Biological activity
of indigenously made recombinant human G-CSF (Neukine)
was assessed by in-vitro assay using NFS-60 cell (murine
myelobalstic cell lines) and compared with the reference
standard from National Institute of Biological Standards
and Controls (NIBSC). The biological activity of Neukine
is more than 1 108IU/mg of protein and comparable to the
specific activity of reference standard.
The relative potency
of Neukine 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 doses of 250, 2500 and 5000 mcg/kg of Neukine.
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 the 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 histopathological examination of body organs. There
was no abnormality detected in any of the parameters in
both the animals. Neukine 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 monocytes, 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.
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, is approximately 3.5 hours. Clearance
rates of Recombinant G-CSF are 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
a 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 prevention 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 Neukine in Indian
patients:
The efficacy and safety of Neukine was evaluated in an open label, phase III
confirmatory trial conducted in Indian patients for prevention of neutropenia.
This multicenter study enrolled 100 adult patients with all types of cancers
except leukemia and Neukine 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
Neukine administration). In this study, the median ANC in the index cycle was
480 cell/mm3 and in subsequent cycles were 1800 and 2552 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 Neukine administration as compared to index cycle
without Neukine. There were more incidences of severe (ANC <500 cells) and
febrile (<1000 with fever) neutropenia in-patients receiving cancer chemotherapy
without Neukine support than in cycles with prophylactic administration of
Neukine. The use of antibiotics was significantly reduced during cycles with
Neukine administration. The drug was well tolerated in all the patients and
no significant adverse effect was reported with Neukine in this study.
INDICATIONS AND USAGE
Cancer Patients Receiving Myelosuppressive
Chemotherapy
Recombinant G-CSF is
indicated to decrease the incidence of infection,
as manifested by febrile neutropenia, in-patients
with nonmyeloid malignancies receiving myelosuppressive
anti-cancer drugs associated with a significant incidence
of severe neutropenia with fever. A complete blood
count (CBC) and platelet count should be obtained
prior to chemotherapy, and twice per week during
Recombinant G-CSF therapy to avoid leukocytosis and
to monitor the neutrophil count.
Patients with Acute Myeloid
Leukemia Receiving Induction or Consolidation Chemotherapy
Recombinant G-CSF
is indicated for reducing the time to neutrophil recovery
and the duration of fever, following induction or consolidation
chemotherapy treatment of adults with AML.
Cancer Patients Receiving Bone
Marrow Transplant
Recombinant G-CSF is indicated
to reduce the duration of neutropenia and neutropenia-related
clinical sequelae, eg, febrile neutropenia, in-patients
with nonmyeloid malignancies undergoing myeloablative
chemotherapy followed by marrow transplantation. It
is recommended that CBCs and platelet counts be obtained
at a minimum of 3 times per week following marrow infusion
to monitor the recovery of marrow reconstitution.
Patients Undergoing Peripheral
Blood Progenitor Cell Collection and Therapy
Recombinant G-CSF is indicated for the mobilization
of hematopoietic progenitor cells into the peripheral
blood for collection by leukapheresis. Mobilization
allows for the collection of increased numbers of progenitor
cells capable of engraftment compared with collection
by leukapheresis without mobilization or bone marrow
harvest.
CONTRAINDICATIONS
Recombinant G-CSF is
contraindicated in patients with known hypersensitivity
to E. coli-derived proteins, Recombinant G-CSF, or any
component of the product.
For
further details and product specifications please contact
us.
