Darzalex Mechanism of Action

Monoclonal antibody.
Pharmacology: Pharmacodynamics: Mechanism of Action: Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 protein expressed at a high level on the surface of cells in a variety of hematological malignancies, including multiple myeloma tumor cells, as well as other cell types and tissues at various levels. CD38 protein has multiple functions such as receptor mediated adhesion, signaling and enzymatic activity.
Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumor cells.
Based on in vitro studies, daratumumab may utilize multiple effector functions, resulting in immune mediated tumor cell death. These studies suggest that daratumumab can induce tumor cell lysis through complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) in malignancies expressing CD38. A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+T_regs) and B cells (CD38+B_regs) are decreased by daratumumab. T cells (CD3+, CD4+, and CD8+) are also known to express CD38 depending on the stage of development and the level of activation. Significant increases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observed with Daratumumab (Darzalex) treatment in peripheral whole blood and bone marrow. T-cell receptor DNA sequencing verified that T-cell clonality was increased with Daratumumab (Darzalex) treatment, indicating immune modulatory effects that may contribute to clinical response.
Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumab modulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating the hydrolase activity. The significance of these in vitro effects in a clinical setting, and the implications on tumor growth, are not well-understood.
Pharmacodynamic Effects: Natural killer (NK) cell and T-cell count: NK cells are known to express high levels of CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56^dim) NK cells in peripheral whole blood and bone marrow were observed with Daratumumab (Darzalex) treatment. However, baseline levels of NK cells did not show an association with clinical response.
Immunogenicity: In multiple myeloma patients treated with Daratumumab (Darzalex™) in monotherapy and combination clinical trials, less than 1% of patients developed treatment-emergent anti-daratumumab antibodies.
Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to daratumumab with the incidence of antibodies to other products may be misleading.
Clinical studies: Newly Diagnosed Multiple Myeloma: Combination treatment with lenalidomide and dexamethasone in patients ineligible for autologous stem cell transplant: Study MMY3008 an open-label, randomized, active-controlled Phase 3 study, compared treatment with Daratumumab (Darzalex) 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On Daratumumab (Darzalex) infusion days, the dexamethasone dose was given as a pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 737 patients were randomized: 368 to the DRd arm and 369 to the Rd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age. The majority were white (92%), male (52%), 34% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1 and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II and 29% had ISS Stage III disease. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria and overall survival (OS).
With a median follow-up of 28 months the primary analysis of PFS in study MMY3008 demonstrated an improvement in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73; p<0.0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd. Results of an updated PFS analysis after a median follow-up of 64 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 61.9 months in the DRd arm and 34.4 months in the Rd arm (HR=0.55; 95% CI: 0.45, 0.67; p<0.0001), representing a 45% reduction in the risk of disease progression or death in patients treated with DRd. (See Figure 1.)

Click on icon to see table/diagram/image

After a median follow-up of 56 months, DRd has shown an OS advantage over the Rd arm (HR=0.68; 95% CI: 0.53, 0.86; p=0.0013), representing a 32% reduction in the risk of death in patients treated in the DRd arm. Median OS was not reached for either arm. The 60-month survival rate was 66% (95% CI: 61, 71) in the DRd arm and was 53% (95% CI: 47, 59) in the Rd arm. (See Figure 2.)

Click on icon to see table/diagram/image

Additional efficacy results from Study MMY3008 are presented in the table as follows. (See Table 1.)

Click on icon to see table/diagram/image

In responders, the median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group.
Combination treatment with bortezomib, melphalan and prednisone (VMP) in patients ineligible for autologous stem cell transplant: Study MMY3007, an open-label, randomized, active-controlled Phase 3 study, compared treatment with Daratumumab (Darzalex) 16 mg/kg in combination with bortezomib, melphalan and prednisone (D-VMP), to treatment with VMP in patients with newly diagnosed multiple myeloma. Bortezomib was administered by subcutaneous (SC) injection at a dose of 1.3 mg/m² body surface area twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle (Cycle 1;8 doses), followed by once weekly administrations at Weeks 1, 2, 4 and 5 for eight more 6-week cycles (Cycles 2-9; 4 doses per cycle). Melphalan at 9 mg/m², and prednisone at 60 mg/m² were orally administered on Days 1 to 4 of the nine 6-week cycles (Cycles 1-9). Daratumumab (Darzalex) treatment was continued until disease progression or unacceptable toxicity.
A total of 706 patients were randomized: 350 to the D-VMP arm and 356 to the VMP arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 71 (range: 40-93) years, with 30% of the patients ≥75 years of age. The majority were white (85%), female (54%), 25% had an ECOG performance score of 0, 50% had an ECOG performance score of 1 and 25% had an ECOG performance score of 2. Patients had IgG/IgA/Light chain myeloma in 64%/22%/10% of instances, 19% had ISS Stage I, 42% had ISS Stage II and 38% had ISS Stage III disease. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).
With a median follow-up of 16.5 months, the primary analysis of PFS in study MMY3007 demonstrated an improvement in the D-VMP arm as compared to the VMP arm; the median PFS had not been reached in the D-VMP arm and was 18.1 months in the VMP arm (HR=0.5; 95% CI: 0.38, 0.65; p<0.0001), representing 50% reduction in the risk of disease progression or death in patients treated with D-VMP. Results of an updated PFS analysis after a median follow-up of 40 months continued to show an improvement in PFS for patients in the D-VMP arm compared with the VMP arm. Median PFS was 36.4 months in the D-VMP arm and 19.3 months in the VMP arm (HR=0.42; 95% CI: 0.34, 0.51; p<0.0001), representing a 58% reduction in the risk of disease progression or death in patients treated with D-VMP. (See Figure 3.)

Click on icon to see table/diagram/image

After a median follow-up of 40 months, D-VMP has shown an overall survival (OS) advantage over VMP arm (HR=0.60; 95% CI: 0.46, 0.80; p=0.0003), representing a 40% reduction in the risk of death in patients treated in the D-VMP arm. Median OS was not reached for either arm. (See Figure 4.)

Click on icon to see table/diagram/image

Additional efficacy results from Study MMY3007 are presented in the table as follows. (See Table 2.)

Click on icon to see table/diagram/image

In responders, the median time to response was 0.79 months (range: 0.4 to 15.5 months) in the D-VMP group and 0.82 months (range: 0.7 to 12.6 months) in the VMP group. The median duration of response had not been reached in the D-VMP group and was 21.3 months (range: 18.4, not estimable) in the VMP group.
Combination with bortezomib, thalidomide and dexamethasone in patients eligible for autologous stem cell transplant (ASCT): Study MMY3006, an open-label, randomized, active-controlled Phase 3 study compared induction and consolidation treatment with Daratumumab (Darzalex) 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (DVTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete.
Bortezomib was administered by subcutaneous (SC) injection or intravenous (IV) injection at a dose of 1.3 mg/m² body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28-day (4-week) induction treatment cycles (Cycles 1-4) and two consolidation cycles (Cycles 5 and 6) following ASCT after Cycle 4. Thalidomide was administered orally at 100 mg daily during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23 of Cycles 1 and 2, and at 40 mg on Days 1-2 and 20 mg on subsequent dosing days (Days 8, 9, 15, 16) of Cycles 3-4. Dexamethasone 20 mg was administered on Days 1, 2, 8, 9, 15, 16 in Cycles 5 and 6. On the days of Daratumumab (Darzalex) infusion, the dexamethasone dose was administered intravenously as a pre-infusion medication. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer's prescribing information.
A total of 1085 patients were randomized: 543 to the DVTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 58 (range: 22 to 65 years). The majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of 1 and 10% had an ECOG performance score of 2. Forty percent had ISS Stage I, 45% had ISS Stage II and 15% had ISS Stage III disease.
Efficacy was evaluated by the stringent Complete Response (sCR) rate at Day 100 post-transplant. (See Table 3.)

Click on icon to see table/diagram/image

With a median follow-up of 18.8 months, the primary analysis of PFS in study MMY3006 demonstrated an improvement in PFS in the DVTd arm as compared to the VTd arm; the median PFS had not been reached in either arm. Treatment with DVTd resulted in a reduction in the risk of progression or death by 53% compared to VTd alone (HR=0.47; 95% CI: 0.33, 0.67; p<0.0001). Results of an updated PFS analysis after a median follow-up of 44.5 months continued to show an improvement in PFS for patients in the DVTd arm compared with the VTd arm. Median PFS was not reached in the DVTd arm and was 51.5 months in the VTd arm (HR=0.58; 95% CI: 0.47, 0.71; p<0.0001), representing a 42% reduction in the risk of disease progression or death in patients treated with DVTd. (See Figure 5.)

Click on icon to see table/diagram/image

Relapsed/Refractory Multiple Myeloma: Combination treatment with lenalidomide and dexamethasone: Study MMY3003, an open-label, randomized, active-controlled Phase 3 trial, compared treatment with Daratumumab (Darzalex) 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or BMI <18.5). On Daratumumab (Darzalex) infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a Daratumumab (Darzalex) pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the Daratumumab (Darzalex) and the control arm. The median patient age was 65 years (range 34 to 89 years), 11% were ≥75 years, 59% were male; 69% Caucasian, 18% Asian, and 3% African American. Patients had received a median of 1 prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (86%) received a prior proteasome inhibitor (PI), 55% of patients had received a prior immunomodulatory agent (IMiD), including 18% of patients who had received prior lenalidomide, and 44% of patients had received both a prior PI and IMiD. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).
With a median follow-up of 13.5 months, the primary analysis of PFS in study MMY3003 demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (HR=0.37; 95% CI: 0.27, 0.52; p<0.0001) representing 63% reduction in the risk of disease progression or death in patients treated with DRd. Results of an updated PFS analysis after a median follow-up of 55 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 45.0 months in the DRd arm and 17.5 months in the Rd arm (HR=0.44; 95% CI: 0.35, 0.54; p<0.0001), representing a 56% reduction in the risk of disease progression or death in patients treated with DRd. (See Figure 6.)

Click on icon to see table/diagram/image

After a median follow-up of 80 months, DRd has shown an OS advantage over the Rd arm (HR=0.73; 95% CI: 0.58, 0.91; p=0.0044), representing a 27% reduction in the risk of death in patients treated in the DRd arm. The median OS was 67.6 months in the DRd arm and 51.8 months in the Rd arm. The 78-month survival rate was 47% (95% CI: 41, 52) in the DRd arm and was 35% (95% CI: 30, 41) in the Rd arm. (See Figure 7.)

Click on icon to see table/diagram/image

Additional efficacy results from Study MMY3003 are presented in the table as follows. (See Table 4.)

Click on icon to see table/diagram/image

Combination treatment with bortezomib and dexamethasone: Study MMY3004, an open-label, randomized, active-controlled Phase 3 trial, compared treatment with Daratumumab (Darzalex) 16 mg/kg in combination with bortezomib and dexamethasone (DVd), to treatment with bortezomib and dexamethasone (Vd) in patients with multiple myeloma who had received at least one prior therapy. Bortezomib was administered by SC injection or IV injection at a dose of 1.3 mg/m² body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the 8 bortezomib cycles (80 mg/week for two out of three weeks of each of the bortezomib cycle) or a reduced dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of Daratumumab (Darzalex) infusion, 20 mg of the dexamethasone dose was administered as a pre-infusion medication. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a Daratumumab (Darzalex) pre-infusion medication. Bortezomib and dexamethasone were given for 8 three-week cycles in both treatment arms; whereas Daratumumab (Darzalex) was given until treatment progression. However, dexamethasone 20 mg was continued as a Daratumumab (Darzalex) pre-infusion medication in the DVd arm. Dose adjustments for bortezomib and dexamethasone were applied according to manufacturer's prescribing information.
A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. The baseline demographic and disease characteristics were similar between the Daratumumab (Darzalex) and the control arm. The median patient age was 64 years (range 30 to 88 years); 12% were ≥75 years, 57% were male; 87% Caucasian, 5% Asian and 4% African American. Patients had received a median of 2 prior lines of therapy and 61% of patients had received prior autologous stem cell transplantation (ASCT). Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% of patients received an IMiD (42% received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment and the proportions of patients refractory to any specific prior therapy were well balanced between the treatment groups. Thirty-three percent (33%) of patients were refractory to an IMiD only, and 28% were refractory to lenalidomide. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).
With a median follow-up of 7.4 months, the primary analysis of PFS in study MMY3004 demonstrated an improvement in the DVd arm as compared to the Vd arm; the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53]; p-value <0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd. Results of an updated PFS analysis after a median follow-up of 50 months continued to show an improvement in PFS for patients in the DVd arm compared with the Vd arm. Median PFS was 16.7 months in the DVd arm and 7.1 months in the Vd arm (HR [95% CI]: 0.31 [0.24, 0.39]: p-value <0.0001), representing a 69% reduction in the risk of disease progression or death in patients treated with DVd versus Vd. (See Figure 8.)

Click on icon to see table/diagram/image

After a median follow-up of 73 months, DVd has shown an OS advantage over the Vd arm (HR=0.74; 95% CI: 0.59, 0.92; p=0.0075), representing a 26% reduction in the risk of death in patients treated in the DVd arm. The median OS was 49.6 months in the DVd arm and 38.5 months in the Vd arm. The 72-month survival rate was 39% (95% CI: 33, 45) in the DVd arm and was 25% (95% CI: 20, 31) in the Vd arm. (See Figure 9.)

Click on icon to see table/diagram/image

Additional efficacy results from Study MMY3004 are presented in the table as follows. (See Table 5.)

Click on icon to see table/diagram/image

Monotherapy: The clinical efficacy and safety of Daratumumab (Darzalex) for the treatment of patients with relapsed and refractory multiple myeloma whose prior therapy included a proteasome inhibitor and an immunomodulatory agent, was demonstrated in two open-label studies.
In Study MMY2002, 106 patients with relapsed and refractory multiple myeloma received 16 mg/kg Daratumumab (Darzalex) until disease progression. The median patient age was 63.5 years (range, 31 to 84 years), 49% were male and 79% were Caucasian. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent (IMiD), 77% were refractory to alkylating agents, 63% were refractory to pomalidomide and 48% of patients were refractory to carfilzomib.
Efficacy results based on Independent Review Committee (IRC) assessment are presented in the table as follows. (See Table 6.)

Click on icon to see table/diagram/image

Overall response rate (ORR) in MMY2002 was similar regardless of type of prior anti-myeloma therapy. With a median duration of follow-up of 9 months, median Overall Survival (OS) was not reached. The 12-month OS rate was 65% (95% CI: 51.2, 75.5).
In Study GEN501, 42 patients with relapsed and refractory multiple myeloma received 16 mg/kg Daratumumab (Darzalex) until disease progression. The median patient age was 64 years (range, 44 to 76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% were refractory to both a PI and IMiD, 60% were refractory to alkylating agents, 36% were refractory to pomalidomide and 17% were refractory to carfilzomib.
Treatment with daratumumab at 16 mg/kg led to a 36% ORR with 5% CR and 5% VGPR. The median time to response was 1 (range: 0.5 to 3.2) month. The median duration of response was not reached (95% CI: 5.6 months, not estimable). With a median duration of follow-up of 10 months, median OS was not reached. The 12-month OS rate was 77% (95% CI: 58.0, 88.2).
Pharmacokinetics: The pharmacokinetics (PK) of daratumumab following intravenous administration of Daratumumab (Darzalex) were evaluated in patients with relapsed and refractory multiple myeloma at dose levels from 0.1 mg/kg to 24 mg/kg. A population PK model of daratumumab was developed to describe the PK characteristics of daratumumab and to evaluate the influence of covariates on the disposition of daratumumab in patients with multiple myeloma. The population PK analysis included 223 patients receiving Daratumumab (Darzalex) in two clinical trials (150 subjects received 16 mg/kg).
In the 1- to 24 mg/kg cohorts, peak serum concentrations (C_max) after the first dose increased in approximate proportion to dose and volume of distribution was consistent with initial distribution into the plasma compartment. Increases in AUC were more than dose-proportional and clearance (CL) decreased with increasing dose. These observations suggest CD38 may become saturated at higher doses, after which the impact of target binding clearance is minimized and the clearance of daratumumab approximates the linear clearance of endogenous IgG1. Clearance also decreased with multiple doses, which may be related to tumor burden decreases.
Terminal half-life increases with increasing dose and with repeated dosing. The mean (standard deviation [SD]) estimated terminal half-life of daratumumab following the first 16 mg/kg dose was 9 (4.3) days. Based on population PK analysis, the mean (SD) half-life associated with non-specific linear elimination was approximately 18 (9) days; this is the terminal half-life that can be expected upon complete saturation of target mediated clearance and repeat dosing of daratumumab.
At the end of weekly dosing for the recommended schedule and dose of 16 mg/kg, the mean (SD) serum C_max value was 915 (410.3) micrograms/mL, approximately 2.9-fold higher than following the first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing was 573 (331.5) micrograms/mL.
Based on the population PK analysis of Daratumumab (Darzalex) monotherapy, daratumumab steady state is achieved approximately 5 months into the every 4-week dosing period (by the 21^st infusion), and the mean (SD) ratio of C_max at steady-state to C_max after the first dose was 1.6 (0.5). The mean (SD) central volume of distribution is 56.98 (18.07) mL/kg.
Three additional population PK analyses were conducted in patients with multiple myeloma that received daratumumab in various combination therapies (N=1390). Daratumumab concentration-time profiles were similar following the monotherapy and combination therapies. The mean estimated terminal half-life associated with linear clearance in combination therapy was approximately 15-23 days.
Based on population PK analysis body weight was identified as a statistically significant covariate for daratumumab clearance. Therefore, body weight based dosing is an appropriate dosing strategy for the multiple myeloma patients.
Simulation of daratumumab pharmacokinetics 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 the treatment.
Special populations: Age and gender: Based on population PK analyses in patients receiving monotherapy or various combination therapies, age (range: 31-93 years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab was similar between younger (aged <65 years, n=518) and older (aged ≥65 to <75 years, n=761; aged ≥75 years, n=334) patients.
Gender did not affect exposure of daratumumab to a clinically relevant degree in population PK analyses.
Renal impairment: No formal studies of Daratumumab (Darzalex) in patients with renal impairment have been conducted.
Population PK analyses were performed based on pre-existing renal function data in patients receiving Daratumumab (monotherapy or various combination therapies, including 441 patients with normal renal function (creatinine clearance [CrCl] ≥90 mL/min), 78 with mild renal impairment (CrCl <90 and ≥60 mL/min), 68 with moderate renal impairment (CrCl <60 and ≥30 mL/min), and 6 with severe renal impairment (CrCl <30 mL/min). No clinically important differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.
Hepatic impairment: No formal studies of Daratumumab (Darzalex) in patients with hepatic impairment have been conducted. Population PK analyses were performed in patients receiving daratumumab monotherapy or various combination therapies, including 1404 patients with normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]), 189 with mild hepatic impairment (TB 1.0× to 1.5× ULN or AST >ULN) and 8 patients with moderate (TB >1.5× to 3.0× ULN; n=7) or severe (TB >3.0× ULN; n=1) hepatic impairment. No clinically important difference in the exposure to daratumumab were observed between patients with hepatic impairment and those with normal hepatic function.
Race: Based on the population PK analyses in patients receiving either daratumumab monotherapy or various combination therapies, the exposure to daratumumab was similar between white (n=1371) and non-white (n=242) subjects.
Toxicology: Non-clinical information: Carcinogenicity and Mutagenicity: No animal studies have been performed to establish the carcinogenic potential of daratumumab.
Routine genotoxicity and carcinogenicity studies are generally not applicable to biologic pharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA or chromosomal material.
Reproductive Toxicology: No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development.
Fertility: No animal studies have been performed to determine potential effects on fertility in males or females.