Clinical Pharmacokinetics and Pharmacodynamics of Daratumumab

AbstractDaratumumab is a fully human, monoclonal immunoglobulin G1 and a first-in-class CD38-targeting drug approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory and newly diagnosed multiple myeloma or newly diagnosed light-chain amyloidosis. CD38 is heavily expressed on malignant myeloma cells, and daratumumab exerts anti-myeloma activity via immune-mediated mechanisms, direct induction of apoptosis, and immunomodulation. Daratumumab is used as monotherapy or in combination with standard-of-care myeloma therapies, including proteasome inhibitors, immunomodulatory agents, DNA-alkylating agents, and corticosteroids. Following an intravenous infusion, daratumumab exhibits nonlinear pharmacokinetics (PK), as clearance decreases with higher doses and over time because of target-mediated effects. Dosing schedules vary depending on indications and co-administered drugs, but generally daratumumab is administered weekly for 6 –9 weeks followed by a less frequent dosing regimen, once every 2–4 weeks. Daratumumab exposure is strongly correlated with efficacy, and the exposure–efficacy relationship follows a maximal effect model, whereas exposure is not correlated with safety endpoints. The approved dose of 16 mg/kg o f daratumumab results in the saturation of 99% of the target at the end of weekly dosing in most patients, and high target saturation is maintained over time during the less frequent dosing schedule. Infusion-related r...
Source: Clinical Pharmacokinetics - Category: Drugs & Pharmacology Source Type: research