Romosozumab is a humanized monoclonal antibody (IgG2) that binds and inhibits sclerostin, thereby increasing bone formation due to the activation of bone lining cells, increasing bone matrix production by osteoblasts, and recruitment of osteoprogenitor cells. Additionally, romosozumab results in changes to expression of osteoclast mediators, thereby decreasing bone resorption. Together, this dual effect of increasing bone formation and decreasing bone resorption results in rapid increases in trabecular and cortical bone mass, improvements in bone structure, and strength.
In postmenopausal women with osteoporosis, romosozumab increased the bone formation marker procollagen Type 1 N terminal propeptide (P1NP) early in treatment, with a peak increase of approximately 145% relative to placebo 2 weeks after initiating treatment, followed by a return to placebo levels at month 9 and a decline to approximately 15% below placebo at month 12. Romosozumab decreased the bone resorption marker type-1 collagen C-telopeptide (CTX) with a maximal reduction of approximately 55% relative to placebo 2 weeks after initiating treatment. CTX levels remained below placebo and were approximately 25% below placebo at month 12.
After discontinuation of romosozumab therapy in postmenopausal women with osteoporosis, P1NP levels returned to baseline within 12 months; CTX increased above baseline levels within 3 months and returned toward baseline levels by month 12, reflecting reversibility of effect. Upon retreatment with romosozumab (in a limited number of patients) after 12 months placebo treatment, the levels of increase in P1NP and decrease in CTX by romosozumab were similar to that observed during the initial treatment.
The median time to maximum romosozumab concentration (tmax) was 5 days (range: 2 to 7 days). Following a 210 mg subcutaneous dose, bioavailability was 81%.
Romosozumab is a humanized monoclonal antibody (IgG2) with high affinity and specificity for sclerostin, and therefore is cleared via a rapid saturable elimination pathway (i.e. target mediated nonlinear clearance, mediated by degradation of the romosozumab-sclerostin complex) and via a slow nonspecific elimination pathway mediated by the reticuloendothelial system.
After Cmax, serum levels declined with a mean effective half-life of 12.8 days. Steady-state was generally reached by month 3 with less than 2-fold accumulation following monthly dosing.
Following subcutaneous administration, romosozumab exhibits non-linear pharmacokinetics as a result of binding to sclerostin. Multiple doses administered ranged from 70 to 210 mg.
Following a 210 mg dose of romosozumab in a clinical trial of 16 patients with severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease (ESRD) receiving haemodialysis, mean Cmax and AUC were 29% and 44% higher in patients with severe renal impairment as compared to healthy subjects. Mean romosozumab exposure was similar in patients with ESRD receiving haemodialysis as compared to healthy subjects.
Population pharmacokinetic analysis indicated an increase in romosozumab exposure with increasing severity of renal impairment. However, based on an exposure-response model of BMD changes and comparison to exposures obtained at tolerated clinical doses, no dose adjustment is recommended in these patients. Monitoring of hypocalcemia in patients with severe renal impairment or receiving dialysis is recommended.
No clinical trials have been conducted to evaluate the effect of hepatic impairment. Hepatic impairment is not expected to impact on the pharmacokinetics of romosozumab since the liver is not a major organ for romosozumab metabolism or excretion.
The pharmacokinetics of romosozumab were not affected by age from 20 years to 89 years.
Romosozumab exposure decreased with increasing body weight however this decrease had a minimal impact on lumbar spine BMD gain based on exposure-response analysis and is not clinically meaningful. Based on population PK analyses, the expected median steady state AUC for a 61 kg and 114 kg patient is 558 μg.day/ml and 276 μg.day/ml respectively following a monthly subcutaneous dose of 210 mg romosozumab.
No dose adjustment is necessary for any patient characteristics. Based on a population pharmacokinetic analysis, gender and race (Japanese versus non-Japanese) had no clinically meaningful impact on the pharmacokinetics of romosozumab (<20% change in exposure at steady state).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, carcinogenic potential or in bone safety studies.
In a carcinogenicity study, doses up to 50 mg/kg/week were administered by subcutaneous injection to Sprague-Dawley male and female rats from 8 weeks of age for up to 98 weeks. These doses resulted in systemic exposures that were up to 19 times higher than the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison). Romosozumab caused a dose-dependent increase in bone mass with macroscopic bone thickening at all doses. There were no effects of romosozumab on mortality or tumor incidence in male or female rats.
Studies in female and male rats did not show any romosozumab-related effects on mating, fertility, or male reproductive assessments (sperm parameters or organ weights), and there were no effects on estrous cycling or any ovarian or uterine parameters at exposures around 54 times the clinical exposure.
Skeletal malformations, including syndactyly and polydactyly, were observed at a low incidence in 1 out of 75 litters at exposures around 30 times the clinical exposure following administration of romosozumab to rats during the period of organogenesis. There were no adverse effects on postnatal growth and development.
Sclerostin has been suggested to have a role in digit formation, however, as digit formation in the human occurs in the first trimester when placental transfer of immunoglobulins is limited, the risk of a similar finding in humans is low.
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