Sargramostim is a recombinant human GM-CSF. The binding to GM-CSF receptors expressed on the surface of target cells (haematopoietic progenitors and mature immune cells), initiates an intracellular signalling cascade which induces the cellular responses (i.e., division, maturation, activation). GM-CSF is a multilineage factor and, in addition to dose-dependent effects on the myelomonocytic lineage, it can promote the proliferation and maturation of megakaryocytic and erythroid progenitors.
The pharmacokinetics of sargramostim are not available in patients acutely exposed to myelosuppressive doses of radiation.
Modelling and simulation of the healthy human adult pharmacokinetic data indicate that sargramostim Cmax and area under the curve (AUC) exposures at dose of 7 mcg/kg in healthy adults are expected to exceed sargramostim Cmax (97.6% of patients) and AUC (100% of patients) exposures at the same dose of 7 mcg/kg in Rhesus monkeys.
The pharmacokinetics of sargramostim in healthy paediatric patients were estimated by scaling the adult population pharmacokinetic model to the paediatric population. The model-predicted mean AUC0-24 values at 7, 10, and 12 mcg/kg doses of sargramostim in paediatric patients weighing greater than 40 kg (~adolescents), 15 to 40 kg (~young children), and 0 to less than 15 kg (~newborns to toddlers), respectively, were similar to AUC values in adults after a 7 mcg/kg dose.
Based on a population pharmacokinetics analysis of lyophilised sargramostim data, the mean Cmax after a 7 mcg/kg subcutaneous dose (equivalent to a 250 mcg/m² dose in a 70 kg human with a body surface area of 1.96 m²) was 3.03 ng/mL and mean AUC024 was 21.3 ng•h/mL. There is no accumulation of sargramostim after repeated subcutaneous dosing and steady state conditions are met after a single subcutaneous dose.
After subcutaneous administration, sargramostim was detected in the serum early (15 min) and reached maximum serum concentrations between 2.5 and 4 h.
A more than dose proportional increase in AUC was observed following a single subcutaneous administration of sargramostim across the 2 to 8 mcg/kg dose range in healthy male subjects.
In a study, healthy subjects were administered 250 mcg sargramostim by intravenous infusion over 2 hours. The observed volume of distribution (Vz) after intravenous administration was 14 L.
Specific metabolism studies were not conducted, because sargramostim is a protein and is expected to degrade to small peptides and individual amino acids.
When sargramostim was administered subcutaneously to healthy adult volunteers, it had a terminal elimination half-life of 1.4 h. The observed total body clearance/subcutaneous bioavailability (CL/F) was 23.9 l/h.
In a repeated-dose toxicity study, sargramostim was administered subcutaneously daily to cynomolgus monkeys at doses of 20 and 200 mcg/kg/day for 30 days. The lympho-haematopoietic system was identified as the primary target of toxicity: an increase in white blood cells and platelets as well as splenic inflammatory and lymphoid cell infiltration were observed at ≥20 mcg/kg/day.
Moderate to moderately severe bone marrow myeloid hyperplasia and mononuclear cell infiltrates in the heart and other organs were observed at 200 mcg/kg/day at terminal sacrifice, and moderate to moderately severe thymic atrophy was observed at 200 mcg/kg/day in both terminal and recovery animals. All findings were considered related to the pharmacology of sargramostim and therefore are potentially clinically relevant; however, the majority of the findings were observed at a dose that is approximately 17 to 29-fold greater than clinical exposure at the recommended human doses (7 to 12 mcg/kg/day) based on body weight scaling.
A similar pattern of toxicity but at a lower dose (20 mcg/kg/day) was observed in a 42-day repeated- dose toxicity study in which cynomolgus monkeys were subcutaneously administered 20, 63 and 200 mcg/kg/day with a sargramostim formulation containing ethylenediaminetetraacetic acid (EDTA), different from sargramostim. In this study, the systemic exposure (AUC) at 20 mcg/kg/day was approximately 2-fold greater than the clinical exposure at the recommended human doses (7 to 12 mcg/kg/day).
All reprotoxicity studies were carried out with a sargramostim formulation containing EDTA, different from sargramostim.
In the fertility and early embryonic development study, sargramostim was administered subcutaneously to rabbits at doses of 25, 70 and 200 mcg/kg/day from 6 days prior to artificial insemination and continuing through gestation day (GD) 7. Maternal toxicity was evident at ≥70 mcg/kg/day. A decrease in implantation sites and an increase in preimplantation loss and reduction in viable embryos was observed at 200 mcg/kg/day. The AUC at the no-observed-adverse-effect-level (NOAEL) for female reproductive and early embryonic developmental toxicity of 70 mcg/kg/day was initially (at the start of the dosing period) approximately 7.2-fold the clinical exposure at the recommended adult clinical dose (7 mcg/kg/day).
In the embryo-foetal developmental study, pregnant rabbits were administered subcutaneously doses of sargramostim during the period GD 6 to GD19 or GD19 to GD28 at 25, 70, and 200 mcg/kg/day.
Maternal toxicity was evident at ≥25 mcg/kg/day. An increase in late resorptions and reduced foetal weights were observed at ≥70 mcg/kg/day. An increase in spontaneous abortions and post-implantation loss, a reduction in viable foetuses and a reduced gravid uterine and placental weight were evident at 200 mcg/kg/day. The AUC at the NOAEL for embryo-foetal toxicity of 25 mcg/kg/day was initially (at the start of the dosing period) approximately 2.9-fold the clinical exposure at the recommended adult clinical dose (7 mcg/kg/day).
In the pre- and postnatal development study, rabbits were administered SC doses of sargramostim during GD6 to GD19, GD19 to parturition, or lactation day (LD)1 to LD14 at 25, 70, and 200 mcg/kg/day. Maternal toxicity was observed at ≥25 mcg/kg/day. At doses ≥25 mcg/kg/day, a reduction in postnatal offspring survival was observed when rabbits were dosed during lactation. The high-dose of 200 mcg/kg caused a decreased pup body weight when rabbits were dosed during lactation and from GD19 to parturition. Treatment from GD6-GD19 and GD19-parturition at 200 mcg/kg/day resulted in abortions, while after GD6-GD19 treatment with 200 mcg/kg/day total litter loss, early resorptions, reduced number of kits born and reduced live litter size on Post Natal Day 0 were also observed. There is no NOAEL for neonatal toxicity. The AUC of 25 mcg/kg/day dose was initially (at the start of the dosing period) approximately 2.6-fold the clinical exposure at the recommended adult clinical dose (7 mcg/kg/day).
By the end of the dosing periods, the systemic exposures decreased due to the production of anti-sargramostim antibodies reaching 1-fold, 0.2-fold and 0.2-fold the clinical exposure in the fertility and early embryonic development, embryo-foetal developmental and pre- and postnatal development studies, respectively.
Studies to evaluate the mutagenic and carcinogenic potential of sargramostim have not been conducted.
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