Efbemalenograstim alfa is a colony-stimulating factor that acts on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.
Over the tested dose range of 30 to 360 μg/kg in healthy adult males, neutrophils generally increased in a dose-dependent manner; however, the effect on neutrophils plateaued at the top two doses of 240 and 360 μg/kg.
In patients with breast cancer given EC chemotherapy, in cycle 1, median ANC peaked on Day 4 (about 24 hours after efbemalenograstim alfa administration) for the 240 and 320 μg/kg doses, declined to nadir on Days 8–9, and then recovered to a count of 2.0 × 109/L and higher by Day 11. The ANC levels in cycles 2, 3, and 4 tended to be higher than those observed in cycle 1.
In patients with breast cancer given TAC chemotherapy, in cycle 1, median ANC peaked on Day 3 (about 24 hours after efbemalenograstim alfa administration) in cycle 1 and 3, reached nadir on Day 8, and recovered to 2.0 × 109/L on Days 9 and 10 for the 320 μg/kg and 240 μg/kg doses, respectively. Mean ANC nadir was higher with 320 μg/kg compared to 240 μg/kg in both cycle 1 (0.75 × 109/L and 0.29 × 109/L, respectively), and cycle 3 (1.19 × 109/L and 0.57 × 109/L, respectively).
The pharmacokinetics of efbemalenograstim alfa was studied in female patients with breast cancer and healthy male subjects. Efbemalenograstim alfa exhibited nonlinear and time-dependent pharmacokinetics over the dose range of 30 to 360 μg/kg. At the approved recommended dose in healthy subjects, the mean (CV) Cmax was 1202 ng/mL (56), and the AUC0-inf was 76357 h*ng/mL (65%). At the approved recommended dose in patients with breast cancer, the geometric mean (CV%) Cmax was 1085 ng/mL (92%) in Cycle 1 and 525 ng/mL (163%) in Cycle 3; the geometric mean (CV%) AUC0-inf was 54858 h*ng/mL (110%) in Cycle 1 and 26217 h*ng/mL (167%) in Cycle 3.
The median tmax of efbemalenograstim alfa administered as 80 to 320 μg/kg in female patients with breast cancer receiving EC chemotherapy ranged from 24 hours to 48 hours in Cycle 1 and 9 to 30 hours in Cycle 3. The median tmax of efbemalenograstim alfa administered as 240 to 320 μg/kg in female participants with breast cancer receiving TAC chemotherapy was 36 hours in Cycle 1 and ranged from 24 to 30 hours in Cycle 3.
The geometric mean (CV%) apparent volume of distribution of efbemalenograstim alfa was 18.8 L (257%) in Cycle 1 and 40.7 L (387%) in Cycle 3 in female patients with breast cancer.
The geometric mean (CV%) apparent clearance of efbemalenograstim alfa was 0.36 L/h (110%) in Cycle 1 and 0.76 L/h (167%) in Cycle 3. The geometric mean (CV%) elimination half-life of efbemalenograstim alfa was 35.6 h (108%) in Cycle 1 and 36.9 h (120%) in Cycle 3. Neutrophil receptor binding is an important component of the clearance of efbemalenograstim alfa, and serum clearance is directly related to the number of neutrophils.
Efbemalenograstim alfa is expected to be metabolized into small peptides by catabolic pathways.
No clinically significant differences were observed based on age (20 to 83 years) or body weight (40 to 137 kg). The impact of sex, race/ethnicity, renal impairment, hepatic impairment, and pregnancy on the pharmacokinetics of efbemalenograstim alfa are unknown.
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