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Pharmacology: Pharmacodynamics: Pegfilgrastim is a covalent conjugate of recombinant human G-CSF (r-metHuG-CSF) with a single 20kD polyethylene glycol (PEG) molecule. Pegfilgrastim is a sustained duration form of Filgrastim due to decreased renal clearance. Pegfilgrastim and Filgrastim have been shown to have identical modes of action, causing marked increase in peripheral blood neutrophils counts within 24hrs, with minor increases in monocytes and for lymphocytes. Similarly to Filgrastim, neutrophils produced in response to Pegfilgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. As with other hematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells. G-CSF can promote growth of myeloid cells, including malignant cells, in vitro and similar effects may be seen on some non-myeloid cells in vitro.
Clinical Report: The clinical trial Project No. Pegfil.08.001.01 conducted by Zydus Cadila was an open label, multicentric trial, where the efficacy and safety of Pegylated Form of Recombinant Human Granulocyte Colony stimulating Factor (Pegfilgrastim) were assessed in 63 patients undergoing myelosuppressive chemotherapy. Pegfilgrastim was given as single 6 mg subcutaneous injection per cycle.
The study showed the following results: Reduction in the duration of grade 3 neutropenia from 4 days in documentation cycle to 2 days in cycle 1(p=0.0078*) and 3 days in cycle 2 (p=0.0219*).
Reduction in the time to neutrophil recovery from 15.5 days in documentation cycle to 12 days in cycle 1 (p=0.0005*) and 8 days in cycle 2 (p<0.0001*).
Reduction in the incidence of febrile neutropenia from 4.92% in the documentation cycle to 1.75% in cycle 2, while none of the subjects had febrile neutropenia in cycle 1.
Reduction in the incidence of parenteral antibiotics from 9.83% in documentation cycle to 6.56% in cycle 1 and 1.75% in cycle 2. There was no significant difference seen in the duration of parenteral antibiotics in all the cycles.
Pegfilgrastim was well tolerated among the patients with favorable safety profile.
The results are also comparable to the published Filgrastim reports demonstrating that a single fixed dose of 6 mg of Pegfilgrastim provides support to patients with chemotherapy induced neutropenia in a manner similar to multiple daily doses of Filgrastim.
The results of Cycle 1 and Cycle 2 in which Pegfilgrastim was given were compared to the documentation cycle of chemotherapy where no Pegfilgrastim was administered.
As such, a fixed dose of Pegfilgrastim provides all the clinical benefits of Filgrastim but with the advantage of once-per-cycle dosing. Once-per-cycle fixed dose Pegfilgrastim is expected to simplify the management of chemotherapy-induced neutropenia, and also provide significant quality-of-life benefits to oncology patients in the form of fewer injections.
Pharmacokinetics: After a single subcutaneous dose of Pegfilgrastim, the peak serum concentration of Pegfilgrastim occurs at 16 to 120 hrs after dosing and serum concentrations of Pegfilgrastim are maintained during the period of neutropenia after myelosuppressive chemotherapy. The elimination of Pegfilgrastim is non-linear with respect to dose; serum clearance of Pegfilgrastim decreases with increasing dose.
Pegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance, which becomes saturated at higher doses. Consistent with a self-regulating clearance mechanism, the serum concentration of Pegfilgrastim declines rapidly at the onset of neutrophil recovery.
Due to the neutrophil-mediated clearance mechanism, the pharmacokinetics of Pegfilgrastim is not expected to be affected by renal or hepatic impairment.
In addition to numbers of neutrophils, body weight appeared to be a factor. Patients with higher body weights experienced higher systemic exposure to Pegfilgrastim after receiving a dose normalized for body weight. A large variability in the pharmacokinetics of Pegfilgrastim was observed in cancer patients. The half-life of Pegfilgrastim ranged from 15 to 80 hours after subcutaneous injection.
Limited data indicate that the pharmacokinetics of Pegfilgrastim in elderly subjects >65 years is similar to that in adults.
The pharmacokinetic profile in pediatric populations or in patients with hepatic insufficiency has not been assessed.
Toxicology: Preclinical Safety Data: Acute subcutaneous toxicity in Wistar Rats: Single dose of 3.1, 6.2 and 12.4 mg/kg.
No clinical signs.
No mortality.
No statistical significant changes in body weight.
Spleen enlargement in mid and high dose groups of male and high dose groups of female.
Histopathological evaluation of spleen showed proliferation of megakaryocytes in red pulp.
These findings can be attributed to its pharmacological properties.
Acute subcutaneous toxicity in Swiss Albino Mice: Single dose of 6.15, 12.3 and 24.6 mg/kg.
No clinical signs.
No mortality.
No statistical significant changes in body weight.
Spleen enlargement in mid and high dose groups of male and female.
Histopathological evaluation of spleen showed proliferation of megakaryocytes in red pulp.
These findings can be attributed to its pharmacological properties.
Acute intramuscular toxicity in Wistar Rats: Single dose of 3.1, 6.2 and 12.4 mg/kg.
No clinical signs.
No mortality.
No statistical significant changes in body weight. However, some degree of reduction in body weight gain was observed in treatment groups as compared to control.
Spleen enlargement in high dose group of male and female.
Histopathological evaluation of spleen showed proliferation of megakaryocytes in red pulp.
These findings can be attributed to its pharmacological properties.
Acute intramuscular toxicity in Swiss Albino Mice: Single dose of 6.15, 12.3 and 24.6 mg/kg.
No clinical signs.
No mortality.
No statistical significant changes in body weight.
Spleen enlargement in mid and high dose groups of female.
Histopathological evaluation of spleen showed proliferation of megakaryocytes in red pulp.
These findings can be attributed to its pharmacological properties.
Repeated dose subcutaneous toxicity study in Wistar Rats: Doses of 0, 1.55, 3.1, 6.2 mg/kg.
Development of articular swelling and partial hind limb dysfunction in some high dose treated animals.
Dose dependent increase in WBC and Absolute neutrophil count and decrease in RBC, hemoglobin, HcT and platelet count. Reversible effect.
Dose dependent increase in spleen size associated with proliferation of megakaryoctes in red pulp.
These findings can be attributed to its pharmacological properties.
Mild congestion of liver and kidney.
Repeated dose subcutaneous toxicity study in Rabbits (New Zealand White): Doses of 0.755, 1.55 and 3.1 mg/kg.
Increase in WBC and neutrophil count and dose dependent decrease in RBC, hemoglobin and Hct. Reversible effect.
In males, marginal decrease in AST and urea level and in female increased triglyceride level.
Increasing trend was seen in Alp and decreasing trend in urea level. Increase in absolute organ weight of liver and spleen of low and mid dose of males as compared to control group.
Histopathologically; Proliferation of neutrophils in red pulp area of spleen. Mild congestion in liver. Focal area of minimal tubular swelling and degeneration in kidney.
One mortality in high dose female group. This occurred in the high dose group (3.1 mg/kg) whose equivalent dose in human is much higher than the therapeutic dose.
Skin sensitization test - Guinea Pig Maximization Test: No clinical signs.
No mortality.
No skin reaction at 2.3 mg/ml at Challenge and Re-challenge exposure.
Therefore as per the Maximization sensitization classification system, Pegfilgrastim can be classified as Non-sensitizer.
Immunogenicity test in Wistar Rats and Rabbits (New Zealand White): In treated animals moderate levels of anti G-CSF antibody was found which were higher in rabbits than rats.
The anti-HCP titers of treated animals were not significantly different from their respective controls.
The low levels of anti-HCP titers confirm our direct observation of low HCP contamination in our product as tested by HCP-specific ELISA.
Reproductive toxicity: No adverse effects observed in offspring from pregnant rats given Pegfilgrastim subcutaneously, but in rabbits Pegfilgrastim has been shown to cause embryo/fetal toxicity (embryo loss) at low subcutaneous doses. In rat studies, it was shown that Pegfilgrastim may cross the placenta. The relevance of these findings for humans is not known.
