Split First Dose Administration of Daratumumab for the Treatment of Patients with Multiple Myeloma (MM): Clinical Pharmacology and Population Pharmacokinetic (PK) Analyses
Authors: Xu Xu Steven , Moreau Philippe , Usmani Saad Z. , Lonial Sagar , Jakubowiak Andrzej , Oriol Albert , Krishnan Amrita , Bladé Joan , Luo Melody , Sun Yu-Nien , Zhang Liping , Deraedt William , Qi Ming , Ukropec Jon , Clemens Pamela L 
Published: October 2019

Abstract
Introduction: Daratumumab (DARA) is an anti-CD38 monoclonal antibody with on-tumor and immunomodulatory mechanisms of action which is approved as monotherapy for relapsed/refractory (RR) MM and in combination with standard of care regimens for RR and transplant-ineligible newly diagnosed MM. In clinical studies, the median duration of first intravenous (IV) infusion of DARA 16 mg/kg was 7.0 hours; subsequent infusions required approximately 3-5 hours. The feasibility of splitting the first 16 mg/kg infusion into 2 separate infusions of 8 mg/kg over approximately 4 hours each during the first 2 days of Cycle 1 was investigated through computer simulations for various recommended dosing regimens of DARA and in the multi-cohort, phase 1b MMY1001 study. Strong association has been demonstrated between DARA concentration and efficacy in RR MM (Xu XS, et al. Clin Pharmacol Ther 2017;101:721-4), highlighting the importance of attaining similar serum concentrations of DARA for the split first dose regimen compared to the corresponding approved single first dose regimen of DARA.
Methods: A simulation evaluation compared PK profiles between split and single first dose DARA regimens as monotherapy and with various backbone regimens. Simulation of DARA PK following split and single first dose regimens was conducted for: DARA monotherapy, DARA + lenalidomide/dexamethasone (D-Rd), DARA + bortezomib/dexamethasone (D-Vd), DARA + pomalidomide/dexamethasone (D-Pd), DARA + bortezomib/melphalan/prednisone (D-VMP), DARA + carfilzomib/dexamethasone (D-Kd), and DARA + carfilzomib/lenalidomide/dexamethasone (D-KRd). All simulations were conducted using the RxODE package in R.
Clinical PK data from 3 cohorts of the phase 1b open-label multicenter MMY1001 study were included to confirm the simulation evaluation. In 2 cohorts, 97 patients (pts) received the first 16 mg/kg DARA dose as a split dose of 8 mg/kg on Cycle 1 Day 1 (C1D1) and 8 mg/kg on C1D2: 75 pts in the D-Kd cohort and 22 pts in the D-KRd cohort. The third cohort consisted of 10 pts who received a single first dose regimen of 16 mg/kg DARA on C1D1 in the D-Kd cohort. Observed PK data are summarized by timepoint.
Results: DARA concentration-time profiles for the 3 approved DARA dosing schedules (7 different treatments) were virtually identical following split and single first dose regimens (Figure). Cmax on the first day of split dosing (C1D1) was lower, however, following the second 8 mg/kg dose on C1D2, the concentration was similar compared to the single first dose regimen. Thereafter, following the second split dose of 8 mg/kg on Day 2, the difference in the simulated PK profiles became minimal (Figure).
Data from the MMY1001 study confirmed that mean (SD) DARA serum concentration following the first total dose of 16 mg/kg was comparable between single first dose (C1D1: 321 [49] mg/mL) and split first dose (C1D2: 257 [69] mg/mL). At the end of weekly dosing, the mean (SD) Ctrough prior to the C3D1 dose was similar between pts who received a single first dose (517 [137] µg/mL) and those who received a split first dose (606 [237] µg/mL).
Conclusions: A split or single first dose provides virtually identical PK, with the exception of the PK profile during the first day of treatment, for all approved indications and recommended dosing regimens for DARA. Therefore, it is anticipated that the efficacy and safety following the split first dose for all approved DARA regimens would be similar to that of DARA 16 mg/kg administered as a single first dose. The transient difference in concentration on C1D1 is not expected to have any impact on overall clinical outcomes. Preliminary clinical data from MMY1001 D-KRd and D-Kd cohorts have demonstrated that split first dose of DARA is safe (Jakubowiak AJ, et al. ASCO 2017. Abstract 8000; Chari A, et al. ASCO 2018. Abstract 8002). Furthermore, split first dose of DARA may provide an additional flexible option for pts as well as for infusion centers.

Disclosures
Xu: Janssen Research & Development, LLC: Employment. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Lonial:Amgen: Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Oriol:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Krishnan:Takeda: Speakers Bureau; Sutro: Speakers Bureau; Onyx: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau. Bladé:Janssen: Honoraria. Luo:Janssen Research & Development, LLC: Employment. Sun:Janssen Research & Development, LLC: Employment. Zhang:Janssen Research & Development, LLC: Employment. Deraedt:Janssen Research & Development, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Ukropec:Janssen Scientific Affairs, LLC: Employment. Clemens:Janssen Research & Development, LLC: Employment.