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

Area of Science:

• Pharmacology
• Oncology
• Biochemistry

Background:

• Bone metastases are a common complication in solid tumors, leading to significant morbidity.
• Denosumab is a monoclonal antibody used to reduce skeletal-related events in patients with bone metastases.
• Understanding the dose-response relationship of denosumab is crucial for optimizing treatment efficacy.

Purpose of the Study:

• To quantitatively characterize the dose-exposure-response relationship for denosumab-induced urinary N-telopeptide normalized to urinary creatinine (uNTx/Cr) suppression.
• To identify the optimal denosumab dosing regimen for suppressing bone resorption markers in patients with bone metastases from solid tumors.

Main Methods:

• Analysis of data from 373 patients receiving denosumab at various doses (30-180 mg) and intervals (every 4 or 12 weeks) for up to 3 years.
• Utilized an inhibitory sigmoid I(Max) model to assess uNTx/Cr suppression based on serum denosumab concentrations.
• Employed the M3 method within a mixed-effects model to analyze values below the limit of quantification and evaluated potential covariates.

Main Results:

• The typical baseline uNTx/Cr was 49.2 nmol/L/mmol/L, with denosumab achieving maximal suppression of 93.7%.
• The concentration for half-maximal suppression (potency) was 31.8 ng/mL; no covariates affected efficacy or potency.
• Simulations revealed that 120 mg of denosumab subcutaneously every 4 weeks achieved >90% uNTx/Cr suppression in the most patients compared to other regimens.

Conclusions:

• A subcutaneous denosumab dose of 120 mg every 4 weeks is identified as the optimal regimen for suppressing uNTx/Cr.
• This optimal dosing strategy is recommended for patients with bone metastases from solid tumors to manage bone resorption.