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

Prolia pharmacokinetics were not affected by the formation of binding antibodies.

A population pharmacokinetic analysis was performed to eva luate the effects of demographic characteristics. This analysis showed no notable differences in pharmacokinetics with age (in postmenopausal women), race, or body weight (36 to 140 kg).

Drug Interactions
No drug-drug interaction studies have been conducted with Prolia.

Specific Populations
Gender:Mean serum denosumab concentration-time profiles observed in a study conducted in healthy men ≥ 50 years were similar to those observed in a study conducted in postmenopausal women using the same dose regimen.

Age:The pharmacokinetics of denosumab was not affected by age across all populations studied whose ages ranged from 28-87 years.

Race:The pharmacokinetics of denosumab was not affected by race.

Renal Impairment:In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab; thus, dose adjustment for renal impairment is not necessary.

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 doses that were 13- to 50-fold higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg).

13.2 Animal Toxicology and/or Pharmacology
Prolia is an inhibitor of osteoclastic bone resorption via inhibition of RANKL.

In ovariectomized monkeys, once-monthly treatment with denosumab suppressed bone turnover and increased bone mineral density (BMD) and strength of cancellous and cortical bone at doses 50-fold higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg). Bone tissue was normal with no evidence of mineralization defects, accumulation of osteoid, or woven bone.

Adolescent primates treated with denosumab at doses > 10 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered once every 6 months, based on mg/kg, had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab [see Use in Specific Populations (8.4)].

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, namely OPG-Fc, provided additional information on the pharmacodynamic properties of denosumab. RANK/RANKL knockout mice exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-a