Table of Content

Volume 25 Issue 1
26 January 2020

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Applications of model-informed drug development (MIDD) on new drug research and development

LI Jian, YANG Jinbo, WANG Yuzhu

2020, 25(1):  1-8.  doi:10.12092/j.issn.1009-2501.2020.01.001

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Model-informed drug development (MIDD) refers to the application of various mathematical models in drug development, in order to facilitate the decision-making process. There have been common and mature applications of MIDD to address drug development and regulatory questions in interactional industries and advanced regulatory agencies, especially the US FDA. However, its application in innovative drug development is relatively rare in China. Representative case studies, clinical pharmacology review ex-periences, and relevant guidelines are reviewed in this article to present a preliminary discussion on the main applications of MIDD. Additionally, several suggestions for the application of MIDD in new drug development as well as general considerations for new drug registration are proposed in this paper, for the discussion or reference of industries and researchers.

Personalizing pertuzumab and trastuzumab dosing regimens for adjuvant treatment of HER2-positive breast cancer

MA Peiming, FU Yu, Marcus VETTER

2020, 25(1):  9-21.  doi:10.12092/j.issn.1009-2501.2020.01.003

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AIM: To design and implement personalized dosing regimens of trastuzumab and pertuzumab for an Asian patient with early breast cancer. METHODS: Trastuzumab and pertuzumab are important therapeutics for patients with HER2-positive breast cancer. Despite the similar pharmacokinetics (PK), their recommended dosing regimens differ: pertuzumab dosing is fixed whereas trastuzumab dosing depends on body weight; the dosing frequency is once every three weeks for pertuzumab but includes both once every week (QW) and once every three weeks (Q3W) for trastuzumab. A practicing physician has limited choices for dosing regimens when using the drugs in combination with chemotherapies. Besides convenience in drug administration, efficacy and safety as responses to the drug must be examined as part of studying dose-exposure-response relationship, which is the basis for deciding a dosing regimen. To understand the dose-exposure-response relationship of an individual patient, we reviewed literature on population PK analyses. The associated PK-covariate relationships including influential covariates such as disease status and demographics (e.g., body weight) that informed the patients underlying dose-exposure-response relationships. Safety and efficacy factors essential for choosing appropriate dosing regimens were also considered — minimal target concentrations, higher adverse event rates in Asian patients, as well as administration convenience. RESULTS:Based on a thorough review of population PK and PK-covariate relationships of pertuzumab and trastuzumab, an individualized dosing regimen of once every two weeks (Q2W) was selected as the treatment option and implemented for this patient. CONCLUSION: The design of an individualized dosing regimen requires the knowledge of individualized dose-exposure-response relationships, and population analysis is an ideal tool for understanding the individualized dose-exposure-response relationships.

Application of biomarkers in clinical development of biologics and bioanalytical strategies

CHE Jinjing

2020, 25(1):  22-31.  doi:10.12092/j.issn.1009-2501.2020.01.004

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China's biologic drug research and development is on a fast track lane. The rising cost of new drug development has not improved the success rate of drug launch, and a shift in the model of drug development is urgently needed. In order to improve the success rate, a biomarker strategy of the new drug development model has been proposed and is generally accepted. This paper reviews the research and development of new translational medicine drugs with biomarkers as the core, the application of biomarkers in the clinical study of biological drugs, biomarker biological analysis strategies, and the opportunities and challenges of biomarkers in the clinical study of biological drugs. By comparing international standards, seeking China's advantages and seeking opportunities from the research and development model of translational medicine based on biomarkers, China can make innovative drugs with global influence in the near term.

Development of therapeutic biologics in cancer treatment

ZHANG Kaiting, CHEN Naihan

2020, 25(1):  32-43.  doi:10.12092/j.issn.1009-2501.2020.01.005

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Cancer treatment is always the focus of pharmaceutical development while therapeutic biologics play an important role alongside. This review is focused on the development of therapeutic biologics in cancer treatment and categorized by targeted therapy and immunotherapy by mechanism. In targeted therapy, monoclonal antibodies, biosimilars and antibody-drug conjugates are discussed in details, while for immunotherapy, checkpoint inhibitors, T-cell transfer therapy and bispecific antibody are introduced, respectively.

Risk management of biological agents in phase I clinical trials: Case sharing

YANG Haijing, YU Jicheng, WANG Jingjing, LI Nanyang, WU Jufang, ZHANG Hai, XUE Tao, DAI Weiguo, DING Tianling, CAO Guoying

2020, 25(1):  44-48.  doi:10.12092/j.issn.1009-2501.2020.01.006

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To point out the importance of risk management for biological agents in phase I clinical trials, taking a healthy subject for an example who suffered from agranulocytosis after the application of Tozumab. In order to ensure the safety of the subjects and smooth progress of clinical trials, risk management should be implemented in several aspects such as: informing, screening, administration, subject training, and adverse event management and so on.

Agkistrodon halys venom platelet inhibitor inhibits GPVI expression and changes hemorheology in rats with acute myocardial ischemia reperfusion injury

WU Juan, ZHANG He, FENG Guilin

2020, 25(1):  49-54.  doi:10.12092/j.issn.1009-2501.2020.01.007

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AIM:To explore effect and meaning of Agkistrodon halys venom platelet inhibitor on GPVI expression and hemorheology in rats with acute myocardial ischemia reperfusion injury. METHODS:Thirty matched SD male rats were randomly divided into sham operation group (6 rats), myocardial ischemia-reperfusion injury(MIRI) model group(6 rats) and agkistrodon halys venom platelet inhibitor (AHV-PI) group(18 rats). The AHV-PI experimental group was divided into low, middle and high dose groups according to the dose of AHV-PI injected into sublingual vein (0.05, 0.1, 0.2 mg/kg), with 6 rats in each group. Electrocardiogram(ECG) changes of rats were monitored by RM6240 biological signal collection and processing system. Western blot was used to monitor the expression of platelet membrane glycoprotein VI (GPVI) in rats under the intervention of AHV-PI. Blood coagulation time (R), blood clots forming time (K), Alpha Angle (A), and maximum amplitude of blood coagulation (MA) were assayed by Thrombelastography (TEG5000).Platelet aggregation rate was measured by turbidimetry. RESULTS:Compared with MIRI model group, the expression level of GPVI AHV-PI medium dose experimental group and high dose experimental group were significantly decreased (P＜0.05), and the R and K values were significantly prolonged, while the A value and MA values were significantly decreased (P＜0.05). Platelet aggregation time, aggregation amplitude and aggregation rate were significantly decreased (P＜0.05). CONCLUSION: AHV-PI can significantly inhibit the expression of GPVI in MIRI rats and improve the hemorheological properties related to myocardial injury in rats, thus weakening the injury process.

Silencing carbonic anhydrase 1 inhibits the proliferation, invasion and migration of A549 cells in lung cancer

ZHANG Kang, HE Binjun, HU Wenbin, HAN Xiaoliang

2020, 25(1):  55-60.  doi:10.12092/j.issn.1009-2501.2020.01.008

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AIM: To investigate the effects of silencing carbonic anhydrase 1 (CA1) on proliferation, apoptosis, invasion and migration of human lung cancer A549 cells. METHODS: CA1-specific siRNA (si-CA1 group) and negative control (si-NC group) were transfected into lung cancer A549 cells by lipofection. The A549 cells transfected with empty liposome were used as blank control group. Real-time quantitative PCR (qPCR) and Western blot (Western blot) were used to detect the expression of CA1 mRNA and protein. Cell counting kit method (CCK-8), flow cytometry and Transwell assay were used to detect proliferation and apoptosis of A549 cells, invasion and migration capabilities. RESULTS:qPCR and Western blot showed that the expression levels of CA1 mRNA and protein in A549 cells transfected with CA1 siRNA were significantly down-regulated (P<0.05). The results of CCK-8 assay showed that silencing of CA1 in Si-CA1 group was observed. The OD values at 24, 48 and 72 h were significantly lower than those in the si-NC group (P<0.05). The results of flow cytometry showed that the apoptosis rate of A549 cells in si-CA1 group was significantly higher than that in si-NC group (P<0.05). Transwell results showed that the number of invading and migrating cells in the si-CA1 group was significantly lower than that in the si-NC group (P<0.05). Compared with the Blank group, the differences of the above indicators in the si-NC group were not significant (P>0.05). CONCLUSION: Silencing CA1 can inhibit the proliferation, invasion and migration of lung cancer A549 cells and promote cell apoptosis.

Mechanism of turmeric in treating asthma based on network pharmacology

ZHANG Lei

2020, 25(1):  61-67.  doi:10.12092/j.issn.1009-2501.2020.01.009

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AIM: To predict and screen the active components and potential targets of turmeric in the treatment of asthma by network pharmacology technology. METHODS: Active components and target sites of turmeric were predicted and screened through BATMAN-TCM, and Cytoscape3.7.0 software was used to construct the component and target network of turmeric for asthma treatment, PPI network was constructed with STRING database, and GO enrichment and KEGG signal pathway of target sites were analyzed with KOBAS database. RESULTS:A total of 29 turmeric active ingredient were obtained, 15 targets involving asthma were screened, mainly related to ADRB2, ADORA1, ADORA2B targets, including 13 targets has interaction relations; with P<0.05 as filter, 1 769 GO biological processes were obtained; its function involved the metabolic process of compounds containing phosphate and phosphorus metabolism and cAMP metabolic process, etc. Fifty-four signaling pathways were screened, among which the first 10 KEGG pathways were cAMP signaling pathway and Fc epsilon RI signaling pathway. CONCLUSION:The mechanism of action of turmeric in treating asthma through multi-component, multi-target and multi-pathway pathways such as cAMP signaling pathway and Fc epsilon RI is revealed, which provides theoretical support for the development and elucidation of targeted drugs.

Bioequivalence of olmesartan medoxomil tablets in Chinese healthy subjects in fasting state

XU Meiyan, WU Wei, LI Cui

2020, 25(1):  68-74.  doi:10.12092/j.issn.1009-2501.2020.01.010

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AIM: To investigate the bioequivalence of domestic olmesartan medoxomil tablets and imported olmesartan medoxomil tablets (Benicar) in Chinese healthy subjects in fasting state. METHODS: This is an open, random and two-way crossover clinical trial involved 24 healthy subjects. A single oral dose 20 mg of domestic olmesartan medoxomil tablets (test preparation) and imported olmesartan medoxomil tablets (control preparation) was administrated under the condition of fasting. The plasma concentrations of olmesartan were determined by LC-MS/MS. The pharmacokinetics parameters were calculated and the bioequivalence of two formulations were evaluated by WinNonlin7.0 program. RESULTS:The main pharmacokinetic parameters of the test and control preparation were as follows: Cmax (702.08±149.24) vs.(706.50±127.00) μg/L; tmax 1.98 (1.33-4.00) vs. 1.98 (1.33-3.50) h; AUC0-t (4 516.93±995.07) vs. (4 543.74±818.45) μg·h·L-1; AUC0-∞ (4 578.16±1 005.73) vs. (4 605.70±820.54) μg·h·L-1;t1/2 (8.00±1.07) vs. (7.94±1.30) h, respectively. The 90% confidence limit of test preparation of the logarithmic transformed parameters Cmax, AUC0-t and AUC0-∞ were in 92.33%-105.29%, 91.86%-105.26%, 91.89%-105.16% vs. the reference preparation, respectively.CONCLUSION: The developed and validated method is rapid, sensitive, selective and reliable for the determination of olmesartan in human plasma; the domestic olmesartan medoxomil tablets are bioequivalence to the imported olmesartan medoxomil tablets.

Optimal dosage of dexmedetomidine on prevention of agitation induced by sevoflurane anesthesia in children

PENG Wenyong, TU Wenlong, LIAO Junfeng, LAN Zhijian

2020, 25(1):  75-80.  doi:10.12092/j.issn.1009-2501.2020.01.011

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AIM: To explore the optimal dosage of dexmedetomidine for prevention of agitation induced by sevoflurane anesthesia in children. METHODS: One hundred and sixty ASA Ⅰ-Ⅱ pediatric patients, who underwent indirect inguinal hernia or hydrocele were randomly divided into 4 groups: C group (saline group), D0.2 group (dexmedetomidine 0.2 μg/kg), Group D0.4 (dexmedetomidine 0.4 μg/kg); D0.6 group (dexmedetomidine 0.6 μg/kg), 40 cases in each group. The dexmedetomidine was treated with intravenous infusion of the same volume of saline at 10 min before the induction of anesthesia. Observation with induction period and intraoperative hemodynamic situation, postoperative FLACC behavior score, Ramsay sedation scores, extubation time, adverse reactions, such as respiration depression (SpO2<92%), postoperative nausea and vomiting, postoperative agitation were carried out. RESULTS:The intraoperative hemodynamics of D0.4 and D0.6 groups were more stable than the groups of C and D0.2 (P<0.05). The FLACC scores of groups D0.4 and D0.6 were lower than the groups C at the time of T5, T6. The FLACC scores of group D0.6 was lower than the groups C at the time of T7 (P<0.05). The FLACC scores of groups D0.4 and D0.6 were lower than the groups D0.2 at the time of T5, T6 also (P<0.05). The Ramsay sedation score of groups D0.4 and D0.6 were higher than the group C at the time of T5, T6, T7 (P<0.05). The Ramsay sedation score of groups D0.4 and D0.6 were higher than the group D0.2 at the time of T5, T6, and the Ramsay sedation score of group D0.6 was higher than the group D0.2 at the time of T7 also (P<0.05). There was no statistically significant difference in postoperative hypoxic incidence (SpO2<92%) in the four groups (P>0.05). The case of postoperative agitation in the group D0.4 (12 cases), D0.6 (8 cases) lower than the group C (23 cases) and D0.2 (16 cases) (P<0.05). The awakening time of group D0.6 was longer than the group of C (P<0.05). The rate of other adverse reaction were no statistically significant difference in the four groups (P>0.05).CONCLUSION:The usage of 0.4 μg/kg dexmedetomidine for the pediatric inguinal hernia or hydrocele surgery under the anesthesia of sevoflurane has the characteristics of stable hemodynamics during the operation, reducing the incidence of restlessness after sevoflurane anesthesia, not affecting the recovery of children, and not increasing adverse reactions.

N-acetylcysteine combined with pulmonary surfactant alleviates neonatal severe fetus seizure syndrome through regulating fetal inflammatory factors and oxygenation

JIANG Li, LI Yuning, PANG Lihong, ZHANG Xingdao, WANG Fang

2020, 25(1):  81-86.  doi:10.12092/j.issn.1009-2501.2020.01.012

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AIM: To analyze the effects of N-acetylcysteine (NAC) combined with alveolar surfactant (PS) on the efficacy and serum inflammatory factors and oxygenation in children with meconium aspiration syndrome (MAS). METHODS: Sixty-eight children with severe MAS who were treated in our hospital from March 2017 to March 2019 were enrolled. The patients were randomly divided into the control group (34 cases) for anti-infection and ventilator-assisted treatment. PS treatment was used on the basis of the control group and the NAC nebulizing solution was inhaled. The mean airway pressure (MAP), resistance (Raw), compliance (Cydn), lung function index, serum interleukin-8 (IL-8), IL-10, and platelet-derived growth factor (PDGF) were observed. Vascular endothelial growth factor (VEGF) levels were recorded, and the hospital stay, oxygen exposure time, upper ventilator time, and complications were recorded. RESULTS:During the 24 h observation group, Raw and MAP were lower than 0 h, the control group was lower, Cydn was higher than 0 h, and the control group was increased. In 72 h, the Raw and MAP of the observation group were lower than that of the control group, the Cydn was lower than that of the control group, and the Cydn was higher than the control group. The difference was statistically significant (P＜0.05). PaCO2, PaO2, a/APO2 in the observation group were higher than those in the control group at 1 h, 12 h and 24 h after treatment. The OI was lower than the control group, the difference was statistically significant (P＜0.05). The serum IL-10 level in the observation group was higher than that in the control group at 24 hours after treatment, and the serum IL-8 level was lower than that in the control group (P＜0.05). The serum of the observation group was observed at 24 h and 72 h after treatment. The levels of PDGF and VEGF were lower than those of the control group, and the difference was statistically significant (P＜0.05).CONCLUSION:Acetylcysteine combined with pulmonary surfactant can significantly improve the clinical efficacy of children with meconium aspiration syndrome. It may inhibit lung inflammation by regulating the expression of VEGF and PDGF, thus improving lung function in children.

Correlation between vitamin D and thyroid disease

SU Shan, ZHANG Di, WANG Qiangmei, ZHEN Donghu

2020, 25(1):  94-100.  doi:10.12092/j.issn.1009-2501.2020.01.014

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In addition to the role of vitamin D in regulating calcium and phosphorus homeostasis and bone metabolism, immune regulation and anti-tumor proliferation have been gradually proposed by researchers. At present, a large number of studies have found that patients with thyroid diseases have low vitamin D levels, and it is believed that vitamin D insufficiency/ deficiency may be involved in the pathogenesis of thyroid diseases, but the specific relationship and mechanism between vitamin D and thyroid diseases have not been fully clarified. This article reviewed in the relationship between vitamin D and several common thyroid diseases in recent years, in order to analyze the role of vitamin D in the pathogenesis of thyroid diseases, as well as the influence of vitamin D supplementation on the occurrence and development of thyroid diseases.

Neurobiological factors of trait anxiety and its influences on individual cognitive performance

DING Lulu, GUO Jianyou

2020, 25(1):  101-106.  doi:10.12092/j.issn.1009-2501.2020.01.015

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Trait anxiety is a relatively stable anxiety tendency with individual differences in personality traits. The level of trait anxiety is related to gene polymorphism, oxidative stress, and brain volume and brain chemicals. At the same time, trait anxiety can affect an individual's cognitive performance, such as the extinction of fear memories and the process of threat-related information. Fully understanding the neurobiological factors of trait anxiety and its impacts on individual cognitive performance can help us cope with life events better and prevent or treat anxiety, depression and other mental illnesses more effectively.

Progress in the treatment of multiple myeloma

CHANG Xiangxiang, WEI Zhongling, ZHENG Xingyuan, LI Huimin, HUANG Laiquan

2020, 25(1):  107-116.  doi:10.12092/j.issn.1009-2501.2020.01.016

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Multiple myeloma is a malignant tumor that occurs in plasma cells. Clonal plasma cells in bone marrow proliferate abnormally and secrete monoclonal immunoglobulin or its fragment (M protein), resulting in damage to related organs or tissues. At present, with the development of new drugs, the development of cellular immunotherapy and the improvement of hematopoietic stem cell transplantation technology, the depth of remission and survival of multiple myeloma are significantly prolonged. This article reviews the latest advances in the treatment of multiple myeloma in recent years.

Experience in quality control of clinical trials of DMARDs

WANG Xiaoxia, WANG Hong, LIU Yan, BAI Jie

2020, 25(1):  117-120.  doi:10.12092/j.issn.1009-2501.2020.01.017

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In recent years, many new DMARDs have been emerging, mainly in bDMARDs and tsDMARDs. With the increasing number of clinical trials, it is of great significance to strengthen the quality control of clinical trials. This paper analyzes the key points and difficulties in practice that the investigator should pay attention to in the b/tsDMARDs clinical trials, as well as the quality control concerns of the clinical trials of such drugs. Some methods are put forward to solve questions above in order to help improve the quality of such clinical trials.