Summary

• For complete product information that is relevant to this topic, please refer to the approved labeling.
• Simulation of daratumumab pharmacokinetics (PK) was conducted for all recommended dosing schedules using individual PK parameters of patients with multiple myeloma (n=1309). The simulation results confirmed that the split and single dosing for the first dose should provide similar PK, with the exception of the PK profile in the first day of treatment.¹
• The PK of daratumumab following IV administration were evaluated in patients with relapsed and refractory multiple myeloma at dose levels from 0.1 to 24 mg/kg.^2,3 A population pharmacokinetic (PPK) model suggested that daratumumab clearance was concentration- and time-dependent, and that daratumumab nonlinear clearance decreased over time.⁴
• PPK analyses were performed on pooled datasets from 4 clinical trials of DARZALEX in combination with standard therapies. The PK of daratumumab were similar between the monotherapy and combination therapy studies.^5,6
• In CENTAURUS trial, the PK of daratumumab 16 mg/kg IV were evaluated in 123 patients with intermediate- or high-risk smoldering multiple myeloma (SMM) who received intense, intermediate, or short dosing schedules. The PK analysis suggested that the majority of patients in the intense group achieved mean trough concentrations near or above the target-saturating trough concentrations (236 µg/mL needed to achieve 99% target saturation) throughout weekly, every-2-week, and every-4-week dosing schedules; however, in the intermediate and short groups, the mean trough concentrations were below the target-saturating trough concentrations by cycle 3 day 1 and by 8 weeks after the last dose, respectively.^7,8
• Xu et al (2018 and 2020)^9,10 reported PK findings utilizing data collected from the phase 1b MMY1001^11-13 study as well as evaluated PPK simulations of daratumumab split first dose and single first dose dosing regimens for daratumumab monotherapy and various daratumumab combination dosing schedules. Except for the first day of treatment, similar PK data was observed when comparing daratumumab split first dose and single first dose regimens using the PK data from MMY1001 as well as the PPK simulation analysis across multiple indications and combination dosing schedules.
• Cohen et al (2021)¹⁴ assessed the PK of daratumumab with or without cetrelimab among patients with relapsed or refractory multiple myeloma (RRMM). PK analyses of daratumumab (peak and trough serum concentrations) were comparable with those observed in previous studies of daratumumab. The combination of daratumumab and cetrelimab did not appear to alter the PK of daratumumab.
• Garcia-Manero et al (2021)¹⁵ reported the PK results from a study evaluating the safety and efficacy of daratumumab in transfusion-dependent patients with lower-risk myelodysplastic syndromes (MDS) who were relapsed or refractory to erythropoiesis-stimulating agents (ESAs). Serum daratumumab concentrations did not correlate with efficacy or safety in this patient population.

BACKGROUND

The exact mechanism by which daratumumab is cleared from the human body is unknown. As an IgG1қ monoclonal antibody, daratumumab is presumably biotransformed in the same manner as any other endogenous IgG (degraded into small peptides and amino acids via catabolic pathways), and is subject to similar elimination.^16,17 Renal excretion and hepatic enzyme-mediated metabolism of intact daratumumab are therefore unlikely to represent major elimination routes.¹⁸

pHARMACOKINETIC STUDIES

GEN501 and SIRIUS Pharmacokinetic Analysis

Clemens et al (2015, 2017)^2,3 evaluated the PK of IV daratumumab monotherapy in patients with multiple myeloma relapsed from or refractory to prior proteasome inhibitors (PIs) and/or immunomodulatory agents (IMiDs) who participated in the GEN501 and SIRIUS studies (N=223).

Study Design/Methods

• GEN501 was a phase 1/2, open-label, multicenter study.
  • The study consisted of a dose-escalation phase (part 1) and a single-arm, dose-expansion phase at 2 dose levels (part 2).
    • In part 1 (n=32), sequential cohorts of patients received daratumumab 0.005 to 24 mg/kg.
      • There was a 3-week washout period after the first infusion, then doses were administered weekly up to 7 full infusions.
      • Predoses (10% of the full dose and ≤10 mg) were administered a day prior to the first 2 full infusions.
    • In part 2 (n=72), patients received either:
      • Daratumumab 8 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and monthly until disease progression (n=30), or
      • Daratumumab 16 mg/kg for the first infusion followed by a 3-week washout period, then weekly for 7 weeks, every 2 weeks for 14 weeks, and then monthly until disease progression (n=42)
  • Patients had documented myeloma requiring systemic therapy, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 and had relapsed from or were refractory to ≥2 prior therapies, including PIs, IMiDs, chemotherapy, or autologous stem-cell transplantation.
  • There were 104 patients enrolled in the study, 100 of whom were evaluable for PK.
• SIRIUS was an open-label, international, multicenter study.
  • Patients received either:
    • Daratumumab 8 mg/kg every 4 weeks (n=18), or
    • Daratumumab 16 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and monthly thereafter (n=106)
  • Patients had documented myeloma with disease progression on their most recent line of therapy, an ECOG PS ≤2, and had received ≥3 lines of prior therapies, including a PI and an IMiD, or were refractory to both a PI and an IMiD.
  • There were 124 patients enrolled in the study, 123 of whom were evaluable for PK.
• Noncompartmental analysis and PPK modeling were conducted to characterize the PK of daratumumab.
  • Serial PK sampling for noncompartmental analysis was included in all cohorts of GEN501 part 1 and in one daratumumab 16 mg/kg cohort of GEN501 part 2.
  • Sparse PK sampling for PPK modeling was included for all patients in both studies.

Results

PK Observations

• PK data were available from 100 patients in GEN501 and 123 patients in SIRIUS.
  • All concentrations of daratumumab were below the limit of quantification in patients who received daratumumab 0.005 mg/kg and 0.05 mg/kg.
• PK parameters from the first and last (7th) full Infusions in GEN501 part 1 are detailed in Table: PK Parameters From the First and Last (7th) Full Infusions in GEN501 Part 1.
  • After the first full infusion, the maximum concentration (C_max) was nearly dose proportional for doses of 1 to 24 mg/kg and increased greater than dose-proportionally after the last (7th) dose.
  • After the first full infusion, C_max increased in a ratio of 1:2:4:8:20:25 as dose increased in a ratio of 1:2:4:8:16:24.
  • The area under the curve (AUC) increased greater than dose-proportionally after the first and last doses.
  • Clearance decreased with increasing dose and with multiple doses.
• PK parameters following the first full infusion in GEN501 part 2 are detailed in Table: Summary of Daratumumab PK Parameters Following the First Full Infusion in GEN501 Part 2.
  • Volume of distribution estimates suggested that daratumumab is primarily localized to the vascular system with limited extravascular tissue distribution.
• PK parameters following the first full infusion in the SIRIUS study are detailed in Table: Summary of Daratumumab PK Parameters Following the First Full Infusion in the SIRIUS Study.
  • PK parameters were only derived for patients receiving daratumumab 8 mg/kg due to the drug administration and sampling schedules.
• The majority of patients exhibited a decrease in paraprotein from baseline.
  • GEN501: >50% reduction in 46% of patients receiving daratumumab 16 mg/kg; >90% reduction in 24% of patients receiving daratumumab 16 mg/kg.
  • SIRIUS: >50% reduction in 38% of patients receiving daratumumab 16 mg/kg; >90% reduction in 16% of patients receiving daratumumab 16 mg/kg.
  • There was a significant positive correlation between maximum reduction in paraprotein and daratumumab exposure.

PPK Modeling of Daratumumab⁴

• A total of 2572 samples from 223 patients were evaluated (n=150 received daratumumab 16 mg/kg).
• Data were best described by a 2-compartment PPK model with parallel linear and nonlinear Michaelis-Menten eliminations.
• The model suggested that nonlinear (target-mediated) clearance of daratumumab was concentration- and time-dependent, potentially due to saturation and depletion of the target.
• At steady state, the target-mediated clearance of daratumumab approached 0. By the end of the weekly dosing period, nonspecific (linear) clearance became the dominant clearance pathway.
• Concentration- and time-dependency of daratumumab clearance suggested that dynamics of target/tumor burden significantly influenced daratumumab disposition.
• The PPK model predicted that a concentration of 21.4 µg/mL and 236 µg/mL would be needed to achieve 90% and 99% target saturation, respectively.
• At the end of every 4 weeks dosing, 82% and 67% of patients achieved >90% target saturation at doses of daratumumab 16 mg/kg and 8 mg/kg, respectively.
• Exposure to daratumumab was relatively consistent across the range of body weights of patients after administration on a mg/kg basis.
• Age, race, renal impairment, and mild hepatic impairment had neither statistically significant nor clinically relevant effects on exposure to daratumumab.
• Exposure was consistent across the different subgroups for PS (ECOG), refractory status, and number of prior lines of therapy.
• Baseline albumin levels, type of myeloma (IgG vs nonIgG), and sex had a statistically significant effect on daratumumab PK. However, additional analyses showed that these covariates did not have clinically relevant impacts on efficacy or safety profiles.

CENTAURUS Pharmacokinetic Analysis

Landgren et al (2020)^7,8 evaluated whether DARZALEX monotherapy treatment could delay progression from patients with intermediate- or high-risk SMM to multiple myeloma compared with historical observations from the phase 2, randomized, open-label, multicenter CENTAURUS study.

Study Design/Methods

• Patients aged ≥18 years with intermediate- or high-risk SMM for <5 years and Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 were included in the study.
• Intermediate- or high-risk SMM was defined as ≥10% to <60% plasma cells in bone marrow and ≥1 of the following criteria: serum M-protein ≥3 g/dL (IgA ≥2 g/dL); urine M-protein >500 mg/24 hour; abnormal free light chain (FLC) ratio (<0.126 or >8) with serum M-protein <3 g/dL but ≥1 g/dL; or absolute involved serum FLC ≥100 mg/L with an abnormal FLC ratio (<0.126 or >8), but not ≤0.01 or ≥100.
• Patients were randomized in 1:1:1 ratio to receive DARZALEX 16 mg/kg IV in 8-week cycles:
  • Intense group: Once weekly [QW] in cycle 1, every other week [Q2W] in cycles 2-3, every 4 weeks [Q4W] in cycles 4-7, and every 8 weeks [Q8W] up to cycle 20
  • Intermediate group: QW in cycle 1 and Q8W in cycles 2-20
  • Short group: QW for 1 cycle
• Pre- and post-infusion daratumumab serum samples were collected on day 1 of cycle 1 through cycle 8, and 4 and 8 weeks post-treatment.

Results

• A total of 123 patients were randomized to treatment (intense group, n=41; intermediate group, n=41; short group, n=41).
• Of the 123 patients, 68 (55.3%) were female, the median age was 61.0 years (range, 31-81), and 101 (82.1%) and 22 (17.9%) had an ECOG performance status score of 0 and 1, respectively.

PK Analysis

• On cycle 1 day 1 (C1D1), the mean (SD) C_max was similar across the intense, intermediate, and short groups (386.93 [71.0] μg/mL, 385.96 [82.6] μg/mL, and 389.16 [67.4] μg/mL, respectively).
• Through the first cycle, the peak and trough concentrations were similar across the intense, intermediate, and short groups.
• In the intense group, majority of the patients achieved mean trough (predose) concentrations near or above the target-saturating trough concentrations (236 µg/mL needed to achieve 99% target saturation) throughout the QW, Q2W, and Q4W dosing schedules.
• In the intermediate and short groups, the mean trough concentrations were below the target-saturating trough concentrations by C3D1 (230.04 [185.7] μg/mL) and by 8 weeks after the last dose (172.87 [157.6] μg/mL), respectively. See Figure Mean Serum Peak and Trough Concentrations (μg/mL) of Daratumumab in the Intense, Intermediate and Short Groups
• The PK data were consistent with those obtained previously with daratumumab in patients with MM.

Population Pharmacokinetic Study

Xu et al (2016, 2018)^5,19 conducted PPK and exposure-response analyses for DARZALEX in combination with standard therapies for multiple myeloma in patients previously treated with 1 or more lines of therapy.

Study Design/Methods

• PPK analyses were performed on pooled datasets from 4 clinical trials of DARZALEX in combination with standard therapies as follows:
  • GEN503 - phase 1/2 open-label study that evaluated DARZALEX in combination with lenalidomide and dexamethasone (Rd).²⁰
  • MMY1001 - phase 1/2 open-label study that evaluated DARZALEX in combination with bortezomib and dexamethasone (Vd); bortezomib, melphalan and prednisone (VMP); bortezomib, thalidomide, and dexamethasone (VTd); or pomalidomide and dexamethasone [Pom-d].¹¹
  • POLLUX - phase 3 open-label study that compared Rd to DARZALEX plus Rd (DRd).²¹
  • CASTOR - phase 3 open-label study that compared Vd to DARZALEX plus Vd (DVd).²²

Results

• A total of 4,426 measurable PK samples from 694 patients were included in the PPK dataset (684 of these patients received daratumumab 16 mg/kg).
• The PK of daratumumab were similar between the monotherapy and combination therapy studies.
  • Data were adequately described by a 2-compartment PPK model with parallel linear and nonlinear Michaelis-Menton eliminations.
  • Model-derived half-life was 23.3 ± 11.8 days in the combination studies and 18 ± 9.0 days in the monotherapy studies.
  • Steady state was achieved at approximately 5 months in both the combination and monotherapy studies.
  • Daratumumab concentrations were statistically lower in patients with abnormal albumin levels and immunoglobulin G myeloma but the impact was small and not clinically relevant.
  • Age, sex, race, region, renal and hepatic impairment, type of combination therapy, ECOG status, refractory status, and number of prior lines of therapy had no clinically important effects on exposure to daratumumab.
  • Clearance and volume of distribution of daratumumab increased with increasing body weight but exposure was consistent when administered on a mg/kg basis.
• Risk of disease progression and death decreased with increasing daratumumab exposure.
• There was no apparent relationship between daratumumab exposure and infusion-related reactions, thrombocytopenia, anemia, neutropenia, lymphopenia, or infection across all combination regimens.

PK Analysis and PPK Simulation

Xu et al (2018 and 2020)^9,10 conducted PK analysis of data collected from the phase 1b MMY1001^11-13 study regarding splitting the first treatment cycle dose of daratumumab 16 mg/kg into 2 separate infusions of 8 mg/kg on days 1 and 2 as compared to single first dose regimen. PPK analysis and computer simulations were also performed comparing split first dose and single first dose regimens using data collected from studies that utilized various daratumumab combination dosing schedules and indications.

Study Design/Methods

PK Analysis

• PK analysis were performed using MMY1001 clinical PK data from 3 cohorts (n=107):
  • In cohorts 1 and 2 (n=97), patients received the first daratumumab dose as a split first dose of 8 mg/kg on cycle 1 day 1 (C1D1) and on cycle 1 day 2 (C1D2)
    • 75 patients were in the daratumumab in combination with carfilzomib and dexamethasone (DKd) cohort and 22 patients were in the daratumumab in combination with carfilzomib, lenalidomide, dexamethasone (DKRd) cohort.
  • In cohort 3 (n=10), patients received daratumumab as a single first dose regimen of 16 mg/kg on C1D1 in the DKd cohort.
  • Observed PK data were summarized based on timepoint
• DKd and DKRd cohorts (all patients): Pre- and post-infusion daratumumab serum samples were collected on day 1 of cycle 1 through cycle 4, and 3 and 9 weeks post-treatment
  • DKd and DKRd split first dose cohort: Pre- and post-infusion serum samples were also collected on C1D2

PPK Simulations

• Simulations and modeling were used to compare the PK profile of daratumumab split first dose regimen (8 mg/kg on C1D1 and C1D2) with single first dose regimens (16 mg/kg on C1D1) using individual PK parameters from 7 daratumumab multiple myeloma studies:
  • Daratumumab monotherapy (GEN501²³ and SIRIUS²⁴) and daratumumab in combination with lenalidomide and dexamethasone (DRd; GEN503²⁰ and POLLUX²¹), pomalidomide and dexamethasone (DPd; MMY1001^11-13), DKd (MMY1001^11-13), DKRd (MMY1001^11-13), bortezomib and dexamethasone (DVd; MMY1001^11-13 and CASTOR²²) and bortezomib, melphalan and prednisone (DVMP; MMY1001^11-13 and ALCYONE²⁵).
• Simulations were conducted with the following dosing regimens and schedules:
  • Group 1: daratumumab monotherapy, DRd, DPd, DKd, DKRd: 16 mg/kg once weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter
  • Group 2: DVd: 16 mg/kg once weekly for 9 weeks, every 3 weeks for 15 weeks, and thereafter
  • Group 3: DVMP: 16 mg/kg once weekly for 6 weeks, every 3 weeks for 48 weeks, and every 4 weeks thereafter

Results

Safety

• MMY1001 preliminary observations did not demonstrate an increased rate of infusion-related reactions (IRRs) when comparing split first dose and standard first dose.¹²
  • The DKd arm of MMY1001 noted the rate of IRRs to be 43% (n=32) in the split first dose group and 50% (n=5) in the single first dose group.

PK Analysis

• On C1D1, mean (standard deviation [SD]) split first dose (8 mg/kg) daratumumab post-infusion concentrations were lower (159 [47] µg/mL) than single first dose (16 mg/kg) post-infusion concentrations (321 [49] µg/mL).
• Similar mean (SD) daratumumab concentrations following administration of the first total dose of 16 mg/kg were noted in both the split first dose cohort (C1D2 post-infusion 257 [68.6] µg/mL) and the single first dose cohort (C1D1 post-infusion 321 [49.0] µg/mL).
• Following weekly dosing, similar mean (SD) cycle 3 day 1 (C3D1) trough concentrations (C_trough) were noted in both the split first dose cohort (606 [237] µg/mL) and the single first dose cohort (517 [137] µg/mL). See Figure Mean Daratumumab Serum Concentrations (µg/mL) for the Single and Split First Dose of Daratumumab among PK-evaluable Patients Who Received DKd and DKRd in MMY1001 Study

• On C1D1, median split first dose (8 mg/kg) daratumumab post-infusion concentrations were lower (DKd, 151.5 µg/mL; DKRd, 177.8 µg/mL; combined, 156.7 µg/mL) than single first dose (16 mg/kg) post-infusion concentrations (DKd, 319.2 µg/mL).
• Similar median daratumumab concentrations following administration of the first total dose of 16 mg/kg were noted in both the split first dose cohort (C2D1 post-infusion, DKd, 688.6 µg/mL; DKRd, 692.4 µg/mL; combined, 688.9 µg/mL) and the single first dose cohort (DKd, 726.6 µg/mL). See Figure Median Daratumumab Serum Concentrations for the Split and Single Dose of Daratumumab among PK-evaluable Patients Who Received DKd and DKRd in the MMY1001 Study

PPK Analysis

• PPK simulation concentration-time profiles of daratumumab were similar with respect to the overall PK profile between the split first dose (8 mg/kg on C1D1 and C1D2) and single first dose (16 mg/kg on C1D1) regimens. On C1D1, when the dosing regimens were different (8 mg/kg versus 16 mg/kg), simulated PK profiles of the split first dose and single first dose regimens differed. See Figure: Simulated Concentration-time Profiles 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 (Group 1); D-Vd (Group 2); and D-VMP (Group 3) Regimens.
• After C1D2, pre-infusion C_trough and post-infusion maximum concentration values were comparable between the split first dose and single first dose infusions for both monotherapy and combination regimens. See Figure: Boxplot Comparison of Percent Difference in Simulated Daratumumab C_trough in Patients Who Received Daratumumab 16 mg/kg Monotherapy, D-Rd, D-Kd, D-KRd, and D-Pd (Group 1); D-Vd (Group 2); and D-VMP (Group 3) Regimens.
• Following the C1D2 split dose (8 mg/kg), concentration differences were reduced to ≤1% between the 2 dosing regimens.

Pharmacokinetic Analysis of Daratumumab and Cetrelimab in RRMM

Cohen et al (2021)¹⁴ assessed the PK of daratumumab with or without cetrelimab among patients with RRMM.

Study Design/Methods

• Open-label, multicenter, multiple-phase study.
• The study consisted of a screening phase followed by 3 treatment phases:
  • Part 1: single treatment arm, safety run-in phase in which patients received (in 28-day cycles):
    • Daratumumab 16 mg/kg IV weekly in cycle 1 and 2 (days 1, 8, 15, and 22), every other week in cycle 3 to 6 (days 1 and 15), then every 4 weeks on day 1 of each cycle thereafter, and
    • Cetrelimab 240 mg IV on days 2 and 15 of cycle 1, then on days 1 and 15 of each cycle thereafter
  • Part 2 and 3: randomized patients 1:1 to receive daratumumab or daratumumab + cetrelimab as above
• Key inclusion criteria: adults ≥18 years of age; documented, measurable RRMM; ≥3 prior line of therapy, including a PI and IMiD or refractory to both a PI and IMiD
• Patients who received prior treatment with daratumumab, other anti-CD38 therapies, or anti-programmed death receptor-1/programmed death-ligand 1 therapies were excluded.
• PK analyses were conducted for patients who received at least 1 dose of daratumumab or cetrelimab and who had ≥1 post-infusion sample.
• Samples were collected before and after infusions on day 1 of cycles 1, 2, 3, 5, 7, 12, 16 (cetrelimab only), 24, and every 12 cycles thereafter, at the end of treatment visit, and at the follow-up visit.
• C_max, C_trough, and coefficient of variation were measured.

Results

• Between November 20, 2017 and September 24, 2018 (data cutoff), 10 patients were enrolled in the study. Enrollment in the study was terminated early on May 25, 2018 due to administrative reasons.
• In Part 1, 9 patients received daratumumab plus cetrelimab. In Part 2, 1 patient was randomized to receive daratumumab alone.

PK Analysis

• The PK-evaluable population included 9 patients from the safety run-in phase.
• After the first dose of daratumumab (C1D1 post-dose), the mean C_max was 304.99 μg/mL (standard deviation [SD], 60.0).
• After 8 weekly doses of daratumumab, the mean C_trough (C3D1 pre-dose) was 706.39 μg/mL (SD, 104.1).
• Daratumumab concentrations accumulated through the first 9 infusions (last PK sampling time point for weekly dosing) and resulted in a 3.3-fold increase in mean daratumumab concentration (C3D1 post-dose C_max, 1014.53 μg/mL [SD, 127.6]).
• Interpatient variability for daratumumab exposure was moderate (∼30% coefficient of variation for post-dose).
• PK analyses of daratumumab (peak and trough serum concentrations) were comparable with those observed in previous studies of daratumumab.
• The combination of daratumumab and cetrelimab did not appear to alter the PK of daratumumab.

Pharmacokinetic Analysis of Daratumumab in MDS

Garcia-Manero et al (2021)¹⁵ reported the PK results from a study evaluating the safety and efficacy of daratumumab in transfusion-dependent patients with lower-risk MDS who were relapsed or refractory to ESAs.

Study Design/Methods

• Phase 2, randomized, multicenter, open-label study.
• Patients were planned to be randomized 1:1 to daratumumab or talacotuzumab (a CD123 targeting monoclonal antibody), however, a protocol amendment closed the talacotuzumab arm.
• Patients received daratumumab 16 mg/kg IV weekly in cycle 1 and 2 (days 1, 8, 15, and 22), every other week in cycle 3 to 6 (days 1 and 15), then every 4 weeks on day 1 of each cycle thereafter.
• Serum samples were collected before and after infusions on day 1 of cycles 1, 2, 3, 7, and 12

Results

• A total of 33 patients received daratumumab and were included in the PK analysis.
• The mean C_max after the first dose (C1D1) of daratumumab was 204 μg/mL (SD, 56.79).
• Accumulation of daratumumab continued through weekly doses in the first two cycles, resulting in a 2.98-fold increase in mean serum concentration at the end of the 9^th infusion (C3D1).  
• Serum daratumumab concentrations did not correlate with efficacy or safety.
• Mean daratumumab trough concentration at the end of weekly dosing was lower than observations from multiple myeloma trials, however, the mean daratumumab concentrations for responders and non-responders were above the threshold required to achieve 99% CD38 target saturation for multiple myeloma.

CxD1, cycle x day 1, where x represents the cycle number; EOI, end of infusion; SD, standard deviation

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on
14 November 2024.