Denosumab Dose Selection for Patients with Bone Metastases from Solid Tumors
A partir de données portant sur 373 patients présentant des métastases osseuses et ayant reçu régulièrement du denosumab pendant 3 ans, cette étude évalue différents dosages et durées du cycle d'administration du traitement
Purpose: 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 (0.01 to 3 mg/kg) and administered every 4 or 12 weeks (Q4W, Q12W) for up to 3 years were used in this analysis. An inhibitory sigmoid IMax 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 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. Model-based simulations were undertaken to explore and predict the role of denosumab dose and regimen on uNTx/Cr suppression. Results: The typical value (between-subject variability) for baseline uNTx/Cr was 49.2 nM/mM (76.8%), denosumab maximal uNTx/Cr suppression (efficacy) was 93.7% (127%) and denosumab concentration providing half-maximal uNTx/Cr suppression (potency) was 31.8 ng/mL (287%). No effect of covariates on denosumab parameters was identified. Simulations indicated that a subcutaneous denosumab dose of 120 mg administered Q4W provides greater than 90% suppression of uNTx/Cr in the maximum proportion of patients relative to other Q4W and Q12W doses evaluated. Conclusions: Over the range of dosing regimens examined, a subcutaneous denosumab dose of 120 mg administered Q4W is the optimal dosing regimen to suppress uNTx/Cr in patients with bone metastases from solid tumors.