A randomized, double-blind, placebo-controlled, single-dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of denosumab administered subcutaneously to postmenopausal Japanese women.

Denosumab is a fully human monoclonal antibody that has high affinity for RANK ligand (RANKL). RANKL is the essential mediator of osteoclast formation, function and survival. The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of denosumab in healthy postmenopausal Japanese women were assessed. This was a randomized, double-blind, dose-escalation study in which 40 subjects received denosumab at doses of 0.03, 0.1, 0.3, 1.0 or 3.0mg/kg, or placebo administered subcutaneously. Blood and urine samples for determination of serum denosumab, CTX-I, NTX-I/Cr, bone specific alkaline phosphatase (bone ALP) and intact parathyroid hormone (iPTH) were collected. The PK and PD time profiles were compared to those obtained in separate studies conducted in the US. No serious adverse events occurred and all subjects completed this study. Denosumab demonstrated nonlinear PK and dose- and concentration-dependent dispositions. The maximum mean decrease from baseline ranged from 65% to 95% for CTX-I concentrations and from 50% to 85% for NTX-I/Cr. Additionally, the changes were dose-dependent. The suppression of bone turnover markers was rapid (within 2 days after dosing) and duration of suppression was dose-dependent. No marked differences in the PK and PD profiles between Japanese and non-Japanese subjects were noted. The observed results indicate that denosumab may have therapeutic potential for conditions resulting from increased bone turnover, such as osteoporosis in Japanese.