Recombinant human thrombopoietin.
Strength of active ingredient: Recombinant Human Thrombopoietin Concentrated Solution 15000 U/ml.
Excipients/Inactive Ingredients: Recombinant Human Thrombopoietin Concentrated Solution, Human Albumin Solution, NaCl.
Pharmacology: Pharmacodynamics: Thrombopoietin (TPO) is an endogenous cytokine which can stimulate the growth and differentiation of megakaryocyte. It can increase the platelet count through its stimulative function on each growth phase of megakaryocyte including proliferation of precursor cell, development and maturation of polyploid megakaryocyte. 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 platelet count with endogenous thrombopoietin.
rhTPO 150 U/Kg, rhTPO 600 U/Kg or human albumin solution 20μg/Kg was separately injected once per day for 20 continuous days to myelosuppression macaque created by great dosage systemic radiation of 60Coγ. The testing result shows that rhTPO can increase the average value of platelet count, shorten the time of thrombocytopenia and increase the aggregation rate of peripheral blood platelet under myelosuppression. Its lowest effective dosage is 150 U/Kg per day.
Balb/c mice, which were injected with carboplatin (150 mg/kg) by intraperitoneal injection as model of thrombocytopenia. rhTPO (1.1x102 U, 1.1x103 U and 1.1x104 U/kg) and physiological saline separately were given once per day for 10 continuous days, rhTPO therapy can alleviate the thrombocytopenia caused by carboplatin obviously when the dose is more than 1.1 x 103 U/kg.
After adding rhTPO into the vitro culture system of normal human bone marrow cell, HEL and DAMI cell lines with megakaryocyte antigen expression, rhTPO can specifically enhance the expression of CD41 antigen in megakaryocyte line and monocyte of normal human bone marrow, and promote the production of CFU-Meg.
Clinical Studies: 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 rhTPO. And the subjects 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 was 24% to 52% than prior to administration. Occasionally the 100% increase of platelet level occurred. The platelet count increased to the peak in 10 to 14 days after administration and returned to the baseline (level prior to administration) in 21 days after administration. One subject had transient lower fever and inertia and one subject had drowsiness, but both disappeared by itself. One subject had transient mild ALT and AST increase and recovered one week later.
Additionally 7 hematologic tumor patients received continuous subcutaneous injection for tolerance study. The dosage was 300U/kg, once per day, for 7 to 14 continuous days. The platelet level of total patients increased to different degrees and reached the peak in 14 to 28 days after administration. One subject was found to get pain in right tibia in 7 days after administration. After 2 days' symptomatic treatment, the pain relieved and no similar phenomena recurred. One subject had transient mild ALT and AST increase and returned to normal one week later.
Phase II Clinical Study: Random-crossing and self-control methods were adopted on 62 solid tumor patients receiving chemotherapy. During treatment course, rhTPO was administered to the patients in 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. In administration period and control period, the minimum of platelet count were 61±51x109/L and 48±35x109/L (P<0.05) respectively; the maximum of the recovered platelet count after chemotherapy were 260±164x109/L and 152±81x109/L (P<0.001) respectively; after chemotherapy, the median days for platelet count recovering to more than 75x109/L were 14 days and 18 days respectively (P<0.001). The adverse effect of rhTPO was rare and mild. 2 subjects had side effects related to rhTPO, such as fever to 38.8°C after administration, which faded by itself or the body temperature recovered to normal after withdrawal. rhTPO had no obvious effect on the recovery of hemoglobin, red blood cell, and white blood cell after administration; no obvious effect on platelet shape, platelet aggregation function, liver & kidney function etc. 7 subjects received the dynamic monitor of anti-rhTPO antibody during administration period. Among them, one subject was detected to have lower titer (1:5) antibody in serum on the 14th day after administration, but no influence on the function of rhTPO to increase the platelet count was found.
Phase III Clinical Study: The phase III multiple centers clinical study enrolled 213 subjects with solid tumor. There were 154 subjects in random cross self-control trial and 59 subjects in non-random self-control trial. In administration period, rhTPO was administered to the patients in 6 to 24 hours after chemotherapy by s.c. at 1.0μg/kg, once daily for 14 days. In control period, no rhTPO was administered after chemotherapy as self-control. The results showed that rhTPO could increase platelet level at the last visit (208.08±114.67x109/L VS. 137.03±70.05x109/L, P<0.01) and increase the highest level of platelet after chemotherapy (263.32±162.51x109/L VS. 148.31±70.80x109/L, P<0.01); Alleviate platelet damage level caused by chemotherapy, increase the lowest level of platelet after chemotherapy (64.06±45.51x109/L VS. 49.12±29.51x109/L, P<0.01); The days platelet recovered to 75.00×109/L was shortened about one week (12.00 VS. 19.00 days, P< 0.01); The days platelet recovered to 100.00×109/L was shortened about one week (16.00 VS. 23.00 days, P< 0.01); The duration of the platelet count below 75.00×109/L in administration period was significant lower than control period (7.00 VS. 8.00 days, P< 0.01); Reduce platelet transfusion rate (10% VS. 17.50%, P<0.05) and decrease the times and amount of platelet transfusion (P< 0.05). For the related adverse effect in phase III clinical study, please refer to Adverse Reactions.
Pharmacokinetics: Pharmacokinetics study on single s.c. 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 subjects 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 administration every other day (s.c. rhTPO 1.0 μg/kg, equal to 300U/Kg, totally 7 times) and Group 2 received administration each day (s.c. rhTPO 1.0 μg/kg, equal to 300U/Kg, totally 14 times). Each group consisted of 4 subjects. Along with the increase of administration times, each patient's rhTPO blood concentration increased accordingly. The Cmin of Group 1 and Group 2 reached respectively steady state concentration 1637 ± 969 pg/ml after 5 times of administration and 2906 ± 1736 pg/ml after 7 times of administration. The Cmax changing tendency of two groups kept the same as those of Cmin. The steady state Cmax were 2135 ± 1095 pg/ml and 4193±3436 pg/ml respectively. There wasn't obvious difference in kinetics parameters such as AUC, Tpeak and T1/2 between after first administration and after last administration. It was indicated that this drug basically hadn’t the time-dependent pharmacokinetics change. In the condition of multiple subcutaneous injection of rhTPO, the increase level of blood concentration was in positive correlation to the accumulative dosage of rhTPO. Within 14 times of administration, rhTPO didn’t show the tendency of accumulation.
Toxicology: Acute toxicity: rhTPO were separately injected slowly to rat and mice through vein in tail at the dosage of 1.35x105 U/kg and 2.25x105 U/kg (corresponding to 450 and 750 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 by histopathology test.
rhTPO were separately injected to rat and mice back by s.c. at the dosage of 1.8x105 U/kg and 4.5x105 U/kg (corresponding to 600 and 1500 times of recommended dosage on clinical use). No obvious toxicity reaction after administration. No toxicity reaction or death was found during 14 days after injection. No abnormality was found in main organs by histopathology test.
Chronic toxicity: rhTPO was injected to Wistar rats by s.c. at the dosage of 1.5x104 U/kg, 7.5x103 U/kg and 1.5x103 U/kg (respectively corresponding to 50 times, 25 times and 5 times of recommended dosage on clinical use) for 35 continuous days. Two control groups were injected with 0.5% human albumin solution and physiological saline respectively. 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 each time point. In 3 weeks after injection, peripheral platelet count continuously decreased obviously along with the administration times, especially in high dosage group. Megakaryocyte of bone marrow in high and medium dosage group recovered slowly after withdrawal. It was demonstrated that obvious cumulative toxicity in high and medium dosage group occurred in 2 weeks after administration. Cumulative toxicity in low dosage group occurred in 4 weeks after administration, disappeared in 2 weeks after withdrawal along with bone marrow megakaryocyte lines recovered obviously. 1.5x103 U/kg should be the dosage under which rhTPO is injected to rats by s.c. without obvious side and toxic effect.
rhTPO, 0.5% human albumin solution and physiological saline were respectively injected by s.c. to 24 rhesus monkeys for 30 days. rhTPO was administered at the dosage of 9x102 U/kg, 1.8x103 U/kg and 5.4x103 U/kg (respectively corresponding to 3 times, 6 times and 18 times of recommended dosage on clinical use). Such rhesus monkeys were observed for 58 days after injection (30 days of administration, 28 days after withdrawal). The observation result demonstrated that there was no significant difference among each group on general situation, orexia, weight, body temperature, biochemical analysis of blood serum, urine test, ECG and histo-pathology of male/female rhesus monkeys. In middle, high dosage group, 30 days of rhTPO administration caused the peripheral platelet count radically increased in the earlier period, and then turned to dramatically decrease and the recovery of platelet count was slow. It was indicated that large dosage and long-term continuous administration would cause megakaryocyte production obstacle of rhesus monkeys after promoting the production of platelet radically. No obvious accumulative toxicity occurred in lower dosage group in 30 days after administration to rhesus monkeys. 9x102U/kg BW should be the dosage under which rhTPO is injected to rhesus monkeys without obvious side and toxic effect.
Mutagenic toxicity: rhTPO had no effect of increasing micronucleus rate of bone marrow polychromatic erythrocytes of NIH mouse. rhTPO at 3x103U/kg, 1.5x103U/kg, 7.5×102U/kg, 3.8×102U/kg and 1.9x102U/kg had no effect to induce gene mutation of Salmonella typhimurium. rhTPO at 2.4x104U/ml had no effect to induce chromosome aberration on human diploid cell. The results of micronucleus test, Ames test and chromosome test were all negative.
TPIAO is suitable for the chemotherapy-induced thrombocytopenia in patients with solid tumour. TPIAO therapy is recommended to patients with the platelet count less than 50x109/L and the doctor considered it is necessary to increase the platelet count.
TPIAO 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 with malignant solid tumor receives chemotherapy, and the dosage of drug is predicted to induce thrombocytopenia and hemorrhage, then TPIAO shall be given by subcutaneous injection in 6 to 24 hours after chemotherapy. The dose is 300U/kg bodyweight once per day by subcutaneous injection for 14 continuous days.
The administration shall be stopped when the platelet count recovers to ≥ 100x109/L during the process of administration or the absolute increment of platelet count is ≥ 50x109/L. If anemia or leukopenia associated with chemotherapy occurs, TPIAO shall be used respectively in combination with rhEPO or rhG-CSF.
It is contraindicated in patients with known hypersensitivity to the ingredients of TPIAO.
It is contraindicated in patients with severe cardio-cerebral vascular angiopathy.
It is contraindicated in patients with blood agglutination or a history of thrombosis happened recently.
For the patients with severe infection, it shall be used after the infection is controlled.
For specific person with idiosyncrasy, the platelet count might increase in excess when the TPIAO is administered, so it should be under direct medical supervision in 3A hospital.
TPIAO is suitable for chemotherapy-induced thrombocytopenia in cancer patients with solid tumours. TPIAO therapy is recommended to patients with the platelet level lower than 50x109/L or physicians considered it necessary to increase the level of platelet.
For the patients with chemotherapy-induced thrombocytopenia in solid tumours, TPIAO shall be given in 6 to 24 hours after chemotherapy.
During TPIAO therapy, the periodic routine blood test should be performed, generally once every other day, to monitor the changes of peripheral platelet count. If platelet count reaches the target level, TPIAO should be stopped. Routine blood tests should be monitored (including platelet count and peripheral blood smear) before, during and after TPIAO therapy. Peripheral blood classification should be tested to establish the baselines of RBC&WBC morphologic abnormality before TPIAO therapy. Periodic routine blood test (including platelet count and peripheral blood smear) should be performed before TPIAO therapy and in 2 weeks at least after withdrawal.
There aren't sufficient clinical supporting data to endorse the safety of TPIAO therapy in pregnant or lactation women. Like many other medicinal products, cautions should be taken when TPIAO is administered to a nursing mother.
Adverse reactions related TPIAO administration are rarely and most of them could recover automatically. The symptomatical treatment was applied for individual patient when they had obvious adverse reaction. In 213 patients, there were 11 (5.16%) cases adverse events occurred in 10 (4.69%) patients were related to TPIAO administration (including "possibly related", "much possibly related" and "related"): 6 (2.82%) cases of fever, 2 (0.94%) cases of chill, 1 (0.47%) case of dizziness, 1 (0.47%) case of vomit, 1 (0.47%) case of bone marrow suppression. Most of the symptoms were slight, which disappeared without special treatment. The results of examination in the laboratory showed that TPIAO injection had no influence on subjects' coagulation function, blood/urine/stool routine, liver and kidney function and ECG etc. 74 subjects accepted dynamic detection of antibodies in TPIAO administration period, only 3 subjects' serum appeared low-titer (1:5) non-neutralizing anti-rhTPO antibody on the 14th
day after administration.
The adverse reactions associated with TPIAO (213 subjects): See Table.
Click on icon to see table/diagram/image
There aren't sufficient clinical supporting data to endorse interaction of TPIAO with other drugs.
Store at 2-8°C, avoid direct sunlight.
Shelf-Life: 36 months.
B01AX - Other antithrombotic agents ; Used in the treatment of thrombosis.
Inj (vial) 15,000 U/mL (colorless and transparent liquid without any macroscopic insoluble substance) x 1's.