Pharmacology: Preclinical Pharmacology: Biological activity of indigenously made recombinant human G-CSF Filgrastim (SciLocyte) was assessed by in-vitro assay using NFS-60 cell (murine myeloblastic cell lines) and compared with the reference standard from National Institute of Biological Standards and Controls (NIBSC). The biological activity of Filgrastim (SciLocyte) is more than 1 x 108 IU/mg of protein and comparable to the specific activity of reference standard.
The relative potency of Filgrastim (SciLocyte) was assessed in an in-vivo assay using neutropenic mice, and comparing it with the reference standard. In this test, both the test and reference drug were found comparable and equipotent.
Acute toxicity studies were conducted in rats and mice by administering I.V. and S.C. single dose of 250, 2500 and 5000 mcg/kg of Filgrastim (SciLocyte). The animals were observed for mortality, clinical signs and gross organ examinations. There was no death or any other adverse effect in the animals at all dose levels. In repeat dose subacute toxicity studies in rats and mice a dose of 50, 100, 250 mcg/kg was administered for a period of 28 days by SC and IV routes. The animals were examined for body weight changes, food consumption, blood chemistry and hispathological examination of body organs. There was no abnormality defected in any of the parameters in both the animals. Filgrastim (SciLocyte) was well tolerated in low, medium and high dose levels in these studies.
Clinical Pharmacology: Endogenous G-CSF is a lineage specific colony-stimulating factor, which is, produced by monocyte, fibroblasts, and endothelial cells. G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, differentiation and selected end-cell functional activation (including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory burst, antibody dependent killing and the increased expression of some functions associated with cell surface antigens).
Pharmacologic Effects of Recombinant G-CSF: In patients with various nonmyeloid malignancies, Recombinant G-CSF administration results in a dose-dependent increase in circulating neutrophil counts. With discontinuation of Recombinant G-CSF therapy, neutrophil counts returns to baseline, in most cases within 4 days. Isolated neutrophils display normal phagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic (measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine [fMLP] as the chemotaxin) activity in vitro.
The absolute monocyte count is reported to increase in a dose-dependent manner in most patients receiving Recombinant G-CSF however, the percentage of monocytes in the differential count remains within the normal range. Absolute counts of both eosinophils and basophils do not change and are within the normal range following administration of Recombinant G-CSF. Increases in lymphocyte counts following Recombinant G-CSF administrations have been reported in some normal subjects and cancer patients.
White blood cell (WBC) differentials obtained during clinical trials have demonstrated a shift towards earlier granulocyte progenitor cells (left shift), including the appearance of promyelocytes and myeloblasts, usually during neutrophil recovery following the chemotherapy-induced nadir. In addition, Dohle bodies, increased granulocyte granulation, as well as hypersegmented neutrophils have been observed.
Such changes are transient, and are not associated with clinical sequelae nor are they necessarily associated with infection.
Pharmacokinetics: Absorption and clearance of Recombinant G-CSF follows first-order pharmacokinetic modeling without apparent concentration dependence. A positive linear correlation occurs between the parenteral dose and both the serum concentration and area under the concentration-time curves. Continuous IV infusion of 20 mcg/kg of Recombinant G-CSF over 24 hours results in mean and median serum concentrations of approximately 48 and 56 ng/mL, respectively. Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg result in maximum serum concentrations of 4 and 49 ng/mL, respectively, within 2 to 8 hours. The volume of distribution averages 150 mL/kg in both normal subjects and cancer patients. The elimination half-life, in both normal subjects and cancer patients. The elimination half-life, in both normal subjects and cancer patients, is approximately 3.5 hours. Clearance rates of Recombinant-CSF is approximately 0.5 to 0.7 mL/minute/kg. The half-lives are similar for IV administration (231 minutes, following doses of 34.5 mcg/kg) and for SC administration (210 minutes, following Recombinant G-CSF doses of 3.45 mcg/kg).
Pharmacokinetic data in geriatric patients (>65 years) are not available.
Clinical Effects: Cancer Patients Receiving Myelosuppressive Chemotherapy: Recombinant G-CSF has been shown to be safe and effective in accelerating the recovery of neutrophil counts following variety of chemotherapy regimens. In a phase 3 clinical trial, patients received SC administration of Recombinant G-CSF (4 to 8 mcg/kg/day, days 4 to 17) or placebo. The benefits of Recombinant G-CSF therapy were shown to be preventation of infection as manifested by febrile neutropenia, decreased hospitalization, and decreased IV antibiotic usage.
Several other studies, which did not directly measure the incidence of infection, but which did measure increases in neutrophils, support the efficacy of Recombinant G-CSF.
Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: Treatment with Recombinant G-CSF significantly reduced the median time to ANC recovery and the median duration of fever, antibiotic use, and hospitalization following induction chemotherapy. During consolidation therapy, patients treated with Recombinant G-CSF also experienced significant reductions in the incidence of severe neutropenia, time to neutrophil recovery, the incidence and duration of fever, and in the durations of IV antibiotic use and hospitalization.
Patients treated with a further course of standard or high-dose consolidation chemotherapy also experienced significant reductions in the duration of neutropenia.
Cancer Patients Receiving Bone Marrow Transplant: In patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) treated with myeloablative chemotherapy and autologous bone marrow transplantation (ABMT), a statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm3) occurred in the Recombinant G-CSF-treated group versus the control group. In another study, a statistically significant reduction in the median number of days of severe neutropenia occurred in the Recombinant G-CSF-treated group versus the control group (21.5 days in the control group and 10 days in both treatment groups, p <0.001). The number of days of febrile neutropenia was also reduced significantly (13.5 days in the control group, 5 days in the 10-mcg/kg/day group, and 5.5 days in the 20 mcg/kg/day group [5 days in the combined treatment groups, p < 0.0001]). There were no effects on red blood cell or platelet levels.
Efficacy of Filgrastim (SciLocyte) in Indian patients: The efficacy and safety of Filgrastim (SciLocyte) was evaluated in an open label, phase III confirmatory trial conducted in Indian patients for prevention of neutropenia. This multicenter study enrolled adult patients with all types of cancers except leukemia and Filgrastim (SciLocyte) was used for secondary prophylaxis in-patients receiving chemotherapy. Patients were evaluated for magnitude of neutropenia (median ANC) and days of recovery from neutropenia in the index cycle (chemotherapy without G-CSF support) and subsequent two cycles (cycles with prophylactic Filgrastim (SciLocyte) administration). In this study, the median ANC in the index cycle was 440.50 cell/mm3 and in subsequent cycles were 2130 and 2964 cells/mm3. The difference between the median ANC in the index cycle and subsequent cycles were statistically significant (p<0.0001). The recovery from neutropenia was faster in the cycles with prophylactic Filgrastim (SciLocyte) administration as compared to index cycle without Filgrastim (SciLocyte). There were more incidences of severe (ANC <500 cells) and febrile (<1000 with fever) neutropenia in-patients receiving cancer chemotherapy without Filgrastim (SciLocyte) support than in cycles with prophylactic administration of Filgrastim (SciLocyte). The use of antibiotics was significantly reduced during cycles with Filgrastim (SciLocyte) administration. The drug was well tolerated in all the patients and no significant adverse effect was reported with Filgrastim (SciLocyte) in this study.