Population Pharmacokinetics and Exposure-Response Modeling of Daratumumab Subcutaneous Administration in Patients With Light-chain Amyloidosis.

The purpose of this study is to characterize the population pharmacokinetics (PopPK) of subcutaneous (SC) daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone and explore the relationship between daratumumab systemic exposure and selected efficacy and safety endpoints in patients with newly diagnosed systemic light-chain (AL) amyloidosis. The PopPK analysis included pharmacokinetic and immunogenicity data from patients receiving daratumumab SC in combination with bortezomib, cyclophosphamide, and dexamethasone in the ANDROMEDA study (AMY3001; safety run-in, n = 28; randomized phase, n = 183). Non-linear mixed-effects modeling was used to characterize the PopPK and quantify the impact of potential covariates. The exposure-response (E-R) analysis included data from all patients in the randomized phase of ANDROMEDA (n = 388). Logistic regression and survival analysis were used to evaluate the relationships between daratumumab systemic exposure and efficacy endpoints. The E-R analysis on safety was conducted using quartile comparison and logistic regression analysis. The observed concentration-time data of daratumumab SC were well described by a 1-compartment PopPK model with first-order absorption and parallel linear and nonlinear Michaelis-Menten elimination pathways. None of the investigated covariates were determined to be clinically meaningful. Daratumumab systemic exposure was generally similar across subgroups that achieved different levels of hematologic response, and there was no apparent relationship between daratumumab systemic exposure and the investigated safety endpoints. In conclusion, the PopPK and E-R analyses supported the selected 1,800 mg flat dose of daratumumab SC in combination with bortezomib, cyclophosphamide, and dexamethasone regimen for the treatment of light-chain amyloidosis. No dose adjustment was recommended for investigated covariates. This article is protected by copyright. All rights reserved.