Cancer Therapy: Clinical Denosumab Dose Selection for Patients with Bone Metastases from Solid Tumors

Purpose: To quantitatively characterize the longitudinal dose exposure–response [urinaryN-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 180mg (or 0.01 to 3mg/kg) administered every 4 or 12 weeks for up to 3 yearswere used in this analysis. An inhibitory sigmoid IMaxmodelwas used to characterize the time course of uNTx/Cr as a functionof serumdenosumab concentrations and theM3methodwasused to analyze the 52% of uNTx/Cr values below the limit of quantification in the context of amixed-effectsmodel. Age, weight, sex, race, and cancer typewere evaluated as potential covariates formodel parameters. Model-based simulations were undertaken to explore and predict the role of denosumab dose and dosing intervals on uNTx/Cr