[Drug Names]
Generic Name：Recombinant human thrombopoietin injection
Trade Name：TPIAO
English Name：Recombinant Human Thrombopoietin Injection
Chinese Phonetic Alphabet：Chongzu Ren Xuexiaoban Shengchengsu Zhusheye
Ingredients：Recombinant human thrombopoietin, Human serum albumin, 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 full-length glycosylated thrombopoietin which is expressed in China Hamster Ovary (CHO) cell line via recombinant genetic technology. It has similar pharmacological function 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 (1.1102 U, 1.1103 U and 1.1104 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 1.1103 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 can especially enhance the expression of megakaryocytic 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 1.35105 U/kg and 2.25105 U/kg (Correspond to 900 and 1500 times of recommended 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 1.5104 U/kg, 7.5103 U/kg and 1.5103 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 weeks after stop of administration, meganucleus series of bone marrow also recovered obviously. 1.5103 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 9102 U/kg, 1.8103 U/kg and 5.4103U/kg (Separately corresponding 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 the increase of administration frequency, each patient’s rhTPO blood concentration 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 41933436 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 study
27 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 days after administration. Once patient was found to get pain in right tibia 7 days after administration. After 2 days’ treatment 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±51109/L and 48±35109/L（P0.05）respectively. The maximum of the recovered platelet count after chemotherapy were 260±164109/L and 152±81109/L（P0.001） respectively. After chemotherapy, the median days needed for platelet count recovering to more than 75109/L were 14 days and 18 days separately (P0.001). 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 platelet aggregation 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 Trail
In 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 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 66±41109/L and 55±27109/L（P0.001）respectively. The maximum of the recovered platelet count after chemotherapy were 266±126109/L and 146±56109/L（P0.001）respectively. After chemotherapy, the median days needed for platelet count recover to more than 75109/L were 11 days and 16 days separately (P0.001). 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 50109/L and 32109/L（P0.001）. The median maximum counts of platelet recovery after chemotherapy were 204109/L and114109/L（P0.001）respectively. The median counts with platelet level lower than 50109/L after chemotherapy were 1 day and 6 days (P0.001). For the related adverse effect in phase Ⅲ clinical study, please refer to [Adverse Effect].
Result of phase Ⅲ Clinical Study
Treatment Period Control Period
The minimum of descendent platelet count after chemotherapy （109/L） 66±41 55±27
The maximum of recovered platelet count after chemotherapy（109/L） 266±126 146±56
The median days needed for platelet recovery to or more than 75109/L after chemotherapy 11 16
[Indications]
RhTPO 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 following administration is recommended:
When patient receives chemotherapy on malignant solid tumor, the dosage of drug may lead to thrombocytopenia 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 administration continually for 14 days.
The administration shall be stopped when the level of platelet return to be higher than 100109/L during the process of administration or the absolute value increment of blood platelet is higher than 50109/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 have no notability 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 3 A hospital.
2. RhTPO treatment is recommended for patients with the blood platelet level lower than 50×109/L or the doctor considered it necessary to increase the concentration 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 nursing mother.
[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 Development Zone, Shenyang 110027, P.R. China
[Telephone]
0086-24-25811820
[Website]
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