Romosozumab inhibits the action of sclerostin, a regulatory factor in bone metabolism. Romosozumab increases bone formation and, to a lesser extent, decreases bone resorption. Animal studies showed that romosozumab-aqqg stimulates new bone formation on trabecular and cortical bone surfaces by stimulating osteoblastic activity resulting in increases in trabecular and cortical bone mass and improvements in bone structure and strength.
In postmenopausal women with osteoporosis, romosozumab increased the bone formation marker procollagen type 1 N-telopeptide (P1NP) with a peak increase from baseline of approximately 145% compared to placebo 2 weeks after initiating treatment, followed by a return to concentrations seen with placebo at month 9 and a decline from baseline to approximately 15% below the concentration change seen with placebo at month 12.
Romosozumab decreased the bone resorption marker type 1 collagen C-telopeptide (CTX) with a maximal reduction from baseline of approximately 55% compared to placebo 2 weeks after initiating treatment. CTX remained below concentrations seen with placebo and was approximately 25% below the concentration change seen with placebo at month 12.
After discontinuation of romosozumab, P1NP levels returned to baseline within 12 months; CTX increased above baseline levels within 3 months and returned toward baseline levels by month 12.
Administration of a single dose of 210 mg romosozumab in healthy volunteers resulted in a mean (standard deviation [SD]) maximum romosozumab-aqqg serum concentration (Cmax) of 22.2 (5.8) mcg/mL and a mean (SD) AUC of 389 (127) mcg*day/mL. Steady-state concentrations were achieved by month 3 following the monthly administration of 210 mg to postmenopausal women. The mean trough serum romosozumab-aqqg concentrations at months 3, 6, 9, and 12 ranged from 8 to 13 mcg/mL.
Romosozumab-aqqg exhibited nonlinear pharmacokinetics with exposure increasing greater than dose proportionally (e.g., 550-fold increase in mean AUCinf for the 100-fold increase in subcutaneous doses ranging from 0.1 to 10 mg/kg [0.03 to 3.3 times the approved recommended dosage for a 70 kg woman).
The median time to maximum romosozumab-aqqg concentration (Tmax) is 5 days (range: 2 to 7 days).
The estimated volume of distribution at steady-state is approximately 3.92 L.
Romosozumab-aqqg exhibited nonlinear pharmacokinetics with the clearance of romosozumab-aqqg decreasing as the dose increased. The estimated mean systemic clearance (CL/F) of romosozumab-aqqg was 0.38 mL/hr/kg, following a single subcutaneous administration of 3 mg/kg (the approved recommended dosage for a 70 kg woman). The mean effective t1/2 was 12.8 days after 3 doses of 3 mg/kg (the approved recommended dosage for a 70 kg woman) every 4 weeks.
The metabolic pathway of romosozumab-aqqg has not been characterized. As a humanized IgG2 monoclonal antibody, romosozumab-aqqg is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
Development of anti-romosozumab-aqqg antibodies was associated with reduced serum romosozumab-aqqg concentrations. The presence of anti-romosozumab-aqqg antibodies led to decreased mean romosozumab-aqqg concentrations up to 22%. The presence of neutralizing antibodies led to decreased mean romosozumab-aqqg concentrations up to 63%.
No clinically significant differences in the pharmacokinetics of romosozumab-aqqg were observed based on age (20-89 years), sex, race, disease state (low bone mass or osteoporosis), prior exposure to alendronate, or renal impairment including end-stage renal disease (ESRD) requiring dialysis. The effect of ESRD not requiring dialysis on the pharmacokinetics of romosozumab-aqqg is unknown.
The exposure of romosozumab-aqqg decreases with increasing body weight.
No adverse effects were noted in rats and monkeys after 26 once-weekly subcutaneous romosozumab-aqqg doses up to 100 mg/kg, equivalent to systemic exposures of 37 and 90 times, respectively, the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison).
Bone safety studies of up to 12-month duration were conducted in ovariectomized rats and monkeys with once-weekly romosozumab-aqqg doses yielding exposures ranging from 1 to 21 times the systemic exposure in humans given monthly doses of 210 mg, based on AUC comparison. Romosozumab-aqqg increased bone mass and improved cancellous bone microarchitecture and cortical bone geometry by increasing bone formation on periosteal, endocortical, and trabecular surfaces, and decreasing bone resorption on trabecular and endocortical surfaces. The increases in bone mass were significantly correlated with increases in bone strength. In rats and monkeys, bone quality was maintained at all skeletal sites at doses ranging from 1 to 21 times human exposure, and slightly improved in vertebrae at 19 to 21 times human exposure. There was no evidence of mineralization defects, osteoid accumulation, or woven bone formation.
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