easing greater than dose
proportionally (e.g., 550-fold increase in mean AUCinf for the 100-fold increase in subcutaneous dosesranging from 0.1 to 10 mg/kg [0.03 to 3.3 times the approved recommended dosage for a 70 kg woman).
Absorption
The median time to maximum romosozumab-aqqg concentration (Tmax) is 5 days (range: 2 to 7 days).
Distribution
The estimated volume of distribution at steady-state is approximately 3.92 L.
Elimination
Romosozumab-aqqg exhibited nonlinear pharmacokinetics with the clearance of romosozumab-aqqgdecreasing as the dose increased. The estimated mean systemic clearance (CL/F) of romosozumab-aqqgwas 0.38 mL/hr/kg, following a single subcutaneous administration of 3 mg/kg (the approvedrecommended 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.
Metabolism
The metabolic pathway of romosozumab-aqqg has not been characterized. As a humanized IgG2monoclonal antibody, romosozumab-aqqg is expected to be degraded into small peptides and amino acidsvia catabolic pathways in a manner similar to endogenous IgG.
Anti-Product Antibody Formation Affecting PharmacokineticsDevelopment of anti-romosozumab-aqqg antibodies was associated with reduced serum romosozumabaqqg
concentrations.
The presence of anti-romosozumab-aqqg antibodies led to decreased meanromosozumab-aqqg concentrations up to 22%. The presence of neutralizing antibodies led to decreasedmean romosozumab-aqqg concentrations up to 63% [see Adverse Reactions (6.2)].
Specific Populations
No clinically significant differences in the pharmacokinetics of romosozumab-aqqg were observed basedon age (20-89 years), sex, race, disease state (low bone mass or osteoporosis), prior exposure toalendronate, or renal impairment including end-stage renal disease (ESRD) requiring dialysis. The effectof ESRD not requiring dialysis on the pharmacokinetics of romosozumab-aqqg is unknown.
Body Weight
The exposure of romosozumab-aqqg decreases with increasing body weight.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
In a rat carcinogenicity study, once-weekly romosozumab-aqqg doses of 3, 10 or 50 mg/kg were
administered by subcutaneous injection to Sprague-Dawley rats from 8 weeks up to 98 weeks of age,
resulting in systemic exposures that were up to 19 times the systemic exposure observed in humans
following a monthly subcutaneous dose of 210 mg EVENITY (based on AUC comparison).
Romosozumab-aqqg caused a dose-dependent increase in bone mass with trabecular and cortical bone
thickening at all doses. There were no effects of romosozumab-aqqg on mortality and romosozumab-aqqg
did not cause significant increases in tumor incidence in male or female rats.
Mutagenicity
Mutagenesis has not been eva luated, as monoclonal antibodies are not expected to alter DNA or
chromosomes.
Impairment of Fertility
No effects on fertility were observed in male and female rats given subcutaneous romosozumab-aqqgdoses up to 300 mg/kg (up to 56 times the systemic exposure observed in humans following a monthlysubcutaneous dose of 210 mg EVENITY, based on AUC comparison). No effects were noted inreproductive organs in rats and cynomolgus monkeys dosed subcutaneously for 6 months with weeklydoses up to 100 mg/kg (exposures up to 38 an |
