Denosumab 120mg/1ml solution for injection pre-filled syringes

In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered denosumab dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (C_max) was 6.75 mcg/mL (standard deviation SD = 1.89 mcg/mL). The median time to maximum denosumab concentration (T_max) was 10 days (range: 3 to 21 days). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg⋅day/mL (SD = 101 mcg⋅day/mL.
[L49796]


No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months.
[L49796]


Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years).

After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) C_max values in the serum and seminal fluid samples were 6170 (± 2070) and 100 (± 81.9) ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels. The median (range) T_max values in the serum and seminal fluid samples were 8.0 (7.9 to 21) and 21 (8.0 to 49) days, respectively. Among the subjects, the highest denosumab concentration in the seminal fluid was 301 ng/mL at 22 days post-dose.

On the first day of measurement (10 days post-dose), nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post-dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) seminal fluid concentration of 21.1 (± 36.5) ng/mL across all subjects (n = 12).
[L49796]


In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach a steady state by month 6. In patients with giant cell tumor of bone, after administration of subcutaneous doses of 120 mg once every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day 8, 15, and one month after the first dose were 19.0 (± 24.1), 31.6 (± 27.3), 36.4 (± 20.6) mcg/mL,
respectively.

Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23.4 (± 12.1) mcg/mL.
[L49806]