Pharmacokinetics of Daratumumab Following Intravenous Infusion in Relapsed or Refractory Multiple Myeloma After Prior Proteasome Inhibitor and Immunomodulatory Drug Treatment

Abstract

Daratumumab is a CD38 monoclonal antibody recently approved for the treatment of multiple myeloma (MM). We report daratumumab pharmacokinetic data from GEN501, a phase I/II dose-escalation (0.005–24 mg/kg) and dose-expansion (8 or 16 mg/kg) study, and SIRIUS, a phase II study (8 or 16 mg/kg), in relapsed or refractory MM. Noncompartmental analysis was conducted to characterize daratumumab pharmacokinetics, and, in both studies, daratumumab exhibited nonlinear pharmacokinetic characteristics. Decreasing daratumumab clearance with increasing dose suggests saturation of target-mediated clearance at higher dose levels, whereas decreasing clearance over time with repeated dosing may be due to tumor burden reductions as CD38-positive cells are eliminated. These and other pharmacokinetic data analyses support the use of the recommended dose regimen of daratumumab (16 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter) to rapidly saturate target-mediated clearance during weekly dosing and maintain saturation when dosing every 2 or 4 weeks.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0477-1) contains supplementary material, which is available to authorized users.

Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses

“…The PK profile for the split first dose regimen of daratumumab was similar to the PK profiles of daratumumab demonstrated in previous monotherapy and combination therapy studies, regardless of the population treated. After the first total dose of 16 mg/kg, mean daratumumab serum concentrations (Table 2) for the split first dose (Cycle 1 Day 2) and single first dose (Cycle 1 Day 1) regimens were similar to those observed after the first dose of daratumumab monotherapy in SIRIUS (313 lg/ml) and daratumumab combination therapy in CASTOR (D-Vd; 318 lg/ml) and POLLUX (D-Rd; 329 lg/ml) [17]. The consistency of daratumumab exposure across split-and single-first dose regimens continued through the end of weekly dosing (Cycle 3 Day 1) and was comparable to daratumumab monotherapy in SIRIUS (574 lg/ml) and D-Rd combination therapy in POLLUX (608 lg/ml) [17].…”

“…After the first total dose of 16 mg/kg, mean daratumumab serum concentrations (Table 2) for the split first dose (Cycle 1 Day 2) and single first dose (Cycle 1 Day 1) regimens were similar to those observed after the first dose of daratumumab monotherapy in SIRIUS (313 lg/ml) and daratumumab combination therapy in CASTOR (D-Vd; 318 lg/ml) and POLLUX (D-Rd; 329 lg/ml) [17]. The consistency of daratumumab exposure across split-and single-first dose regimens continued through the end of weekly dosing (Cycle 3 Day 1) and was comparable to daratumumab monotherapy in SIRIUS (574 lg/ml) and D-Rd combination therapy in POLLUX (608 lg/ml) [17]. At the end of weekly dosing, C trough for the split dose regimen was also above the effective C trough of daratumumab monotherapy (274 lg/ml) [18].…”

“…However, it is unknown whether patients can achieve effective daratumumab serum concentrations with a split first dose regimen. Data from monotherapy studies show that daratumumab exhibits nonlinear pharmacokinetics (PK) consistent with target-mediated drug disposition [17]. The recommended dose regimen of 16 mg/kg weekly for 8 weeks rapidly saturates targetmediated clearance, and subsequent dosing every 2 weeks for 16 weeks and every 4 weeks thereafter maintains target saturation.…”

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

“…30 Samples for pharmacokinetic analysis were collected predose and postinfusion on day 1 of cycles 1 to 4 (and on day 2 cycle 1 for patients receiving split first dose) and were analyzed as described previously. 31 Exploratory end points included progression-free survival (PFS), MRD, and pharmacokinetics. MRD testing was optional in this phase 1 study and was evaluated in bone marrow aspirate samples from patients who achieved a CR or better; it was assessed at the time of suspected CR and at 12 and 18 months following the first treatment dose.…”

Long-term CD38 saturation by daratumumab interferes with diagnostic myeloma cell detection

“…According to this model, daratumumab plasma concentrations of 236 µg/mL are necessary to achieve 99% CD38 saturation in vivo. [13][14][15] Performing the cell line saturation assay with dilutions of patient plasma, we determined a daratumumab concentration of 11.5 µg/mL in our patient six weeks after the last infusion, when pre-existing and newly generated myeloma cells showed full CD38 saturation with antibody. This concentration was expected based on pharmacokinetic data from the clinical trials (peak levels, half-life, targetmediated clearance), 4 but clearly challenged the target saturation model.…”