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.
Author(s): Kumagai Y, Hasunuma T, Padhi D.
Affiliation(s): Clinical Trial Center, Kitasato University East Hospital, 2-1-1, Azamizodai,
Minami, Sagamihara, Kanagawa 228-8520, Japan. kuma-guy@za2.so-net.ne.jp
Publication date & source: 2011, Bone. , 49(5):1101-7
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.
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