Denosumab dose selection for patients with bone metastases from solid tumors.

PURPOSE To quantitatively characterize the longitudinal dose exposure-response [urinary N-telopeptide normalized to urinary creatinine (uNTx/Cr) suppression] relationship for denosumab in patients with bone metastases from solid tumors. EXPERIMENTAL DESIGN Data from 373 patients who received denosumab as single or multiple subcutaneous doses ranging from 30 to 180 mg (or 0.01 to 3 mg/kg) administered every 4 or 12 weeks for up to 3 years were used in this analysis. An inhibitory sigmoid I(Max) model was used to characterize the time course of uNTx/Cr as a function of serum denosumab concentrations and the M3 method was used to analyze the 52% of uNTx/Cr values below the limit of quantification in the context of a mixed-effects model. Age, weight, sex, race, and cancer type were evaluated as potential covariates for model parameters. Model-based simulations were undertaken to explore and predict the role of denosumab dose and dosing intervals on uNTx/Cr suppression. RESULTS The typical value (between-subject variability; %) for uNTx/Cr at baseline was 49.2 nmol/L/mmol/L (76.8%), denosumab maximal uNTx/Cr suppression (efficacy) was 93.7% (127%), and the denosumab concentration providing half-maximal uNTx/Cr suppression (potency) was 31.8 ng/mL (287%). No effect of covariates on denosumab efficacy and potency was identified. Simulations indicated that a s.c. denosumab dose of 120 mg administered every 4 weeks provides more than 90% suppression of uNTx/Cr in the maximum proportion of patients relative to other every 4- and 12-week doses evaluated. CONCLUSIONS Over the wide range of dosing regimens examined, a s.c. denosumab dose of 120 mg administered every 4 weeks is the optimal dosing regimen to suppress uNTx/Cr in patients with bone metastases from solid tumors. Clin Cancer Res; 18(9); 2648-57. ©2012 AACR.