Denosumab Dose Selection for Patients with Bone Metastases from Solid Tumors

Abstract

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.

The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review

“…fixed dosing, Doshi et al . performed population PK/PD model‐based simulations of uNTx/Cr concentration–time profiles comparing 2 mg kg −1 weight‐based dosing vs . 120 mg every 4 weeks fixed‐dosing.…”

“…Therefore, the relationship between body weight and denosumab exposure has limited clinical relevance, as the exposure attained with 120 mg every 4 weeks dosing is sufficient to suppress maximally uNTx/Cr concentrations across the wide body weight range evaluated. To investigate further the differences of denosumab weight-based dosing vs. fixed dosing, Doshi et al [21] performed population PK/PD model-based simulations of uNTx/Cr concentration-time profiles comparing 2 mg kg −1 weight-based dosing vs. 120 mg every 4 weeks fixed-dosing. Results indicate that at week 25, predicted uNTx/Cr concentrations were similar for both the 2 mg kg −1 and 120 mg dosing regimens, with a median (Q1, Q3) concentration of 4.91 (2.26, 10.16) and 5.21 (2.31, 12.01) nmol BCE/mmol, respectively.…”

Denosumab for the treatment of giant cell tumor of the bone

“…The pathophysiology of GCTB includes a shift toward excessive RANKL secretion and thus increased bone breakdown characterized by elevated bone turnover markers, such as urinary N-telopeptide normalized to urine creatinine (uNTx/Cr) or serum C-terminal telopeptide I (sCTx). In clinical studies of patients with bone metastases from solid tumors, RANKLinhibition by denosumab consistently reduced uNTx/Cr, demonstrating an antiresorptive effect [49][50][51][52][53]. In a Phase II study of patients with GCTB receiving 120 mg denosumab every 28 days with loading doses on days 8 and 15 in …”

Denosumab: Prevention and management of hypocalcemia, osteonecrosis of the jaw and atypical fractures

“… For the prevention of SREs, denosumab is administered once every 4 weeks at a dose of 120 mg as a subcutaneous injection into the thigh, abdomen or upper arm, based on clinical development study results For the treatment of giant cell tumor of bone and hypercalcemia of malignancy, a loading dose of 120 mg is administered on days 8 and 15 of the initial 4‐week treatment period …”