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

Abstract

Introduction: Daratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for multiple myeloma. In clinical studies, the median durations of the first, second, and subsequent intravenous infusions of daratumumab were 7.0, 4.3, and 3.4 h, respectively. Splitting the first intravenous infusion of daratumumab over 2 days is an approved alternative dosing regimen to reduce the duration of the first infusion and provide flexibility for patients and healthcare providers.

Methods: The feasibility of splitting the first 16-mg/kg infusion into two separate infusions of 8 mg/kg on Days 1 and 2 of the first treatment cycle was investigated in two cohorts [daratumumab, carfilzomib, and dexamethasone (D-Kd) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (D-KRd)] of the phase 1b MMY1001 study. Additionally, a population pharmacokinetic (PK) analysis and simulations were used to compare the PK profiles of the split first dose regimen with the recommended single first dose regimens of daratumumab in previously approved indications.

Results: In MMY1001, following administration of the second half of a split first dose on Cycle 1 Day 2, postinfusion median (range) daratumumab concentrations were similar between split first dose [D-Kd, 254.9 (125.8-435.5) µg/ml; D-KRd, 277.2 (164.0-341.8) µg/ml; combined, 256.8 (125.8-435.5) µg/ml] and single first dose [D-Kd, 319.2 (237.5-394.7) µg/ml]. At the end of weekly dosing, median (range) Cycle 3 Day 1 preinfusion daratumumab concentrations were similar between split first dose [D-Kd, 663.9 (57.7-1110.7) µg/ml; D-KRd, 575.1 (237.9-825.5) µg/ml; combined, 639.2 (57.7-1110.7) µg/ml] and single first dose [D-Kd, 463.2 (355.9-792.9) µg/ml]. The population PK simulations demonstrated virtually identical PK profiles after the first day of treatment for all approved indications and recommended dosing schedules of daratumumab.

Conclusion: These data support the use of an alternative split first dose regimen of intravenous daratumumab for the treatment of MM.

Trial registration: ClinicalTrials.gov number, NCT01998971.

Keywords: Clinical pharmacology; Daratumumab; Intravenous infusion; Multiple myeloma; Pharmacokinetics; Single first dose; Split first dose.

Figures

Fig. 1

Mean daratumumab serum concentrations (µg/ml) among PK-evaluable patients in MMY1001 D-Kd and D-KRd single/split first daratumumab dose cohorts. Values are mean ± SD. PK pharmacokinetic, D-Kd daratumumab/carfilzomib/dexamethasone, D-KRd daratumumab/carfilzomib/lenalidomide/dexamethasone, DARA daratumumab, C Cycle, D Day, SD standard deviation

Fig. 2

Simulated daratumumab concentration-time profiles (a) and simulated daratumumab concentration-time profiles for the first 2 weeks (b) for the split- and single-first dose of daratumumab 16 mg/kg in patients who received daratumumab monotherapy, D-Rd, D-Kd, D-KRd, and D-Pd (left); D-Vd (middle); and D-VMP (right) regimens. The red solid and blue dashed lines represent the median, and the shaded regions are bounded by the 2.5th and 97.5th percentiles of the simulation. D daratumumab, D-Rd daratumumab/lenalidomide/dexamethasone, D-Kd daratumumab/carfilzomib/dexamethasone, D-KRd daratumumab/carfilzomib/lenalidomide/dexamethasone, D-Pd daratumumab/pomalidomide/dexamethasone, D-Vd daratumumab/bortezomib/dexamethasone, D-VMP daratumumab/bortezomib/melphalan/prednisone

Fig. 3

Boxplot comparison of percent difference in simulated daratumumab Ctrough in patients who received daratumumab 16-mg/kg monotherapy, D-Rd, D-Kd, D-KRd, and D-Pd (left); D-Vd (middle); and D-VMP (right) regimens. Percent difference in concentration is calculated by the following formula: (SINGLE–SPLIT DOSE)/SINGLE × 100%, where SINGLE is the daratumumab concentration for single first dose and SPLIT DOSE is the daratumumab concentration for split first dose. A negative % difference in concentration indicates that the daratumumab concentration of the single first dose is less than the concentration of the split first dose. Ctrough, trough concentration; D daratumumab, D-Rd daratumumab/lenalidomide/dexamethasone, D-Kd daratumumab/carfilzomib/dexamethasone, D-KRd daratumumab/carfilzomib/lenalidomide/dexamethasone, D-Pd, daratumumab/pomalidomide/dexamethasone, D-Vd daratumumab/bortezomib/dexamethasone, D-VMP daratumumab/bortezomib/melphalan/prednisone