2021 Volume 23 Issue 10 Published: 28 November 2021
  

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  • Wen Aidong, Liu Meiyou, Fan Tingting, Ding Likun, Ren Danjun
    Abstract ( ) PDF ( )
    With the key mechanism of disease occurrence being revealed and rapid development of modern biopharmaceutical technology, more and more biological innovative drugs have been approved for marketing. With more clinical application of innovative biological drugs in recent years, more adverse reactions were reported. Therefore, it is of great significance and urgent in clinic to construct the supervision standard and system for the safe use of biological innovative drugs. At present, the main problems hindering the clinical safety supervision of biological innovative drugs are as follows. Firstly, the mechanism of adverse drug reactions is unclear and there is a lack of specific detection indicators to predict them. Secondly, the study on the relationship of "exposure-clinical efficacy-toxic and side effects" of drugs in vivo is still insufficient, so it is difficult to support the establishment of the rule of "quantity and toxicity" for safe drug use. Thirdly, there is a lack of clinical research evidence in line with the physiological and pathological characteristics of Chinese people, and the ideal randomized controlled trials results of clinical research on new drugs are not enough to support its safe drug use in the real world. Therefore, it is necessary to strengthen the supervision awareness of the clinical safe use, accelerate the process of clinical monitoring research on biological innovative drugs, reveal more scientific evidence of clinical safe use, so as to help the construction of the supervision standards and system for the safe use of biological innovative drugs.
  • Zhang Mingru, Li Guoquan, Ding Likun, Zhang Di, Ye Jiajun, Li Guiyu, Yang Weidong, Wen Aidong, Wang Jing
    Abstract ( ) PDF ( )
    Objective To explore the application value of radioisotope tracer technology in clinical research of biological drugs. Methods The pharmacokinetic properties of mepuzumab in healthy volunteers were evaluated by measuring the radioactive concentrations of iodine in blood and urine samples of 3 healthy volunteers at different time points within 14 days after intravenous infusion of 131I-labeled international class I new drug mepuzumab (Trial 1). Positron emission computed tomography (PET/CT) was performed on 6 healthy volunteers after intravenous injection of 68Ga-labeled nucleic acid aptamer Sgc8, and the standard uptake values of 68Ga-Sgc8 in different organs were measured to evaluate its biodistribution in healthy humans (Trial 2). Nine patients with suspected neuroendocrine tumors underwent single photon emission and X-ray computed tomography (SPECT/CT) 4 hours after intravenous injection of 99mTc-labeled octreotide to determine the radioactive uptake level in the regions of interest; the affinity and targeting of 99mTc- labeled octreotide to somatostatin receptor subtype 2 (SSTR2) were evaluated in combination with the immunohistochemical staining results of SSTR2 in patients′ biopsy tissues (Trial 3). Results The 3 healthy volunteers included in Trial 1 were male, aged 28, 45, and 25 years respectively; the injection doses of 131I-labeled mepuzumab were 21.0, 25.9, and 17.6-mg, and the injection doses of radioactivity were 364, 420, and 304 MBq, respectively. Among the 6 healthy volunteers included in Trial 2, 3 were male and 3 were female, with an age of (46±11) years, ranging from 35 to 63 years. The dose of radioactivity injected was (80±7) MBq, ranging from 69 to 87 MBq. Among the 9 patients included in Trial 3, 5 were male and 4 were female, with an age of (54±10) years, ranging from 39 to 69 years. The dose of radioactivity injected was (777±74) MBq, ranging from 740 to 925 MBq. After intravenous infusion of 131I-labeled mepuzumab, the blood radioactivity concentration reached the peak 1.5-hours later. 131I-labeled mepuzumab mainly bound to blood cells, and its whole-blood clearance half-life was 420-hours. The urine radioactivity concentration reached the peak 16-24-hours after administration and then gradually decreased after 24-hours of administration. After intravenous injection of 68Ga-labeled Sgc8, the organs with strong to weak radioactive signals were bladder, kidney, heart, uterus, liver, spleen, gallbladder, large intestine and lung. Within 3 hours after drug administration, the clearance rate was fastest in heart, followed by uterus, kidney, and liver; the clearance rate was slower in spleen and gallbladder and were slowest in large intestine and lung. All of the 9 patients had abnormal radioactivity accumulation 4 hours after intravenous injection of 99mTc-labeled octreotide and the immunohistochemical staining results of biopsy tissues showed strong positive expression of SSTR2, indicating that 99mTc-labeled octreotide had good affinity and targeting to SSTR2. The safety evaluation showed that in Trail 1, one subject developed iodine-related hyperthyroidism one month after intravenously infusion of 131I-labeled mepuzumab, which returned to normal after 8 months of continuous monitoring without intervention. No adverse reactions occurred in other subjects. Conclusions Radioisotope tracer tech- nology can noninvasively, dynamically, and visually evaluate the pharmacokinetics, biological distribution, and targeting of biological drugs in human body. It has good safety and great application value in the clinical evaluation of biological drugs.
  • Zhang Menghua, Chen Zhiyao, Liu Xiaoxue, Shan Zhili, Yang Gang, Zhou Qiyang, Zhou Yudi, Zhou Xiaojun, Miao Liyan
    Abstract ( ) PDF ( )
    Objective To explore the value and threshold of steady-state trough plasma concentration (trough concentration) of imatinib mesylate (IM) and its active metabolite N-desmethyl imatinib (NDI) in predicting the risk of moderate to severe adverse reactions in patients with gastrointestinal stromal tumors (GIST). Methods The subjects were selected from GIST outpatient who received IM treatment and re-visited doctor in the First Affiliated Hospital of Soochow University form July 2020 to March 2021. On the day of re-visiting, the relevant clinical information and occurrence of IM-related adverse reactions within 28 d prior to the trial of selected patients was asked and recorded and blood were collected (22 to 24-hours after the last medication) to determine IM and NDI trough concentration. Twenty-eight days after blood collection, telephone follow-up was conducted to record IM-related adverse reactions occurrence. Blood routine and blood biochemical examination results within 28 days before and after blood collection were collected through the hospital information system. After evaluating causality for adverse reactions and grading their severity, patients without or with grade I adverse reactions were regarded as the no/mild group and those with grade Ⅱ~Ⅴadverse reactions were regarded as the moderate-severe group. The risk factors of moderate-severe adverse reactions were analyzed by comparing the main clinical characteristics of patients in the 2 groups, and the value and threshold of IM and NDI trough concentrations in predicting the risk of moderate-severe adverse reactions were analyzed by receiver operating characteristic (ROC) curve. Results A total of 119 patients were recruited in this study and 113 (95.0%) had adverse reactions. There were 65 patients in the no/mild group and 54 in the moderate-severe group. The differences in the gender and dose distribution of patients in the 2 groups were statistically significant (χ2=19.772, P<0.001; χ2=9.817, P=0.020); proportions of females, patients at dose of 300-mg/d, and patients at dose of 600-mg/d in the moderate-severe group were greater than those in the no/mild group. The trough concentration of IM and NDI of patients in the moderate- severe group were significantly higher than those of patients in the no/mild group[1-695 (1-258, 2-261) μg/L vs. 1-360 (938, 1-643) μg/L, P<0.001; 324(223, 379) μg/L vs. 264(217, 338) μg/L, P=0.042]. ROC curve analysis results showed that the breakpoints of IM and NDI trough concentrations for moderate-severe adverse reactions in patients with GIST were 1-539-μg/L (sensitivity 62.3%, specificity 70.3%) and 303-μg/L (sensitivity 56.6%, specificity 68.7%) respectively. The 119 patients were grouped according to the breakpoint concentrations. The incidences of moderate-severe adverse reactions were 63.0% (34/54) and 30.8% (20/65) in patients with IM trough concentration >1-539-μg/L and ≤1-539-μg/L, respectively and 59.6% (31/52) and 34.3% (23/67) in patients with NDI trough concentration >303-μg/L and ≤303-μg/L, respectively. The differences were statistically significant (P<0.001, P=0.006). Conclusions The trough concentrations of IM and NDI are of some value in predicting the risk of moderate-severe adverse reactions in patients with GIST. Drug monitoring should be strengthened in patients with IM trough concentration >1-539-μg/L and NDI trough concentration >303-μg/L to ensure the safety of IM use.
  • Liang Liang, Wang Ting, Feng Ru, Chen Di, Jin Pengfei
    Abstract ( ) PDF ( )
    Objective To evaluate the safety of venetoclax alone or combined with CD20 monoclonal antibody (mAb) in treatment of patients with relapsed/refractory chronic lymphoblastic leukemia (R/R CLL). Methods Databases of PubMed, Embase, CNKI, Wanfang Med Online, VIP, and SinoMed and websites such as ClinicalTrials.gov, the U.S. Food and Drug Administration (FDA), and the European Drug Administration (EMA) were searched. The clinical studies with safety indicators of venetoclax alone or in combination with CD20 mAb in treatment of patients with R/R CLL were collected. Safety-relevant data were extracted and the meta-analysis was performed using R software. The effect values were the ratio of relative risk (RRR) and 95% confidence interval (CI). Results A total of 9 studies were enrolled in the analysis, all of which were single arm studies (8 prospective studies and 1 retrospective study). Eight hundred and nineteen patients were involved in the 9 studies, 719 of which were in the monotherapy group and 100 in the 2-drug combination group. The most common adverse events in venetoclax monotherapy or combined with CD20 mAb were hematologic adverse events. The risk of developing grade 3-4 neutrophilia, thrombocytopenia, and anemia was 46.96% (95%CI: 40.27%-53.76%), 20.46% (95%CI: 14.79%-27.59%), and 15.31% (95%CI: 10.30%-22.15%), respectively. Other grade 3-4 adverse events mainly included infection [17.79% (95%CI: 15.15%-20.77%)], tumor lysis syndrome [3.00% (95%CI: 1.75%-5.09%)], increased blood glucose [5.98% (95%CI: 3.80%-9.29%)], and hypokalemia [4.27% (95%CI: 2.54%-7.08%)]. Due to the adverse events, 28.82% (95%CI: 16.56%-45.24%) of patients interrupted venetoclax treatment for at least one dose, 17.19% (95%CI: 10.96%-25.94%) of patients reduced the venetoclax dose, 9.56% (95%CI: 7.64%-11.89%) of patients permanently discontinued venetoclax, and 1.90% (95%CI: 0.86%-4.17%) of patients died. Risks of grade 3-4 neutropenia and dose reduction of venetoclax were significantly higher in patients treated with venetoclax combined with CD20 mAb than in those treated with venetoclax alone (57.00% vs. 41.69%, RRR=1.36,95%CI: 1.12-1.66; 38.18% vs. 14.97%, RRR=2.55, 95%CI: 1.48-4.39). Conclusions The adverse events in venetoclax treated R/R CLL were mainly hematological adverse events and the risk of grade 3-4 neutropenia was more than 40%. After the combination with CD20 mAb, the risks of the other adverse events did not increase except for those of grade 3-4 neutropenia and dose reduction of venetoclax due to adverse events.
  • Zhang Xianglin
    Abstract ( ) PDF ( )
    Rituximab is a human-mouse chimeric monoclonal antibody synthesized using genetic engineering technology and exert pharmacological effects by specifically binding to the transmembrane protein CD20 on the surface of B cells. The clinical therapeutic effect of rituximab is significant, but its pharmacological mechanism is complex, the pharmacokinetics/pharmacodynamics (PK/PD) presents as nonlinear models and is highly variable, which brings great variability and uncertainty to the effectiveness and safety of rituximab in clinic, so individualized therapy needs to be implemented to improve the rationality of medication. At present, rituximab has the basic conditions for therapeutic drug monitoring (TDM), such as detection technology of blood drug concentration, tumor biomarkers, and related genetic polymorphisms. Using these technologies, combined with comprehensive analysis of factors such as disease diagnosis, population specificity, route of administration, and drug interactions, the PK/PD model of rituximab can be constructed to predict the efficacy, toxicity, and drug resistance. It is of great significance for pharmacists to participate in the individualized rituximab treatment and carry out TDM, which can provide safer and more effective individualized treatment for patients.
  • Wang Dongxue, Cui Yingchun, Xu Feng
    Abstract ( ) PDF ( )
    A 47-year-old male patient received irbesartan 225-mg orally once daily due to nephrotic syndrome. Three days later, the dose was changed to 300-mg once daily according to the doctor′s advice. His hemoglobin (Hb) was 153-g/L before irbesartan treatment. After 6 days of medication, the patient developed fatigue and weakness. Laboratory test showed that his Hb was 89-g/L. No laboratory test abnormality was found in serum creatinine, stool routine, and bone marrow puncture. After 13 days of medication, his Hb was 87-g/L. Moderate anemia related to irbesartan was diagnosed. Irbesartan was discontinued and IV infusion of methylprednisolone sodium succinate for injection 60-mg once daily and subcutaneous injection of erythropoietin 3-000 U thrice a week were given. Seven days later, the symptoms of fatigue and weakness were improved and laboratory test showed Hb 102-g/L. Twenty-seven days later, his Hb returned to 131-g/L.
  • Liu Yanru, He Yanju
    Abstract ( ) PDF ( )
    A 53-year-old female patient received IV infusion of meropenem for injection 1.0 g once every 8 hours for urinary tract infection. Her platelet count (PLT) was 151×109/L before using meropenem. On the 9th day of meropenem treatment, the laboratory test showed PLT 577×109/L and on the 12th day, the patient′s infection was controlled but PLT increased to 829×109/L. The thrombocytosis related to meropenem was considered. Meropenem was stopped and replaced by IV infusion of piperacillin sodium and sulbactam sodium for injection 5 g dissolved in 100-ml of 0.9% sodium chloride injection once 8 hours. Three days later, the patient′s PLT decreased to 782×109/L; 23 days later, PLT was 272×109/L.
  • Dong Yuexin, Yu Dan, Shen Jianghua, Zhang Yan, Chu Yanqi
    Abstract ( ) PDF ( )
    A 69-year-old male patient with retroperitoneal sarcoma received anlotinib capsules (12-mg orally once daily for 14 days, interruption for 7 days) and sintilimab injection (IV infusion of 200-mg on the first day) and 21 days was a cycle. He had no history of diarrhea and previous enteroscopy showed no obvious abnormality. So the diarrhea, which occurred after 18 days of treatments, was considered to be related to the combination use of anlotinib capsules and sintilimab injection. Above 2 drugs were stopped and hormone and symptomatic treatments were given. Six days later, the patient′s diarrhea was improved, and enteroscopy showed colitis. Considering the primary disease, the patient was treated with oral anlotinib capsule monotherapy with the same dose as before. Two days later, the patient had diarrhea again, which was more serious than before, and the anlotinib capsules were stopped again. After 14 days of hormone shock therapy, anti-infection therapy, and symptomatic treatments, the patient′s diarrhea was improved.
  • Ye Zhen, Lyu Xin, Yu Zhe, Wei Jilin, Cheng Cheng, Xue Hui, Deng Xu
    Abstract ( ) PDF ( )
    A 73-year-old male patient with diabetic mellitus complicated with peripheral vascular lesions and neuropathy received sarpogrelate on the basis of previous treatments with ticagrelor, nifedipine controlled-release tablets, candesartan cilexetil, metoprolol tartrate sustained-release tablets, and isosorbide mononitrate dispersible tablets for aggravated numbness and coldness of hands and feet with lower limb pain. Oral mucosal bleeding occurred after 12 days of treatments and platelet count (PLT) was 7×109/L after 16 days of treatments. Before sarpogrelate was added, PLT was 229×109/L. The patient had taken ticagrelor or sarpogrelate alone in the past, no bleeding occurred, and the patient had no history of abnormal blood cells and platelets. Considering that the thrombocytopenia was caused by the combination use of sarpogrelate and ticagrelor, the 2 drugs were stopped, 300-ml of platelet plasma was given that day, and aspirin enteric-coated tablets 100-mg orally once daily was given on the second day. Nineteen days later, the PLT recovered to 187×109/L。
  • Deng Xiaoqin
    Abstract ( ) PDF ( )
    An 86-year-old male patient received aspirin enteric-coated tablets (100-mg orally once daily) and atorvastatin calcium tablets (10-mg orally once daily) due to cerebral infarction. After 1 week, enteric-coated tablets were switched to clopidogrel (75-mg orally once daily), and Xueshuantong injection(血栓通注射液) (450-mg/d) and cattle encephalon glycoside and ignotin injection (5-mg/d) were given by IV infusion. After 4 days of treatment, the platelet count (PLT) decreased from 132×109/L before treatment to 52×109/L. Clopidogrel was discontinued, but PLT continued to decrease, accompanied by fever. After 2 days of drug withdrawal, PLT decreased to 4×109/L;after 3 days of drug withdrawal, PLT was 1×109/L and the patient developed gingival bleeding. Leucogen was given orally, platelets and coagulation factors were supplemented intravenously, but PLT did not increase. On the 5th day of drug withdrawal, the patient gradually developed unconsciousness and rapid atrial fibrillation and finally died due to respiratory and circulatory failure. After the patient died, thrombotic thrombocytopenic purpura due to clopidogrel was diagnosed.
  • Ma Jie, Wang Nan, Liu Min, Song Yanqing
    Abstract ( ) PDF ( )
    A 56-year-old male patient was scheduled to undergo debridement due to his left forearm trauma, and functions of his heart, liver, and kidney were normal. Before operation, human tetanus immunoglobulin 250 U was injected intramuscularly without discomfort; 80-minutes later, intravenous infusion of levofloxacin hydrochloride injection was started. After 2-minutes of infusion (approximately 8-ml), the patient had sudden dyspnea, dysphoria, and vomiting. His blood pressure could not be measured due to agitation and blood oxygen saturation was 0.82. Levofloxacin was immediately stopped and electrocar- diographic monitoring and oxygen inhalation were given. But the patient became unconscious, his heart rate dropped to 50 beats/min, and blood pressure was 71/45-mmHg. Immediately, cardiopulmonary resuscitation was performed, and epinephrine, dexamethasone, etc. were given. Anaphylactic shock caused by levofloxacin was considered and type Ⅱ respiratory failure appeared, he was transferred to the Intensive Care Unit to assist breathing with an invasive ventilator. Laboratory tests revealed cardiac troponin T 0.253-mg/L, myoglobin >3-000-mg/L; aspartate aminotransferase 1-079-U/L, alanine aminotransferase 798-U/L, γ-glutamyl transpeptidase 157-U/L; serum creatinine 157 μmol/L. It was considered that the patient developed multiple organ dysfunction syndrome. Continuous hemofiltration, symptomatic treatments such as liver protection, and nutrient therapy for myocardium were given. After 9 days, the patient was detached from the respirator; after 13 days, hemofiltration was stopped; after 29 days, the patient′s mind became clear and the laboratory indexes of heart, liver and kidney returned to normal.
  • Ran Shan, Zhang Ming, He Zhigao
    Abstract ( ) PDF ( )
    A 78-year-old male patient with peritoneal dialysis received Juhong Tanke (橘红痰咳液) solution 10-ml thrice daily and 4 Jinqiaomai tablets (金荞麦片) thrice daily orally because of cough at night for 3 weeks(conventional abdominal dialysis maintenance treatment was given according to the original schedule). On day 5 of treatments, the peritoneal exudate was turbid. Laboratory tests showed white blood cell count (WBC) 1.1×109/L, neutrophils 0.65, hemoglobin (Hb) 105-g/L, platelet count (PLT) 90×109/L, high sensitivity C-reactive protein 26.9-mg/L, and procalcitonin 10.89-mg/L; the examination for exudate showed WBC 13-131×106/L and neutrophils 0.96. Acute diffuse peritonitis was diagnosed. Meropenem, moxifloxacin, norvancomycin, vancomycin, and linezolid were given successively along with the peritoneal dialysis, the infection was still not well controlled, and then the anti-infective drugs were changed to an IV infusion of tigecycline 50-mg twice daily. On day 9 of tigecycline treatment, the patient had sudden cold sweats and palpitations with fatigue, dizziness, and hunger. The peripheral blood glucose level was 2.0-mmol/L. An intravenous injection of 50% glucose was given and the blood glucose increased to 5.8-mmol/L. The patient had no history of diabetes mellitus, it was considered that hypoglycemia was related to tigecycline. Then tigecycline was discontinued and replaced by oral rifampicin 0.45 g thrice daily and an IV infusion of vancomycin 500-mg dissolved in 0.9% sodium chloride injection 100-ml once every 12-hours. Three days after tigecycline withdrawal, the patient′s blood glucose level was 3.0-mmol/L at dawn. Intravenous and oral glucose supplementation treatments were continued, and 19 days later, the patient′s fasting blood glucose level was 4.8-6.3-mmol/L.
  • Ding Qin, Yang Chendong
    Abstract ( ) PDF ( )
    A 74-year-old female patient was chronically treated with insulin glargine injection, insulin aspart injection, metformin tablets, and nifedipine controlled-release tablets because of type 2 diabetes mellitus and hypertension. Due to poor blood pressure control, candesartan cilexetil 8-mg orally once daily was added. Five days later, the patient developed myalgia and fatigue. Laboratory tests showed myoglobin >2-000-μg/L, creatine kinase 8-567-U/L, creatine kinase MB 279-U/L, aspartate aminotransferase 273-U/L, lactate dehydrogenase 546-U/L, alpha hydroxybutyrate dehydrogenase 498-U/L, and positive protein and occult blood in urine. Rhabdomyolysis caused by candesartan cilexetil was considered. Then the drug was discontinued and symptomatic treatments such as rehydration, alkalinized urine, and diuretics were given. After 7 days of drug withdrawal, the patient′s symptoms were relieved, and after 10 days of drug withdrawal, the laboratory indexes such as myoglobin, creatine kinase, and aspartate aminotransferase returned to normal.
  • Shi Jinping, Li Wei
    Abstract ( ) PDF ( )
    A 2-year-old boy with left nephroblastoma was treated with parenteral nutrition (including medium/long chain fat emulsion injection, ω-3 fish oil fat emulsion injection, etc.) before radical left nephrectomy because he was unable to eat. The blood biochemical tests before treatment showed triacylglycerol (TG) 1.18-mmol/L, total cholesterol (TC) 2.68-mmol/L, high density lipoprotein cholesterol (HDL-C) 0.80-mmol/L, and low density lipoprotein cholesterol (LDL-C) 1.48-mmol/L. After 7 days of treatment, blood biochemical tests showed TG 4.28-mmol/L, TC 5.48-mmol/L, HDL-C 1.32-mmol/L, and LDL-C 3.74-mmol/L. Dyslipidemia caused by excessive parenteral nutrition was considered. Medium/long chain fat emulsion injection was stopped. Two days later, the blood biochemistry tests showed TG 3.34-mmol/L, TC 3.17-mmol/L, HDL-C 0.86-mmol/L, and LDL-C 2.67-mmol/L; 7 days later, all blood biochemical indexes returned to normal.