestinal development and immune regulator. That is why it has great potential in pharmacy, functional foods, nutritional supplements, especially those for infants, postoperative patients, chemotherapy patients and the elderly. In addition, abnormal exosome level is also related to diseases such as cardiovascular diseases, tumor, diabetes, neurodegenerative and autoimmune diseases, as well as infectious diseases. Despite its high biological significance, pharmaceutical and nutritional value, the low abundancy of exosomes in milk is one of the bottlenecks restricting its in-depth research and real-life application. At present, there is no unified standard for the extraction of breast milk exosomes. Therefore, choosing the proper extraction method is very critical for its subsequent research and development. Based on this, this paper reviewed the purification techniques, the function and the possible applications of milk exosomes based on 47 latest references. Humble advices on future directions, prospects on new ideas and methods which are useful for the study of exosomes are proposed at the end of the paper as well.

Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD). METHODS: This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18-59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 µg, 10 µg, 15 µg, 20 µg, and 25 µg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212). FINDINGS: Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 µg group, 13 [65%] of 20 in the 10 µg group, 17 [85%] of 20 in the 15 µg group, 19 [95%] of 20 in the 20 µg group, 16 [100%] of 16 in the 25 µg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 µg group, three (15%) of 20 in the 10 µg group, six (30%) of 20 in the 15 µg group, seven (35%) of 20 in the 20 µg group, five (31%) of 16 in the 25 µg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 µg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19. INTERPRETATION: ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale. FUNDING: National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.

circSLC30A7 Inhibits Hepatocellular Carcinoma Cell Proliferation via the miR-767-5p/FBXW7/NOTCH1 Axis.

Circular RNAs, noncoding RNAs, have attracted much attention in various human tumor research fields. They regulate the development of various human cancers via microRNA sponges. This study aimed to assess the molecular mechanism of circSLC30A7 in hepatocellular carcinoma (HCC). In our study, we identified that circSLC30A7 was significantly downregulated in HCC cell lines and tissues. Furthermore, gain and loss function experiments were conducted to elucidate the biological functions of circSLC30A7 in HCC cell lines. Mechanistically, circSLC30A7 sponged miR-767-5p, inhibiting the expression of its downstream protein, FBXW7. In summary, this study revealed that circSLC30A7 is an essential tumor suppressor that inhibits HCC tumorigenesis through the miR-767-5p/FBXW7/NOTCH1 axis. Taken together, circSLC30A7 reduces HCC malignancy and can be a biomarker for HCC management.

Optimization of Vero Cells Grown on a Polymer Fiber Carrier in a Disposable Bioreactor for Inactivated Coxsackievirus A16 Vaccine Development.

At present, there are no vaccines available for hand, foot, and mouth disease, which is caused by Coxsackie virus A16 (CVA16) infection. In the present study, we isolated epidemic strains of CVA16 and optimized the production of the virus in Vero cells. The system comprised growing the infected cells on polymer fiber paper carriers in a serum-free medium containing 0.5% (w/v) lactalbumin hydrolysate a mini bioreactor. Disposable Bioflo310 and AmProtein Current perfusion bioreactors were used to monitor virus infection and Vero cell culture. The total number of cells increased from 1.5 × 109 to 3.0 × 1010. In our optimized culture process, the virus titer reached 7.8 × 107 TCID50/mL at three days after infection. The inactivated CVA16 prepared from our optimized culture procedure elicited a slightly higher neutralizing antibody titer compared with that derived from routine culture procedures. These results will promote the large-scale production of inactivated CVA16 vaccines using nonwoven polymer fiber paper cell cultures.

Thymol alleviates AGEs-induced podocyte injury by a pleiotropic effect via NF-κB-mediated by RhoA/ROCK signalling pathway.

Advanced glycation end products (AGE) are those of the most powerful pathogenic factors that related to diabetic complications. In our study, we investigated the beneficial effects of thymol on AGE induced cell injury and apoptosis in human podocytes (HPCs) and attempted to clarify its mechanisms. Our results revealed that stimulation with AGE could significantly activate RhoA/NF-κB pathway. Results showed thymol could markedly suppress inflammatory responses, cell apoptosis and disordered cytoskeleton. Also thymol restored the expression of podocin, restrained migration capacity. Western blot analysis indicated that it could restore the expression of RhoA, ROCK and vimentin, nephrin, podocin and p65 and IκBα phosphorylation. Moreover, si-RhoA also suppressed the expression of pro-inflammatory cytokines, ROCK, and vimentin and the phosphorylation of p65 and IκBα. In conclusion, thymol inhibits AGE-induced cell injury in HPCs by suppressing the RhoA-NF-κB pathway and may be apromising therapeutic agent.

Clinical Evaluation of the Tolerability and Pharmacokinetics of Azilsartan, a Potent Angiotensin Receptor Blocker, in Healthy Chinese Subjects.

Azilsartan (AZL), the active metabolite of azilsartan medoxomil, is the newest angiotensin receptor blocker that has been approved for the treatment of hypertension in 2012 in Japan. The present study aimed to evaluate the safety and pharmacokinetic properties of AZL in healthy Chinese subjects. We performed 2 phase 1 studies to investigate the pharmacokinetics and safety of AZL in healthy Chinese adults after a single dose (20 mg or 40 mg) or multiple doses of AZL (40 mg/d for 7 days; Study I) and after a single 40-mg dose under the fasted and fed conditions (Study II). Noncompartmental analysis and nonlinear mixed-effects modeling were used to analyze the pharmacokinetic properties of AZL. Twenty-seven healthy volunteers (14 men and 13 women) aged 20-32 years were enrolled and completed the study. During single dosing of AZL, the pharmacokinetics of AZL exhibited a linear profile between dosage and area under the concentration-time curve. There is no AZL accumulation after multiple doses. Food had no effect on the pharmacokinetic characteristics of AZL. AZL concentrations were best fit with a 2-compartment model, and the typical value of clearance was 1.63 L/h. Body weight had an impact on both the apparent clearance and peripheral volume of distribution. The pharmacokinetic parameters were consistent with previous studies in non-Chinese subjects. Model-based simulations indicated that a 45-kg subject would have approximately double the AZL exposure of a 90-kg subject. Whether the exposure difference has clinical significance needs to be confirmed in further studies among patients.

Pharmacokinetic Profile of a Generic Formulation of Sofosbuvir and Its Metabolite GS-331007 in Healthy Chinese Subjects.

Sofosbuvir is an NS5B nucleotide inhibitor for the treatment of hepatitis C viral infection. In this study the pharmacokinetics (PK) and safety of single and multiple doses of generic sofosbuvir were investigated in healthy Chinese subjects. Twelve subjects (6 male and 6 female) were enrolled in this study. The PK parameters of sofosbuvir and its metabolite (GS-331007) in both blood and urine samples were analyzed after dosing by the established liquid chromatography tandem mass spectrometry analytical method. The safety/tolerability assessment consisted of documenting adverse events, vital signs, electrocardiogram, and laboratory test results. Sofosbuvir was well tolerated. Major PK parameters of the generic formulation of sofosbuvir were similar to those found in previous reports. These data support further clinical evaluation of this generic formulation of sofosbuvir.

Development of a Stable Liquid Formulation for Live Attenuated Influenza Vaccine.

Live attenuated influenza vaccine (LAIV) is considered one of the most effective vaccines and can be manufactured quickly and inexpensively to counter seasonal or pandemic influenza. Lyophilization is widely used in vaccine production. However, it requires a longer production cycle and large-scale equipment, thus posing a considerable financial burden for developing countries. A potential solution is the development of liquid LAIV, which can increase the yield and reduce the cost of production. In this study, influential factors of LAIV, such as potential stabilizing excipients and pH, were optimized by an orthogonal design. We found that pH is the most critical factor for the stability of LAIV; salt concentration and initial virus titer are also important for LAIV stability. With these data, we developed a liquid formulation consisting of 2.5% sucrose, 0.1% monosodium glutamate, 1% arginine, and 0.5% human serum albumin, with pH ranging from 6.2 to 6.9 (optimum pH 6.5-6.7), for optimal production of monovalent or trivalent LAIVs. This liquid formulation has the potential to considerably improve vaccine production capacity to compensate for the immense shortfall in influenza vaccines globally.

Evaluation of reference-scaled average bioequivalence of two oral formulations of abiraterone acetate in healthy Chinese subjects
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OBJECTIVE: This study was designed to evaluate the pharmacokinetic (PK) properties and bioequivalence (BE) of two 250-mg tablet formulations of abiraterone acetate: a newly developed generic formulation (test) and a branded formulation (reference) in healthy adult Chinese subjects under fasted (n = 40) and fed (n = 40) conditions. MATERIALS AND METHODS: The comparison was performed using a single-dose, open, randomized, and four-way replicate study. The concentration of abiraterone in blood samples taken over 48 hours was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). To assess the BE of the test and reference formulations, confidence intervals (CI, 90%) for the peak plasma concentration (Cmax) and area under the concentration-time curves (AUC0-t and AUC0-∞) were calculated using the reference-scaled average bioequivalence (RSABE) method. RESULTS: The results showed that the 90% CIs for the ratios of Cmax, AUC0-t, and AUC0-∞ in the fasted study were 90.14 - 114.11, 93.96 - 115.07, and 93.72 - 113.331, respectively. For the fed study, the 90% CIs were 81.83 - 102.51, 91.51 - 104.89, and 91.46 - 104.58, respectively. CONCLUSION: In conclusion, the tested 250-mg abiraterone tablets were bioequivalent to 250-mg Zytiga tablets (reference) under both fasted and fed conditions. In addition, food intake increased the systemic exposure and Cmax of abiraterone by 3-fold and 7-fold, respectively.
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Association of Variability and Pharmacogenomics With Bioequivalence of Gefitinib in Healthy Male Subjects.

Objective: The aim of the study was to explore the association of pharmacokinetic variability and pharmacogenomics with the bioequivalence of orally administered gefitinib (Iressa®, AstraZeneca) provided by three sponsors in healthy subjects. Methods: The study designs were randomized, open-label, and two-period crossover studies in both fasting and fed healthy subjects. In one fasting study, the sample size was enlarged from 30 to 60 for the failing study. Each study subject received a 250-mg gefitinib tablet with a 21-day washout. The plasma concentrations were measured using LC-MS/MS, and pharmacokinetic parameters were determined by noncompartmental methods. Genetic analyses of CYP3A4, CYP3A5, and CYP2D6 alleles were carried out by the polymerase chain reaction (PCR). Results: Two hundred and sixty healthy male subjects were enrolled. The median maximum plasma concentration (Tmax) was 4-5 h, and the mean elimination half-life (t1/2) was 18-26 h. The maximum plasma concentration (Cmax) and area under the curve (AUC) increased but Tmax and t1/2 were unaffected by the intake of high-fat food. Three fed and two fasting studies achieved a plausible bioequivalence. The intake of high-fat food decreased the intra-subject variability significantly. In addition, CYP2D6 was associated with gefitinib exposure and may contribute to the high inter-subject variability, but it did not influence the bioequivalence result. Conclusions: Gefitinib is well tolerated, and the bioequivalence is easier to achieve under fed conditions compared to fasting conditions. The 90% confidence interval (CI) of geometric mean ratio (GMR) can be narrowed when the sample size is enlarged without changing the formulation-related technology.

Correlation between Soluble α-Klotho and Renal Function in Patients with Chronic Kidney Disease: A Review and Meta-Analysis.

OBJECTIVE: Over decades, numerous inconsistent studies are reported on the relationship between soluble α-Klotho and renal function in patients with chronic kidney disease (CKD). This study aims to perform a meta-analysis to figure out the correlations between soluble α-Klotho and renal function in patients with CKD. MATERIALS AND METHODS: We searched medical and scientific literature databases, PubMed and EMBASE (from the inception to October 2017), for publications that reported studies on associations between soluble α-Klotho and renal function in patients with CKD. Only publications in English were extracted. Summary correlation coefficient (r) values were extracted from each study, and 95% confidence intervals (CIs) were calculated. Publication bias was tested, and sensitivity and subgroup analyses were performed to investigate potential heterogeneity. RESULTS: Of 611 studies, 9 publications with 1457 patients were included into the analysis. The following data were extracted from the literature: first author, year of publication, research region, research index, sample size, average age and Pearson or Spearman correlation coefficient, study design, the αKlotho/FGF23 assays utilized, full length, or the C-terminal fragment of FGF23. The pooled r between α-Klotho and estimated glomerular filtration rate (eGFR), FGF-23 were 0.35 (95%CI, 0.23~0.46, and P<0.05), -0.10 (95%CI, -0.19~-0.01, and P<0.05) with remarkable significance, indicating moderate heterogeneity. There was no significant heterogeneity between subgroups in analyses of α-Klotho and eGFR stratified by research region, mean age, and eGFR, but heterogeneity exists in analyses of α-Klotho and FGF-23 stratified by research region. There was no significant correlation between a-klotho and Ca and PTH and PHOS. There was no evidence of publication bias with Egger's test (p=0.360) or with Begg's test (p=0.902) and the distribution of funnel plots was symmetrical in all of our analysis. CONCLUSIONS: There exists a significant positive correlation between soluble α-Klotho and eGFR in patients with CKD. Also, a significant negative correlation between α-Klotho and FGF23 levels is proven. This raises hope to employ αKlotho and FGF23 as early biomarkers of CKD. However, further large prospective follow-up researches are needed to validate this hypothesis and to explore whether maintaining or elevating the Klotho level could improve renal function and complications in CKD patients.

Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers.

Background: Vicagrel is a novel anti-platelet drug and hydrolyzed to the same intermediate as clopidogrel via esterase, instead of CYP2C19. Here we report the first clinical trial on the tolerability, pharmacokinetics and pharmacodynamics of different doses of vicagrel, and comparison with clopidogrel in healthy Chinese volunteers. Methods: This study was conducted in two parts. Study I was a dose-escalating (5-15 mg) study. For each dose, 15 participants were randomized into three groups (total n = 45); nine participants were given vicagrel, three were given clopidogrel, and three were given a placebo. Study II was conducted to assess interactions between vicagrel and aspirin in 15 healthy participants. The plasma concentrations of the metabolites of vicagrel and clopidogrel were determined using a LC-MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y12 assay. Results: Vicagrel (5-15 mg per day) dosing for 10 days or addition of aspirin was well tolerated in healthy volunteers. The exposure of the active metabolite increased proportionally across the dose range and was higher (~10-fold) than clopidogrel. The levels of IPA dosing 75 mg clopidogrel were between the responses of 5 mg and 10 mg vicagrel. After a single loading dose of vicagrel (30 mg) and a once-daily maintenance dose (7.5 mg) for 8 days, the maximum inhibition of platelet aggregation was similar to that seen with the combined use of vicagrel and aspirin (100 mg/day). Conclusion: Oral vicagrel demonstrated a favorable safety profile and excellent anti-platelet activity, which could be a promising P2Y12 antagonist as anti-platelet drug and can be further developed in phase II/III studies, and marketing for the unmet medical needs of cardiovascular diseases. The study was registered at http://www.chictr.org.cn (ChiCTR-IIR-16009260).