In patients with breast cancer and bone metastases, the median reduction in uNTx/Cr was 82% within 1聽week following initiation of Xgeva 120 mg administered subcutaneously. In Trials 1, 2, and 3, the median reduction in uNTx/Cr from baseline to month 3 was approximately 80% in 2075 Xgeva-treated patients.

Following subcutaneous administration, bioavailability was 62%. Denosumab displayed nonlinear pharmacokinetics at doses below 60 mg, but approximately dose-proportional increases in exposure at higher doses. With multiple subcutaneous doses of 120 mg every 4 weeks in patients with cancer metastatic to the bone, up to 2.8-fold accumulation in serum denosumab concentrations was observed and steady state was achieved by 6 months. At steady state, the mean 卤 SD serum trough concentration was 20.5 卤 13.5 mcg/mL at the recommended Xgeva dose, and the mean elimination half-life was 28 days.

A population pharmacokinetic analysis was performed to eva luate the effects of demographic characteristics. Denosumab clearance and volume of distribution were proportional to body weight. The steady-state exposure following repeat subcutaneous administration of 120 mg every 4 weeks to 45 kg and 120 kg subjects were, respectively, 48% higher and 46% lower than exposure of the typical 66 kg subject.

Specific Populations

The pharmacokinetics of denosumab were not affected by age, gender, and race. The pharmacokinetics of denosumab in pediatric patients have not been assessed.

Hepatic Impairment: No clinical trials have been conducted to eva luate the effect of hepatic impairment on the pharmacokinetics of denosumab.

Renal Impairment: In a trial of 55 subjects with varying degrees of renal function, including subjects on dialysis, the degree of renal impairment had no effect on the pharmacokinetics and pharmacodynamics of denosumab [see Use in Specific Populations (8.6)] .

Carcinogenicity

The carcinogenic potential of denosumab has not been eva luated in long-term animal studies.

Mutagenicity

The genotoxic potential of denosumab has not been eva luated.

Impairment of Fertility

Denosumab had no effect on female fertility or male reproductive organs in monkeys at exposures that were 6.5-聽to聽25-fold higher than the observed human dose of 120 mg subcutaneously administered once every 4 weeks (based on body weight mg/kg).

Denosumab is an inhibitor of osteoclastic bone resorption via inhibition of RANKL. Adolescent nonhuman primates treated with monthly doses of denosumab greater than 5 times the recommended human dose of 120 mg had abnormal growth plates. Because the biological activity of denosumab in animals is specific to nonhuman primates, eva luation of genetically engineered (knockout) mice or use of other biological inhibitors of the RANK/RANKL pathway, OPG-Fc and RANK-Fc, provided additional safety information on the inhibition of the RANK/RANKL pathway in rodent models. A study in 2-week-old rats given the RANKL inhibitor OPG-Fc showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued. Neonatal RANK/RANKL knockout mice also exhibited reduced bone growth and lack