Abstract Background Ainuovirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. The safety profile and pharmacokinetics of ainuovirine was characterized in healthy adults administered with single ascending dose.Table 1.Summary statistics of pharmacokinetic parameters of ainuovirine after single oral doses in healthy participants. Data are expressed in median ± standard deviation (min, max); AUC0–t, area under the plasma concentration-time curve from time zero to time of the last quantifiable concentration; AUC0–∞, AUC from time zero to infinity; AUC_%Extrap, percentage of extrapolated AUC; Cmax, maximum plasma concentration; C24h, concentrations at 24 hours postdose; CLz/F, apparent clearance; MRT0-t, mean retention time from time zero to time of the last quantifiable concentration; MRT0-∞, MRT from time zero to infinity; Vz/F, apparent volume of distribution; T1/2z, plasma terminal half-life; Tmax, time to maximum plasma concentration; λz, elimination rate constant. Methods A single-center, open-label, single-dose escalation study was conducted among healthy Chinese adults. Thirty participants, aged from 18 to 45 years, were randomly allocated to each cohort given a single-dose ainuovirine 75, 150 or 300 mg (10 participants per cohort), respectively. Inhibitory quotient (IQ) was defined as the ratio of the clinical trough concentration (C24h) to the protein-binding adjusted 50% effective concentration (pa-EC50). Results Across all dosage groups, most adverse events were rated as mild in severity. Major reported adverse events were abnormal serum lipids and elevated liver transaminase. No rash was reported and only one participant experienced central nervous system events (150 mg dose group). Pharmacokinetic parameters are shown in Table 1 for single-dose ainuovirine. Ainuovirine was readily absorbed, with a median Tmax of approximately 3 hours. Ainuovirine exposure (Cmax and AUC) increased to a lesser extent than the dose proportionality. Median apparent terminal half-life (T1/2z) remained similar across three dose cohorts, slightly longer than 24 hours. The IQs for wild type (pa-EC50=4.78 ng/mL) were 16.8, 23.8, and 28.1 folds, respectively. Those were 2.0, 2.9, and 3.4 folds for K103N (pa-EC50=39.17 ng/mL), respectively, and 1.1, 1.5, and 1.8 folds for Y181C (pa-EC50=232.2 ng/mL), respectively. All the IQs were above 1 fold. Conclusion Ainuovirine was well tolerated and showed a dose-dependent,nonlinear pharmacokinetics. The pharmacikinetics supported once daily oral dosing regimen of ainuovirine, with candidate doses of 75 to 300 mg in subsequent dose-ranging, proof-of-concept study. Disclosures Juan Yang, M.S., Jiangsu Aidea Pharmaceutical Co., Ltd.: Honoraria Xinming Yun, PhD, Jiangsu Aidea Pharmaceutical Co., Ltd.: Honoraria Hong Qin, MD, PhD, Jiangsu Aidea Pharmaceutical Co., Ltd: Honoraria

OBJECTIVE:HSK7653 is a novel, ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, promising for type 2 diabetes mellitus with a dosing regimen of once every 2 weeks. This trial investigates the pharmacokinetics (PKs), pharmacodynamics (PDs),and safety of HSK7653 in outpatients with normal or impaired renal function.METHODS:This is a multicenter, open-label, nonrandomized, parallel-controlled phase I clinical study that investigates the pharmacokinetic profiles of HSK7653 after a single oral administration in 42 subjects with mild (n = 8), moderate (n = 10), severe renal impairment (n = 10), and end-stage renal disease (without dialysis, n = 5) compared with matched control subjects with normal renal function (n = 9). Safety was evaluated throughout the study, and the pharmacodynamic effects were assessed on the basis of a DPP-4 inhibition rate.RESULTS:HSK7653 exposure levels including the maximum plasma concentration (Cmax), area under the plasma concentration-time curve from zero to last time of quantifiable concentration (AUC0-t), and area under the plasma concentration-time curve from zero to infinity (AUC0-inf) showed no significant differences related to the severity of renal impairment. Renal clearance (CLR) showed a certain downtrend along with the severity of renal impairment. The CLR of the group with severe renal impairment and the group with end-stage renal disease were basically similar. The DPP-4 inhibition rate-time curve graph was similar among the renal function groups. All groups had favorable safety, and no serious adverse events occurred.CONCLUSIONS:HSK7653 is a potent oral DPP-4 inhibitor with a long plasma half-life, supporting a dosing regimen of once every 2 weeks. Impaired renal function does not appear to impact the pharmacokinetic and pharmacodynamic properties of HSK7653 after a single administration in Chinese subjects. HSK7653 is also well tolerated without an increase in adverse events with increasing renal impairment. These results indicate that dose adjustment of HSK7653 may not be required in patients with renal impairment.TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT05497297.

Background The combination of passive immune agents (human rabies immune globulin (HRIG) and equine rabies antiserum (ERA)) with vaccines are effective measures for preventing the onset of rabies post exposure. However, ERA and HRIG have potential risks of serum allergic reactions and blood-transmitted infectious diseases. This study compared the safety, pharmacokinetics and neutralizing activity of recombinant human anti-rabies monoclonal antibody NM57 injection (rhRIG, Ormutivimab) and HRIG in combination with rabies vaccine and vaccine alone. Method: This randomized, double-blind, parallel-controlled Phase Ib clinical study was conducted in healthy Chinese population to evaluate the safety, pharmacokinetics, and neutralizing activity of rhRIG at dosages of 20IU/kg and 40IU/kg in combination with vaccines, and to compare the neutralizing activity of rhRIG + vaccine with that of HRIG + vaccine and vaccine alone. 72 healthy participants divided into 6 groups of 12 individuals. Results The rhRIG at dosages of 20IU/kg and 40IU/kg in combination with vaccines showed favorable safety and presented the pharmacokinetic property of linear elimination. The antibody neutralizing activity of rhRIG has the same level as HRIG in combination with vaccines. The rhRIG did not affect the long-term protective effect of the vaccine. Conclusions The rhRIG could provide immediate immune protection at the wound site and producing earlier protection during the window period before the rabies vaccine established active immunity. Therefore, it is recommended to continue to evaluate the safety and antibody neutralizing activity of rhRIG(20 and 40IU/kg) in combination with the vaccine in Phase II clinical trials. Trials Registration ChiCTR1900023785(https://www.chictr.org.cn)

伦理审查是在开展涉及人的生命科学和医学研究时,对研究参与者的重要保护措施.2023 年 2月发布的《涉及人的生命科学和医学研究伦理审查办法》提出了"免除伦理审查".为了在法律法规许可的范围内推行免伦理审查,在利用研究参与者的数据信息和生物样本时,保护好研究参与者的隐私和权益,需要考虑多方面的因素:谁承担免除伦理审查的职责、免除伦理审查的条件,以及免伦理审查的具体流程.与所有审查程序一样,免除审查也需要制定相应的制度,落实责任,并依赖于受试者保护体系建设,希望通过讨论能为免除伦理审查的实施开展提供思考.

通过伦理审查,是涉及人的生命科学和医学研究开展的必要条件和前提条件.目前部分医疗卫生机构没有伦理审查能力或者审查能力不足.伦理审查能力的欠缺和不足,成为制约涉及人的生命科学和医学研究开展的瓶颈.《关于深化审评审批制度改革鼓励药品医疗器械创新的意见》《关于加强科技伦理治理的意见》等文件提出,机构可以书面委托有能力的机构伦理审查委员会或者区域伦理审查委员会开展伦理审查.委托审查为需要开展涉及人的生命科学和医学研究但是未设立伦理(审查)委员会或者伦理(审查)委员会无法胜任审查的机构,提供了可行的解决途径.开展委托审查需要委托人和受托人正式达成委托.《涉及人的生命科学和医学研究伦理审查办法》规定医疗卫生机构及其伦理审查委员会未接受正式委托为其他机构出具伦理审查意见的,将由县级以上地方卫生健康主管部门对有关机构和人员依法给予行政处罚和处分.签署委托审查合同,实施合法合规的委托审查,才能更有效地保护受托人和委托人的权益,保护研究参与者.

INTRODUCTION:Ropivacaine oil delivery depot (RODD) can slowly release ropivacaine and block nerves for a long timejavascript:;. The aim of the present work was to investigate the safety, pharmacokinetics, and preliminary pharmacodynamics of RODD in subcutaneous injection among healthy subjects.METHODS:The abdomens of 3 subjects were subcutaneously administered with a single-needle RODD containing 12~30 mg of ropivacaine. The irritation, nerve blocking range and optimum dose were investigated. Forty-one subjects were divided into RODD groups containing 150, 230, 300, 350 and 400 mg of ropivacaine and a ropivacaine hydrochloride injection (RHI) 150 mg group. Multineedle subcutaneous injection of RODD or RHI was performed in the abdomens of the subjects. The primary endpoint was a safe dose or a maximum dose of ropivacaine (400 mg). Subjects' vital signs were observed; their blood was analyzed; their cardiovascular system and nervous systems were monitored, and their dermatological reactions were observed and scored. Second, the ropivacaine concentrations in plasma were determined, pharmacokinetic parameters were calculated, and the anesthetic effects of RODD were studied, including RODD onset time, duration and intensity of nerve block.RESULTS:Single-needle injection of RODD 24 mg was optimal for 3 subjects, and the range of nerve block was 42.5±20.8 mm. Multineedle subcutaneous injection of RODD in the abdomens of subjects was safe, and all adverse events were no more severe than grade II. The incidence rate of grade II adverse events, such as pain, and abnormal ST and ST-T segment changes on electrocardiography, was approximately 1%. The incidence rate of grade I adverse events, including erythema, papules, hypertriglyceridemia, and hypotension was greater than 10%. Erythema and papules were relieved after 24 h and disappeared after 72 h. Other adverse reactions disappeared after 7 days. The curve of ropivacaine concentration-time in plasma presented a bimodal profile. The results showed that ropivacaine was slowly released from the RODD. Compared with the 150 mg RHI group, Tmax was longer in the RODD groups. In particular, Tmax in the 400 mg RODD group was longer than that in the RHI group (11.8±4.6 h vs. 0.77±0.06 h). The Cmax in the 150 mg RODD group was lower than that in the 150 mg RHI group (0.35±0.09 vs. 0.58±0.13 μg·mL-1). In particular, the Cmax increased by 48% when the dose was increased by 2.6 times in the 400 mg group. Cmax, the AUC value and the intensity of the nerve block increased with increasing doses of RODD. Among them, the 400 mg RODD group presented the strongest nerve block (the percentage of level 2 and 3, 42.9%). The corresponding median onset time was 0.42 h, and the duration median was 35.7⁓47.7 h.CONCLUSIONS:RODD has a sustained release effect. Compared with the RHI group, Tmax was delayed in the RODD groups, and the duration of nerve block was long. No abnormal reaction was found in the RODD group containing 400 mg of ropivacaine after subcutaneous injection among healthy subjects, suggesting that RODD was adequately safe.TRIAL REGISTRATION:Chictr.org: CTR2200058122; Chinadrugtrials.org: CTR20192280.

目的 比较不同热卡供给对脓毒性休克病人预后的影响,以期为脓毒性休克病人提供最佳热卡供给.方法 采用回顾性分析方法,选取山西医科大学第一临床医学院2019年8月至2021年8月符合纳入标准的100例脓毒性休克病人行营养支持治疗的临床资料,将病人按非蛋白热卡供给量分为A组、B组2组.A组喂养方式为渐进式喂养,入ICU第3天热卡达到目标热卡的70％,逐渐增加热卡到第7天达到目标热卡.B组喂养方式为等热卡喂养,入ICU第3天达到目标热卡,第3天到第7天目标热卡喂养.两组入院时一般资料相近,蛋白提供量相似.分别记录两组病人每日热卡供给量、蛋白供给量,第1天及第7天营养指标、肝肾功、血糖、胰岛素用量,记录住院期间机械通气时间、住院时间、住ICU时间、院内感染率、ICU病死率、28 d病死率等并进行比较.探讨热卡供给量与脓毒性休克病人预后的关系.结果 两组给予7 d营养支持后,A组的胰岛素用量少于B组[20.00(0.00,50.00)IU比50.00(0.00,70.00)IU],A组的机械通气时间比B组短[(7.69±6.80)d比(12.44±14.02)d],A组的住院时间比B组短[(18.92±12.33)d比(28.02±22.07)d],A组的ICU住院时间比B组短[(14.92±10.91)d比(22.22±16.76)d],A组的28 d病死率低于B组[6例(12.2％)比22例(43.1％)],A组的院内感染率低于B组[3例(6.1％)比10例(19.6％)],差异有统计学意义(P＜0.05).结论 脓毒性休克病人在提供充足蛋白质时,在急性期早期(1～3 d)给予低热卡喂养,急性期晚期(4～7 d)给予等热卡喂养,可以减少胰岛素需求,缩短机械通气时间、住院时间、住ICU时间,降低院内感染率、28 d病死率,改善预后.

目的:检测寻常性银屑病患者血清中白细胞介素(IL)-26的表达量,并分析其对疾病严重程度的影响.方法:选取2017年12月-2019年1月来山西医科大学第一附属医院就诊的寻常性银屑病患者84例作为观察组,其中进展期患者40例,静止期患者44例;选择同期在该院进行健康体检的志愿者40例作为对照组.采用流式细胞术检测2组患者外周血中辅助性T细胞(Th)17表达量,采用酶联免疫吸附法(ELISA)检测血清IL-26水平,并进一步分析二者与银屑病皮损面积及严重程度指数(PASI)评分的相关性.结果:观察组患者外周血中Th17细胞所占比例及血清IL-26的表达水平均显著高于对照组(P＜0.05);其中进展期患者外周血中Th17细胞所占比例及血清IL-26的表达量均显著高于静止期患者(P＜0.05).进展期患者PASI评分高于静止期患者,且差异有统计学意义(t=3.30,P＜0.05).观察组外周血中Th17细胞和血清IL-26表达量均与PASI评分呈正相关(P＜0.05),Th17细胞数目与IL-26表达量呈正相关(P＜0.05).多元线性回归分析提示Th17和IL-26是寻常性银屑病患者皮损PASI评分的影响因素(P＜0.05).结论:Th17及其分泌因子IL-26表达水平可在一定程度上反映寻常性银屑病的疾病严重程度.

In November 2018, the U.S. food and drug administration (FDA) issued guidance for the development of drugs for chronic hepatitis B virus infection (draft for comments) (hereinafter referred to as draft for comments), and in April 2022, the FDA issued Chronic Hepatitis B Virus Infection: Developing Drugs for Treatment, which has been updated with some details based on the Draft for Comments. This guidance further emphasizes the importance of HBsAg clearance in clinical trials, and classifies chronic suppressive therapy into two categories, namely noninferiority (NI) (or superiority) test with nucleos(t)ide analogues as control and add-on superiority trial with nucleos(t)ide analogues as control, and as for the latter, HBV DNA is no longer recommended as a primary endpoint of the trial, which poses a huge challenge to the development of innovative drugs targeting HBV DNA. The new finite duration therapy should aim to eliminate HBsAg and reduce virologic relapse and the risk of liver disease progression during treatment cessation. Reduction in HBsAg from baseline is not recommended as a primary endpoint for phase III clinical trials, since the correlation between such reduction and clinical response remains unclear. In addition, this guidance also specifies the duration of treatment cessation and treatment consolidation period and the criteria for withdrawal of nucleos(t)ide analogues.

•Albuvirtide (ABT) is a novel long-acting HIV fusion inhibitor.•ABT combined with LPV/r was non-inferior to LPV/r based three-drug regimen.•ABT combined with LPV/r showed a good safety profile.•ABT combined with LPV/r showed a trend of improvement in renal function.•ABT might be an interesting alternative option for HIV treatment and prevention.

Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33. Pharmacokinetic plasma samples were intensively collected on day 27 (n = 17) and sparsely collected before each injection until 56 weeks after final injection (n = 47). Cabotegravir LA injections were acceptable and well tolerated. Common adverse events included injection site pain, injection site swelling, and upper respiratory tract infection. No drug-related serious adverse events or deaths occurred. Mean cabotegravir concentration remained above 1.33 mu g/mL (8x in vitro protein-adjusted concentration for 90% of the maximum inhibition of viral growth [PA-IC90]) before each injection and above 0.166 mu g/mL (PA-IC90) for >32 weeks after final injection. Trough concentrations remained above PA-IC90 in nearly all participants and showed minimal accumulation. Noncompartmental pharmacokinetic analysis was performed. Geometric mean of terminal half-life was 1.89 and 47 days after oral and LA dosing, respectively. Cabotegravir concentrations were estimated to remain quantifiable for 48.7 weeks after final injection. Steady-state area under the concentration-time curve (AUC), peak concentration, trough concentration, terminal half-life, time to peak concentration, and apparent clearance after cabotegravir oral and LA dosing were similar to those estimated in non-Asian men in historical studies. These results support further clinical development of cabotegravir LA in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT03422172.) Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1.

Objective: To develop a population pharmacokinetic (PK) model for ropeginterferon alfa-2b and to compare its PK properties between Caucasian and Chinese populations. Methods: A population PK model was developed based on data from two phase I clinical trials conducted in Caucasian and Chinese individuals, to evaluate the influence of ethnicity on the PKs of ropeginterferon alfa-2b. Results: We included 456 observations from 30 healthy Caucasian subjects and 438 observations from 27 healthy Chinese subjects in the population PK analysis. The PKs of ropeginterferon alfa-2b were best described by a one-compartment quasi-equilibrium approximated target-mediated drug disposition model with first-order absorption and absorption lag times. The typical value (relative standard error%) of apparent clearance (CL/F) and volume of distribution of ropeginterferon alfa-2b in 70-kg subjects were 0.778 (12%) L/day and 2.32 (14%) L, respectively. Body weight was the only significant factor affecting the CL/F. There were no obvious differences in the PK properties of ropeginterferon alfa-2b, and predicted steady-state exposure was similar in the Chinese and Caucasian populations. Conclusion: No significant ethnic differences in ropeginterferon alfa-2b PKs were observed between the Chinese and Caucasian populations.

作为"临床试验中对受试者疼痛管理的伦理考虑"系列标准之一,主要论述《儿科人群临床试验中对受试者疼痛管理的伦理考虑》的起草背景、制定依据和适用范围,以及儿科人群临床试验中受试者疼痛等负担的来源和识别、在儿科人群临床试验方案设计和临床试验执行过程时使受试者疼痛最小化的措施,以期从伦理角度对儿科人群临床试验中受试者疼痛管理提出指导意见.其适用于伦理审查中对于儿科人群临床试验中受试者疼痛管理的伦理考虑,以及研究者制定临床试验方案和试验流程对儿科人群疼痛管理的关注.对临床试验中儿科人群疼痛予以更多关注,是保护儿科受试者权益的措施之一,有助于保障儿科临床试验顺利开展.

论述《临床试验中对受试者疼痛管理的伦理考虑》的起草背景、制定依据和适用范围,以及临床试验中疼痛的主要来源,临床试验中对受试者疼痛管理的伦理一般考虑和临床试验中试验操作程序引起的受试者疼痛等负担的伦理考虑等,以期从伦理角度对临床试验中受试者疼痛管理提出指导意见.适用于伦理审查中对于受试者疼痛管理的伦理考虑,以及研究者制定临床试验方案和试验流程对受试者疼痛管理的关注.对临床试验中受试者疼痛予以更多关注,是保护受试者权益的措施之一,有助于保障临床试验顺利开展.

Ropeginterferon alfa-2b is a novel mono-pegylated human recombinant interferon (IFN) with the addition of N-terminal proline covalently attached by a 40-kDa polyethylene (peg) moiety. The present study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) profiles and safety of the product in healthy Chinese. Forty subjects were enrolled and treated with a single subcutaneous injection of either 180 mcg peg-IFN alfa-2a or 90, 180, and 270 mcg ropeginterferon alfa-2b. The mean Tmax of ropeginterferon alfa-2b was 92–141 h and the elimination half-life was 78–129 h. Dose-related, non-proportional increase in ropeginterferon alfa-2b exposure was observed, which was higher than for peg-IFN alfa-2a. The PD parameters were similar between each dose level of ropeginterferon alfa-2b. The mean Tmax of β2-microglobulin ranged from 118 to 132 h after a single dose of ropeginterferon alfa-2b. The average Emax was 3 mcg/ml in all dose levels and the mean AUEC0–t ranged from 1608 to 1775 h/mcg/ml. The TEAEs were comparable among each treatment group and no death nor drug-related SAE was reported. Ropeginterferon alfa-2b is safe and well tolerated after a single subcutaneous injection up to 270 mcg in healthy Chinese. www.chinadrugtrials.org.cn , CTR20190451.

伦理审查是开展涉及人的生物医学研究的前提条件.研究项目生命周期中,会经历初始审查、复审审查、定期/年度进展报告审查、方案违背审查、结题审查等伦理审查.形式审查是伦理审查申请的初步环节.从形式审查的角度,描述了伦理审查资料递交存在的常见问题,如递交文件不齐全、文件名称不一致、递交不及时、盖章/签字不符合要求等,分析可能的原因,并提出了相应的解决对策,从而减少或避免类似的问题发生,进一步推进项目的 伦理审查效率和项目实施进度.

Abstract The aim of this study was to evaluate the tolerability, safety, and pharmacokinetics of single and continuous dose administration of recombinant neorudin (EPR‐hirudin, EH) by intravenous administration in healthy subjects, and to provide a safe dosage range for phase II clinical research. Forty‐four subjects received EH as a single dose of between 0.2 and 2.0 mg/kg by intravenous bolus and drip infusion. In addition, 18 healthy subjects were randomly divided into three dose groups (0.15, 0.30, and 0.45 mg/kg/h) with 6 subjects in each group for the continuous administration trial. Single or continuous doses of neorudin were generally well tolerated by healthy adult subjects. There were no serious adverse events (SAEs), and all adverse events (AEs) were mild to moderate. Moreover, no subjects withdrew from the trial because of AEs. There were no clinically relevant changes in physical examination results, clinical chemistry, urinalysis, or vital signs. The incidence of adverse events was not significantly related to drug dose or systemic exposure. After single‐dose and continuous administration, the serum EH concentration reached its peak at 5 min, and the exposure increased with the increase in the administered dose. The mean half‐life (T1/2), clearance (Cl), and apparent volume of distribution (Vd) of EH ranged from 1.7 to 2.5 h, 123.9 to 179.7 ml/h/kg, and 402.7 to 615.2 ml/kg, respectively. The demonstrated safety, tolerability, and pharmacokinetic characteristics of EH can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies. Clinical trial registration: Chinadrugtrials.org identifier: CTR20160444.