Neulasta (Pegfilgrastim) - Description and Clinical Pharmacology

DESCRIPTION

Neulasta^® (pegfilgrastim) is a covalent conjugate of recombinant methionyl human G‑CSF (Filgrastim) and monomethoxypolyethylene glycol. Filgrastim is a water‑soluble 175 amino acid protein with a molecular weight of approximately 19 kilodaltons (kD). Filgrastim is obtained from the bacterial fermentation of a strain of Escherichia coli transformed with a genetically engineered plasmid containing the human G‑CSF gene. To produce pegfilgrastim, a 20 kD monomethoxypolyethylene glycol molecule is covalently bound to the N‑terminal methionyl residue of Filgrastim. The average molecular weight of pegfilgrastim is approximately 39 kD.

Neulasta^® is supplied in 0.6 mL prefilled syringes for subcutaneous injection. Each syringe contains 6 mg pegfilgrastim (based on protein weight), in a sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 mg), sorbitol (30.0 mg), polysorbate 20 (0.02 mg), and sodium (0.02 mg) in water for injection, USP.

CLINICAL PHARMACOLOGY

Both Filgrastim and pegfilgrastim are Colony Stimulating Factors that act on hematopoietic cells by binding to specific cell surface receptors thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.^1,2 Studies on cellular proliferation, receptor binding, and neutrophil function demonstrate that Filgrastim and pegfilgrastim have the same mechanism of action. Pegfilgrastim has reduced renal clearance and prolonged persistence in vivo as compared to Filgrastim.

Pharmacokinetics

The pharmacokinetics and pharmacodynamics of Neulasta^® were studied in 379 patients with cancer. The pharmacokinetics of Neulasta^® were nonlinear in cancer patients and clearance decreased with increases in dose. Neutrophil receptor binding is an important component of the clearance of Neulasta^®, and serum clearance is directly related to the number of neutrophils. For example, the concentration of Neulasta^® declined rapidly at the onset of neutrophil recovery that followed myelosuppressive chemotherapy. In addition to numbers of neutrophils, body weight appeared to be a factor. Patients with higher body weights experienced higher systemic exposure to Neulasta^® after receiving a dose normalized for body weight. A large variability in the pharmacokinetics of Neulasta^® was observed in cancer patients. The half‑life of Neulasta^® ranged from 15 to 80 hours after subcutaneous injection.

Special Populations

No gender‑related differences were observed in the pharmacokinetics of Neulasta^®, and no differences were observed in the pharmacokinetics of geriatric patients (≥ 65 years of age) compared to younger patients (< 65 years of age) (see PRECAUTIONS, Geriatric Use). In a study of 30 patients with varying degrees of renal dysfunction including end-stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim; thus, dose adjustment in patients with renal dysfunction is not necessary. The pharmacokinetic profile in pediatric populations or in patients with hepatic insufficiency has not been assessed.

CLINICAL STUDIES

Neulasta^® was evaluated in three randomized, double‑blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m² and docetaxel 75 mg/m² administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of Neulasta^®. Study 2 employed a weight‑adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (absolute neutrophil count [ANC]< 0.5 x 10⁹/L) with a mean duration of 5‑7 days, and a 30%‑40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with Filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of Neulasta^® was demonstrated by establishing comparability to Filgrastim‑treated patients in the mean days of severe neutropenia.

In Study 1, 157 patients were randomized to receive a single subcutaneous injection of Neulasta^® 6 mg on day 2 of each chemotherapy cycle or daily subcutaneous Filgrastim 5 mcg/kg/day beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of Neulasta^® 100 mcg/kg on day 2 or daily subcutaneous Filgrastim 5 mcg/kg/day beginning on day 2 of each chemotherapy cycle.

Both studies met the primary objective of demonstrating that the mean days of severe neutropenia of Neulasta^®-treated patients did not exceed that of Filgrastim‑treated patients by more than one day in cycle 1 of chemotherapy (see Table 1). The rates of febrile neutropenia in the two studies were comparable for Neulasta^® and Filgrastim (in the range of 10% to 20%). Other secondary endpoints included days of severe neutropenia in cycles 2‑4, the depth of ANC nadir in cycles 1‑4, and the time to ANC recovery after nadir. In both studies, the results for the secondary endpoints were similar between the two treatment groups.

Table 1. Mean Days of Severe Neutropenia (in Cycle 1)

Study	Mean days of severe neutropenia		Difference in means (95% CI)
	Neulasta® 1	Filgrastim (5 mcg/kg/day)
Study 1 n= 157	1.8	1.6	0.2 (-0.2, 0.6)
Study 2 n= 310	1.7	1.6	0.1 (-0.2, 0.4)

Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m² administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of Neulasta^® 6 mg or placebo on day 2 of each chemotherapy cycle. Study 3 met the primary objective of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x10⁹/L) was lower for Neulasta^®-treated patients as compared to placebo-treated patients (1% versus 17%, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia were also lower in the Neulasta^®-treated patients compared with the placebo-treated patients.