Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2    Pharmacodynamics

In postmenopausal women with osteoporosis, EVENITY 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.

EVENITY 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 EVENITY, P1NP levels returned to baseline within 12 months; CTX increased above baseline levels within 3 months and returned toward baseline levels by month 12.

Pharmacokinetic Properties

12.3    Pharmacokinetics

Administration of a single dose of 210 mg EVENITY in healthy volunteers resulted in a mean (standard deviation [SD]) maximum romosozumab 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 concentrations at months 3, 6, 9, and 12 ranged from 8 to 13 mcg/mL.

Romosozumab 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).

Absorption

The median time to maximum romosozumab 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 exhibited nonlinear pharmacokinetics with the clearance of romosozumab decreasing as the dose increased. The estimated mean systemic clearance (CL/F) of romosozumab 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.

Metabolism

The metabolic pathway of romosozumab has not been characterized. As a humanized IgG2 monoclonal antibody, romosozumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.

Anti-Product Antibody Formation Affecting Pharmacokinetics

Development of anti-romosozumab antibodies was associated with reduced serum romosozumab concentrations. The presence of anti-romosozumab antibodies led to decreased mean romosozumab concentrations up to 22%. The presence of neutralizing antibodies led to decreased mean romosozumab concentrations up to 63% [see Adverse Reactions (6.2)].

Specific Populations

No clinically significant differences in the pharmacokinetics of romosozumab 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 is unknown.


Body Weight

The exposure of romosozumab decreases with increasing body weight.