Pharmacokinetics and Pharmacodynamics of a Proposed Pegfilgrastim Biosimilar MSB11455 Versus the Reference Pegfilgrastim Neulasta in Healthy Subjects: A Randomized,Double-blind Trial

PurposeMSB11455 is a proposed biosimilar to the reference pegfilgrastim (Neulasta®). This pivotal equivalence study (NCT03251248) assessed the pharmacokinetic and pharmacodynamic equivalence of MSB11455 to the reference product.MethodsThis 2-way, 2-sequence, group-sequential, crossover study was conducted in healthy subjects. Subjects received a single subcutaneous dose of MSB11455 or the reference product (both 6 mg/0.6 mL) on Day 1 of each study period. Pharmacokinetic and pharmacodynamic (absolute neutrophil count; ANC) samples were taken predose and up to day 16 post-dose. Non-compartmental parameters were calculated. Immunogenicity samples were taken pre-dose and up to day 84 after the first dose. Safety was assessed throughout the study.FindingsA total of 292 subjects were randomized to therapy and treated; 244 received both treatments. For all primary pharmacokinetic and pharmacodynamic parameters, 90% repeated confidence intervals of geometric means ratio of MSB11455 to the reference product were within the pre-defined equivalence range (80.00%–125.00%) for AUC_0-∞ (96.59–112.82); AUC_0–last (97.29–113.96), C_max (97.13–114.99), maximum observed effect on ANC (98.74–102.39), and area under the effect–time curve from time zero to time to last quantifiable concentration (97.30–100.23). Safety, tolerability, and immunogenicity were comparable between treatments. No filgrastim-specific neutralizing antibodies were detected with either treatment sequence.ImplicationsPharmacokinetic and pharmacodynamic equivalence of MSB11455 and the reference product was shown, with comparable immunogenicity, safety, and tolerability between treatments. The study supports the biosimilarity of MSB11455 to the reference product. ClinicalTrials.gov identifier: NCT03251248.     

Solution‐driven approaches to generic substitution challenges – a survey among international experts

The main objective of this study was to explore the perception and understanding of economic, legal, and social barriers that may restrain generic uptake among recognized international experts in health care, and to identify and verify recommendations on how to streamline generic substitution (GS) at no expense of therapeutic safety. A questionnaire survey was devised, and experts with world‐renowned expertise in the field of generic medicinal products were selected. Almost 3/4 of respondents claimed that all drugs that satisfy bioequivalence criteria represent similar efficacy and adverse effects, and 1/4 of respondents believed that some differences could be reported. The majority of experts supported (i) the right of patients to refuse GS, (ii) the right of physicians to veto GS, and (iii) the introduction of a statutory obligation to provide patients with access to the cheapest generics available on the market. The main obstacles to more general uptake of generics were as follows: (i) perception of generics as lower quality products, (ii) absence of a transparent policy governing GS, and (iii) disincentives to pharmacists and physicians. Among the most popular recommendations were as follows: (i) introduction of various measures to aid physicians in generic prescribing, (ii) setting clear guidelines specifying when GS is not advisable, (iii) supporting competition on the generic market. The views of experts and the resulting recommendations were strongly affected by their opinion on the bioequivalence of generics. From this analysis, we have selected several principal recommendations which could help shape successful healthcare policies regarding GS.     

市场导向下的药企间仿制药一致性评价横向合作的现状分析及对策

中国仿制药占上市化学药品的绝大部分,由于仿制药的质量参差不齐,直接影响到人民群众用药的安全性和有效性。现阶段,我国提出要全面提高仿制药质量,将仿制药分期分批与被仿制药进行质量一致性评价,对于整个医药行业是一次重要的战略机遇。在市场导向下,以企业作为主体通过横向合作的方式,引导企业参与生物等效性(BE)研究平台的建设,通过企业联合建立仿制药一致性评价的参比制剂及研究信息共享机制;同时通过政府引导资源配置,适度倾斜照顾中西部地区企业,解决中西部地区药企面临的实际问题,实现医药行业的区域均衡发展,使之成为促进医药行业的供给侧结构改革的重要抓手。     

环孢素A软胶囊囊材的处方优化

以软胶囊内容物中乙醇和1,2-丙二醇含量和环孢素A溶出率为指标,采用正交设计优化软胶囊囊材处方,通过稳定性考察结果优化制备工艺.结果表明,在囊材处方中加入高级多元醇,并在环境相对湿度25％、采用缓慢干燥工艺使胶皮水分在40 h内控制在8％,所制备的软胶囊较稳定.与市售环孢素A软胶囊相比,本品内容物中乙醇的迁移量减少,环孢素A的体外溶出行为相似.药动学研究表明,自制软胶囊与市售软胶囊在Beagle犬体内生物等效.     

瑞巴派特分散片的人体药动学及生物等效性

建立了液相色谱-串联质谱法测定健康志愿者口服瑞巴派特分散片(受试制剂)和普通片(参比制剂,膜固思达(R))后的血药浓度,估算两制剂的药动学参数并评价生物等效性.采用随机、开放、双周期交叉试验设计,22名男性健康志愿者单剂量口服受试或参比制剂0.1g后,血样经乙腈直接沉淀蛋白后进行LC-MS/MS分析,利用DAS2.1.1软件计算药动学参数,并进行生物等效性评价.受试和参比制剂在人血浆中瑞巴派特的cmax为(236.9±103.4)和(233.9±105.1) ng/ml,tmax为(2.7±1.1)和(2.9±1.4)h,t1/2为(2.0±0.8)和(2.3±1.5)h,AUC0→12h为(929.0±291.9)和(970.5±353.2) ng·h·ml1.受试制剂的相对生物利用度为(102.6±29.8)％.     

左乙拉西坦缓释片在Beagle犬中的生物等效性研究

目的以Beagle犬为模型考察自制左乙拉西坦缓释片与参比缓释片(Keppra XR)在动物体内的生物等效性。方法 Beagle犬分别单剂量口服自制缓释片与参比制剂1 000mg,采用LC-MS/MS方法测定犬血浆中左乙拉西坦的浓度,通过药代动力学计算软件WinNonlin 5.2以非房室模型分别计算左乙拉西坦的药代动力学参数。结果自制缓释片与市售参比缓释片单剂量口服后,左乙拉西坦的达峰时间tmax分为1.67h和3.0h;峰浓度Cmax分别为89.50μg/ml和71.18μg/ml;消除半衰期t1/2分别为3.68h和3.50h;药时曲线下面积AUC(0-48)分别为826.57μg·h/ml和757.84μg·h/ml;药时曲线下面积AUC(0-∞)分别为826.68μg·h/ml和757.93μg·h/ml。与参比缓释片相比,自制左乙拉西坦缓释片的相对生物利用度为109.07%。结论初步判定两种制剂在犬体内具有类似的药代动力学特征和生物等效性。     

两种盐酸特拉唑嗪片的人体生物等效性研究

目的 评价单剂量口服国产和进口盐酸特拉唑嗪片的人体生物等效性。 方法 采用单中心、随机、开放、双周期交叉试验设计,21名受试者在不同周期分别空腹口服国产和进口盐酸特拉唑嗪片2 mg,于给药前0 h及给药后60 h内不同时间点采集静脉血4 ml,采用液-质联用(LC-MS/MS)法测定受试者血浆中特拉唑嗪的浓度。 结果 国产和进口盐酸特拉唑嗪片的t_1/2分别为(13.2±2.39)和(12.5±1.93) h;t_max分别为(1.01±0.83)和(1.08±0.69) h;C_max分别为(40.1±10.6)和(37.3±9.57) ng/ml;AUC_0-∞分别为(428±82.1)和(426±85.2) ng·h/ml。国产盐酸特拉唑嗪片的相对生物利用度为(101.2±14.7)%。国产与进口盐酸特拉唑嗪片AUC_0-t和C_max几何均值比的90%置信区间(CI)均落在80%~125%之间。 结论 国产和进口盐酸特拉唑嗪片具有生物等效性。     

Bioequivalence and Food Effect of Dapagliflozin/Saxagliptin/Metformin Extended-release Fixed-combination Drug Products Compared With Coadministration of the Individual Components in Healthy Subjects

PurposeFixed-combination drug products (FCDPs) for patients with type 2 diabetes mellitus (T2DM) may show efficacy comparable to their individual components (ICs) while improving adherence to treatment. This study evaluated the bioequivalence and safety of 2 dapagliflozin/saxagliptin/metformin extended-release (XR) FCDPs relative to their ICs: saxagliptin and dapagliflozin/metformin XR.MethodsThis randomized, open-label, single-dose, single-center crossover study was conducted in 84 healthy subjects aged 18–55 years. The primary objective was to evaluate the fed-state bioequivalence of a dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP and a dapagliflozin 10-mg/saxagliptin 5-mg/metformin 1000-mg XR FCDP relative to the ICs. Secondary objectives included the evaluation of the effect of food on the pharmacokinetic (PK) parameters of saxagliptin, dapagliflozin, and metformin in both FCDPs and characterization of the PK parameters of the active metabolite of saxagliptin, 5-hydroxy saxagliptin, in healthy subjects. PK parameters (AUC_0–∞, AUC_0–t, and C_max) were used to assess the bioequivalence of the 2 FCDPs with their ICs. The C_max and AUC_0–t of the study drugs were compared between female and male subjects to assess sex differences in exposure. Safety and tolerability of both FCDPs and ICs were also assessed with adverse events, vital signs (systolic and diastolic blood pressures and pulse rate), 12-lead ECG, physical examinations, and laboratory assessments.FindingsBoth dapagliflozin/saxagliptin/metformin XR FCDPs were bioequivalent to their ICs. For the dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP, the 90% CI for the geometric mean ratio of dapagliflozin C_max was slightly above the 80%–125% bioequivalence limit, which is unlikely to be clinically relevant. Food delayed the absorption of the study drugs in both FCDPs, which is unlikely to have a clinically relevant impact on efficacy. In both cohorts, exposure was higher in female subjects compared with male subjects, potentially due to the lower body weight of the female subjects. The safety profile and tolerability of the FCDPs were similar to those of their ICs, and no deaths or serious adverse events were reported.ImplicationsThese data support the use of the dapagliflozin/saxagliptin/metformin XR FCDP in patients with T2DM. ClinicalTrials.gov identifier: NCT03169959.     

丙泊酚脂肪乳注射液生物等效性研究实施和管理的专家共识

丙泊酚脂肪乳注射液是临床上广泛使用的静脉用麻醉药。近年来国内丙泊酚临床需求不断增加,丙泊酚生物等效性研究数量持续攀升,然而其设计、实施、管理尚缺乏共识和指南。本专家组共同研讨,达成此共识,旨在为国内开展丙泊酚生物等效性研究提供参考和指导。