据报道：重组人血小板生成素（rhTPO，商品名“特比奥”）在沈阳三生制药股份有限公司10年潜心研发下，日前获得国家一类新药证书，成为世界上第一个完成rhTPO临床试验并被批准上市的基因工程药物，且获得了两项国家发明专利。从而填补了国际上对骨髓三大血细胞系（红细胞系、粒细胞系和巨核细胞系）中缺乏调节巨核细胞特异性药物的空白。科学研究发现，天然TPO是一种造血生长因素。其可通过与特异性受体结合，调节巨核细胞增殖、分化、成熟，从而形成血小板，增加循环血中的血小板数。rhTPO系采用现代重组DNA技术，以哺乳动物细胞作为宿主细胞进行分泌产物，所分泌的产物与天然TPO结构和功能完全一致，能够特异性提高体内血小板的水平，是国际上最被看好的基因工程蛋白药物之一。目前国外一流的生物技术公司还处在对rhTPO进行先期临床实验阶段。rhTPO用于预防和治疗癌症病人放化疗引起的血小板减少。目前治疗血小板减少的常用方法是通过直接输入血小板，该方法具有输注费用昂贵、易感染和免疫力降低等缺点。rhTPO是具有纠正血小板减少症的基因工程药物，不良反应少。据悉，今年第四季度rhTPO即可完成批量生产且上市销售。
           
【通用名】重组人血小板生成素注射液
【商品名】特比澳
【英文名】Recombinant Human Thrombopoietin Injection
【主要成份】重组人血小板生成素、人血白蛋白、氯化钠
【性 状】本品为无色澄明液体，无肉眼可见不溶物。
【药理毒理】
1、药理
血小板生成素（thrombopoietin，TPO）是刺激巨核细胞生长及分化的内源性细胞因子，对巨核细胞生成的各阶段均有刺激作用，包括前体细胞的增殖和多倍体巨核细胞的发育及成熟，从而升高血小板数目。重组人血小板生成素（rhTPO）是利用基因重组技术由中国仓鼠卵巢细胞表达，经提纯制成的全长糖基化血小板生成素，与内源性血小板生成素具有相似的升高血小板的药理作用。
2、毒理
（1）急性毒性：rhTPO1.35×105U/kg和2.25×105U/kg（相当于临床推荐给药剂量的900和1500倍）分别给予大鼠和小鼠尾静脉缓慢注射，给药后即刻及14天内动物未出现毒性反应或死亡。内脏病理组织学检查未见异常。此外，给大鼠和小鼠背部皮下注射rhTPO1.8×105U/kg和4.5×105U/kg（相当临床推荐剂量1200和3000倍），给药后动物无明显毒性反应。观察14天动物未出现毒性反应和死亡。病理组织学检查各主要脏器未见异常。
（2）慢性毒性：Wistar系大鼠经皮下注射rhTPO连续35天，剂量为1.5×104U/kg、7.5×103U/kg和1.5×103U/kg（分别相当临床推荐用药剂量的100倍、50倍和10倍），两组对照组分别注射0.5%人血白蛋白和生理盐水。大鼠的一般状况、饲料的利用率、白细胞分类、凝血时间、尿常规及病理组织学检查结果表明，rhTPO各组与对照组在不同时间点均无显著性差别。给药三周后，末梢血小板总数随给药周数增加持续显著下降，且剂量高组下降更显著。停药后高、中剂量组骨髓巨核系恢复缓慢。说明高、中剂量组给药两周后产生明显蓄积毒性。低剂量组给药四周时产生蓄积毒性，但停药两周能明显恢复至给药前水平，且骨髓巨核系也明显恢复正常。rhTPO 1.5×103U/kg应视为大鼠皮下给药无明显毒副作用的剂量。
（3）致突变毒性：rhTPO对NIH系小鼠骨髓多染红细胞无诱发微核率升高的作用。rhTPO 3×103U、1.5×103U、7.5×102U、3.8×102U、1.9×102U5个剂量组均不诱发鼠伤寒沙门氏菌基因突变。rhTPO在2.4×104U/ml剂量下对人二倍体细胞没有致染色体畸变作用。本品在常规微核试验、Ames试验和染色体试验的结果均为阴性。
【适应症】本品适用于治疗实体瘤化疗后所致的血小板减少症，适用对象为血小板低于50×109/L且医生认为有必要升高血小板治疗的患者。
【用法与用量】本品应在临床医师指导下使用。具体用法、剂量和疗程因病而异，推荐剂量和方法如下：
恶性实体肿瘤化疗时，预计药物剂量可能引起血小板减少及诱发出血且需要升高小板时，可于给药结束后6 ~24小时皮下注射本品，剂量为每日每公斤体重300U，每日一次，连续应用14天；用药过程中待血小板计数恢复至100×109/L以上，或血小板计数绝对值升高≥50×109/L时即应停用。当化疗中伴发白细胞严重减少或出现贫血时，本品可分别与重组人粒细胞集落刺激因子（rhG-CSF）或重组人红细胞生成素（rhEPO）合并使用。
【不良反应】
较少发生不良反应，偶有发热、肌肉酸痛、头晕等，一般不需处理，多可自行成恢复。个别患者症状明显可对症处理。本品在III期临床试验中未见严重不良反应。在311例受试者中有12例（3.86%）共18例次出现与rhTPO用药有关的轻微不良反应，其中发热4例，寒战2例，全身不适1列，乏力2例，膝关节痛2例，头痛2例，头晕3例，血压升高2例，症状大多轻微，无需特殊处理。实验室检查rhTPO对化疗后血红蛋白和白细胞计数的恢复无影响，对血小板形态、血小板聚集功能、凝血功能、肝肾等脏器功能无显著影响。74例患者在治疗周期接受了抗体动态检测，3例患者（4%）于给药后第21天和第28天的血清中检测低滴度（1：5）非中和性抗rhTPO抗体，未发现对rhTPO升高血小板的作用造成影响。

【禁 忌】
1、对本品成份过敏者；
2、严重心、脑血管疾病者；
3、患有其它血液高凝状疾病者，近期发生血栓病者；
4、合并严重感染者，宜控制感染后再使用本品。
【注意事项】
1、本品过量应用或常规应用于特异体质者可造成血小板过度升高，必须在三甲医院并在有经验的临床医师指导下使用；
2、本品适用对象为血小板低于50＜109/L且医生认为有必要升高血小板治疗的患者；
3、本品应在化疗结束后6-24小时开始使用；
4、使用本品过程中应定期检查血常规，一般应隔日一次，密切注意外周血小板计数的变化，血小板计数达到所需指标时，应及时停药。
【孕妇及哺乳期妇女用药】对孕妇及哺乳期妇女的用药安全性尚未确立，故原则上不宜应用。
【药物相互作用】尚不清楚。
【贮藏】2~8℃，避光保存
【包装】1瓶，西林瓶装，1毫升/瓶
【有效期】自分装之日起有效期为36个月

[Drug Names]
Generic Name：Recombinant human thrombopoietin injectionTrade Name：
TPIAO English Name：RecombinantHumanThrombopoietin InjectionChinese Phonetic Alphabet：Chongzu Ren Xuexiaoban Shengchengsu Zhusheye Ingredients：Recombinant humanthrombopoietin,Humanserumalbumin, NaCl
[Character]
Colorless and transparent liquid without any macroscopic insoluble substance.
[Pharmacology]
1. Pharmacology
Thrombopoietin (TPO) is an endogenous cytokine which can stimulate the growth and differentiation of megalokaryocyte. It can increase the quantity of platelet through its stimulative function on each growth phase of megalokaryocyte including multiplication of pro-cell, development and maturation of polyploid megalokaryocyte. Recombinant human
thrombopoietin（rhTPO）is a fulllengthglycosylated thrombopoietin which is expressed in China Hamster Ovary (CHO) cell line via recombinant genetic technology. It has similar pharmacologicalfunction on increasing the quantity of platelet with endogenous thrombopoietin.
rhTPO 150 U/Kg or 600 U/Kg is separately injected with human serum albumin 20μg/Kg to macaque which is created as the model of bone marrow restrain after they were irradiated with great dosage systemic radiation of 60Coγ.Such administration is given once per day and for 20 days.
The testing result shows that rhTPO can increase the average value of platelet count, shorten the time of low value period and increase the congregated rate of peripheral blood platelet in low value. Its lowest effective dosage is 150 U/Kg per day.
          
Balb/c rats, which were injected with carboplatin (150 mg/kg) by intraperitoneal injection to be model of thrombocytopenia, are given.
rhTPO (1.1102 U, 1.1103 U and 1.1104 U/kg) and physiological saline separately once per day for 10 days, rhTPO therapy can improve the platelet decreasing caused by carboplatin obviously when the dose is more than 1.1103 U/kg.
In the vitro culture system with normal human bone marrow and HEL and DAMI cell series expressed by the antigen of megakaryocytic, rhTPO canespecially enhance the expression ofmegakaryocytic series and CD41 antigen of monocyte of normal human bone marrow and promote the production of CFU-Meg
2. Toxicology
(1) Acute toxicity: rhTPO were separately injected slowly to rat and mice through vein in tail at the dosage of 1.35105 U/kg and 2.25105 U/kg (Correspond to 900 and 1500timesofrecommended dosage on clinical use).
No obvious toxicity reaction and death was found during 14 days after injection. No abnormality was found in main organs after histopathology test.
(2) Chronic toxicity: rhTPO was continuously injected to Wistar rats by sc at the dosage of 1.5104 U/kg, 7.5103 U/kg and 1.5103 U/kg (Separately corresponding to 100 times, 50 times and 10 times of recommended dosage on clinical use) for 35 days. Two control groups were separately injected with 0.5% human serum albumin and physiological saline. The testing results of general situation, food intake, classification of leukocytes, clotting time, routine uronoscopy and histopathology showed that there was no distinct difference between rhTPO treatment group and control group at different time point. 3 weeks after injection, total quantity of peripheral blood platelet continuously decreased obviously along with the week increase of administration especially for the high dosage group.
Meganucleus series of bone marrow of high and medium dosage group recuperated slowly after finish of administration. It was demonstrated that obvious cumulative intoxication occurred in high and medium dosage group after injection for 2 weeks. Cumulative intoxication occurred in low dosage group after injection for 4 weeks but disappeared in 2 weeksafterstopofadministration, meganucleus series of bone marrow also recovered obviously. 1.5103 U/kg should be the dosage with which rhTPO is injected to rats by sc without obvious side and toxic effect. 
RhTPO, 0.5% human serum albumin and physiological saline were separately injected to 24 rhesus monkeys for 30 days. RhTPO was administrated at the dosage of 9102 U/kg, 1.8103 U/kg and 5.4103U/kg(Separatelycorresponding to 6 times, 12 times and 36 times of recommended dosage on clinical use). Such rhesus monkeys were observed for 58 days after injection (30 days of administration, 28 days after stop of administration). The observing result demonstrated that there was no distinctive difference between male and female rhesus monkeys on general circulation, orexia, weight, body temperature, biochemical analysis of blood serum, urine test, ECG and histo-pathology. Among them, the administration of middle and high dosage rhTPO caused one condition that the total count of peripheral blood platelet radically increased in the earlier period and then turned to dramatically decrease and the recovery of blood platelet quantity was slow. It indicated that large dosage and long-term continuous administration would be the obstacle of rhesus monkeys Megakaryocyte producing blood platelet after stimulating the
production of blood platelet. Continuous administration with lower dosage in 30 days didn’t show obvious accumulation of toxicity to the rhesus monkeys. 9×102U/kg BW should be the dosage with which rhTPO is injected to rhesus monkeys without obvious side and toxic effect. 
[Pharmacokinetics]
Pharmacokinetics study on single sc administration of rhTPO to normal volunteers:
The healthy volunteers were randomly divided into 3 dosage groups (150 U/Kg, 300 U/Kg and 600 U/Kg). Each group consists of 8 cases and totally 24 subjects. The results showed that the absorption and elimination basically conform to linear pharmacokinetics characters. The t1/2ka of three dosage groups were 2.5±1.1h, 3.2±2.6h and 4.2±2.4h respectively and
Tmax were 9.0±1.9h, 10.8±2.4h and 11.8±5.4h respectively. The elimination of rhTPO was slow and the half-life in vivo was longer. The elimination half life of three dosage groups was similar, separately as 46.3±6.9h, 40.2±9.4h and 38.7±11.9h.Pharmacokinetics study on multiple administration of rhTPO:
8 patients were divided into two groups. Group 1 received the administration every other day (sc. RhTPO 1.0 μg/kg, equal to 300U/Kg, totally 7 times) and Group 2 received administration each day (sc. RhTPO 1.0 μg/kg, equal to 300U/Kg, totally 14 times). Each group consists of 4 subjects.

Along with theincreaseofadministrationfrequency,eachpatientsrhTPObloodconcentration increased accordingly.
The Cmin of Group 1 and Group 2 reached respective steady state concentration 1637 ± 969 pg/ml after 5 times and 2906 ± 1736 pg/ml after 7 times of administration.

The Cmax changing tendency of two groups kept the same as that of Cmin. The steady state  Cmax were 2135 ± 1095 pg/ml and 41933436 pg/ml separately.
There wasn’t obvious difference in kinetics parameters such as AUC, Tpeak and T1/2 after the first time administration and the last time administration. It indicated that this drug basically hadn’t the time-dependent pharmacokinetics change. In the condition of multiple subcutaneous injection of rhTPO, the blood concentration increase level was in positive correlation to the accumulative dosage of rhTPO. Within 14 times of administration, rhTPO didn’t show the tendency of accumulation.
[Clinical Study]
1. Phase I clinical study27 healthy volunteers received single subcutaneous injection of rhTPO for tolerance study.
These 27 volunteers were randomly divided into four dosage groups, respectively given 75U/kg, 150U/kg, 300U/kg and 600U/kg .
The cases in each group were 3, 6, 9 and 9.

The efficacy of rhTPO was dependant on dosage to increase platelet level for single subcutaneous injection. Within the range of 150U/kg to 600U/kg, the average increase of platelet level is 24% to 52% than prior to administration. Occasionally the 100% increase of platelet level occurred. The count of platelet increased to the peak after 10 to 14 days’ administration and returned to the baseline (level prior to administration) after 21 days’ administration. One case was found to have transient lower fever and inertia and one case had drowsiness, but both regressed naturally.

Once case had transient mild ALT and AST increase and recovered one week later.

Additionally 7 blood tumor patients received continuous subcutaneous injection for tolerance study.
The dosage was 300U/kg, once per day, in conjunctive 7 to 14 days. The platelet level of total patients increased to different degree and reached the peak 14 to 28 daysafteradministration. Once patient was found to get pain in right tibia 7 days after administration. After 2 daystreatment according to the disease, the pain relieved and no similar phenomena appeared in later period of
administration. One case had transient mild ALT and AST increase and returned to normal one week later.
2. Class II Clinical Study Random crossing and self-control methods were adopted to 62 solid tumor patients receiving chemotherapy. During treatment course rhTPO was administrated to the patients 6 to 24 hours after chemotherapy. The dosage was 300U/kg, once per day for 7 to 14 days. In control period, no rhTPO was applied after chemotherapy as self-control. The descendent minimum of blood platelet during treatment course and self-control period were 61±51109/L and 48±35109/（P0.05respectively. The maximum of the recovered platelet count after chemotherapy were 260±164109/L and 152±81109/L（P0.001） respectively. After chemotherapy, the median days needed for platelet count recoveringtomorethan75109/L were 14 days and 18 days separately (P0.001). The adverse effect of rhTPO was rare and mild. 2 cases of patients had side effects related to rhTPO such as fever after administration and the highest to 38.8℃, which faded naturally or the body temperature recovered to normal after stopping administration.
RhTPO has taken no obvious effect to hemoglobin, red blood cell, and white blood cell count recovery after administration; no obvious effect to blood platelet shape, blood plateletaggregation function, liver & kidney function etc. 7 cases of patients are monitoring for anti-rhTPO antibody during administration course. Among them, one patient was detected to have lower titer (1:5) antibody in serum 14th days after administration, and no influence to the function of increasing platelet level of rhTPO was found.

3．Phase Ⅲ Clinical TrailIn the multiple centers clinical trial of phase Ⅲ, among 311 subjects of
patients, random crossing self-control methods were applied to 92 cases of solid tumor patients with platelet decrease after receiving chemotherapy.
During treatment course rhTPO was administrated to the patients 6 to 24 hours afterchemotherapy.

The dosage was 300U/kg, once per day for 7 to 14 days. In control period, no rhTPO was applied after chemotherapy as self-control.
The descendent minimum of blood platelet during treatment course and self-control period were 66±41109/L and 55±27109/（P0.001）respectively. The maximum of the recovered platelet count after chemotherapy were 266±126109/L and 146±56109/L（P0.001）respectively. Afterchemotherapy, the median days needed for platelet count recover to more than 75109/L were 11 days and
16 days separately (P0.001). The results showed that after chemotherapy, when the platelet reduced, rhTPO could obviously increase platelet count, reduce the descendent minimum of blood platelet, and speed up the recovery of platelet count. Among 92 cases of solid tumor patients, 42 cases of patients were found that their platelet count obviously descended after chemotherapy in control period. According to the statistic result to this group, the median minimum counts of blood platelet descendent after chemotherapy between Administration period and Control period were
separately 50109/L and 32109/L（P0.001）.
The median maximumcountsofplateletrecoveryafterchemotherapywere204109/Land114

109/L（P0.001）respectively.

The mediancountswithplateletlevellowerthan50109/L after chemotherapy were 1 day and 6 days (P0.001).
For the related adverse effect in phase Ⅲclinical study, please refer to
[Adverse Effect].
Result of phase Ⅲ Clinical StudyTreatment Period Control PeriodThe minimum of descendent platelet count after chemotherapy （109/L） 66±41
55±27The maximum of recovered platelet count after chemotherapy（109/L） 266±126 146±56The median days needed for platelet recovery to or more than 75109/L after chemotherapy 11 16RhTPO is suitable for the thrombocytopenia associated with chemotherapy in cancer patients with solid tumour. RhTPO therapy is recommended to
patients with the platelet level lower than 50×109/L or the doctor considered it necessary to increase the level of platelet
[Dosage and administration]
RhTPO therapy should be given under direct medical supervision.
The administration, dose and course of treatment should be adjusted according to the different disease.
The followingadministrationisrecommended:When patient receives chemotherapy on malignant solid tumor, the dosage of drugmayleadtothrombocytopenia and bleeding, then rhTPO shall be given by subcutaneous injection in 6 to 24 hours after chemotherapy. The dose is 300u/kg bodyweight once everyday by subcutaneous administrationcontinually for 14 days.
The administration shall be stopped when the level of platelet return to behigherthan100109/L during the process of administration or the
absolute value increment of blood platelet is higher than 50109/L. Anemia or leukopenia associated with chemotherapy, rhTPO shall be used respectively in combination with rhG-CSF or rhEPO.
[Adverse reaction]
Adverse reactions have been observed rarely. Fever, myalgia and dizzy occurred occasionally and most of them could recover automatically. And
the clear symptoms happened in individual patient can be corrected by expectant treatments. The severe adverse reactions have not been observed
in the III clinical trials. And among the 311 patients, the gentle adverse reaction associated with rhTPO occurred in 18 patients. Among them, 4 patients were fever, 2 were shiver, 1 was discomfort from head to foot, 2 were fatigue, 2 were arthralgia of knee, 2 were headache. 3 were dizzy and 2 patients’ blood pressure increased. But the symptoms were mostly gentle and need not the special disposal. The results of examining in the laboratory showed the rhTPO had no influence on the recovery of the amount of hemoglobin and leukocyte after chemotherapy. And havenonotability influence on the shape and aggregation of blood platelet, the function of coagulation, liver and renal. 74 patients received the detection of dynamic antibody in the treatment cycle.
The low titer (1:5) non－neutralization antibody of rhTPO were detected in the serum of three patients at the 21 days and 28 days after administration. And the influence on the function of rhTPO to increase the level of blood platelet
has not been observed.
The adverse reactions associated with rhTPO (311 patients)Adverse reaction Patients  Fever 4（1.3%）Shiver 2（0.6%）Discomfort from head to foot 1（0.3%）Fatigue 2（0.6%）Knee arthralgia 2（0.6%）Headache 2（0.6%）Dizzy 3（1.0%）C hyper 2（0.6%）
[Contraindications]
1. RhTPO is contraindicated in patients with known hypersensitivity to the ingredients of TPO
2. RhTPO is contraindicated in patients with severe cardio-cerebral vascular angiopathy
3. RhTPO is contraindicated in patients with blood agglutination or a history of thrombosis happened recently
4. The severe infected patients shall be incorporated in order to inhibit patients from reusing the rhTPO after infection.
[Precautions]
1. The blood platelet shall be increased overly when the excessive rhTPO is administrated, so the rhTPO treatment recommended for patients should
be under direct medical supervision in 3Ahospital.
2. RhTPO treatment is recommended for patients with the blood platelet level lower than 50×109/Lorthedoctorconsidereditnecessarytoincreasetheconcentration of blood platelet.
3. RhTPO shall be administrated in 6 to 24 hours after chemotherapy
4. The blood routine examination shall be made at the fixed period, commonly once two day. And attention must be paid to the variation of peripheral blood platlet count. The administration shoud be stopped, when the count of blood platelet attain to the standard.
[Pregnancy and nursing mothers]
The safety of TPO therapy in pregnant women has not been established. It is not known whether TPO is excreted in human milk. Cautions should be taken when TPO is administered to a nursingmother.
[Drug interactions]
No evidence of interaction of rhTPO with other drugs was observed in the course of clinical trials.
[Specification]
7500U/ml or 15000 U/1ml
[Storage]
Store at 2-8℃. Avoid direct sunshine. 2~8℃1 vial, 1ml/vial
[Shelf life]
The shelf life of the drug is three years from the date of repackaging
[Approval No.]
7500U/1ml GUOYAOZHUNZIS20050049, 15000U/1ml GUOYAOZHUNZIS20050048
[Manufacturer]
Shenyang Sunshine Pharmaceutical Co., Ltd.
[Address]
No.3 A1, 10th Road, Shenyang Economy& Technology DevelopmentZone,Shenyang 110027, P.R. China