Isatuximab is an IgG1-derived monoclonal antibody that binds to a specific extracellular epitope of CD38 receptor. CD38 is a transmembrane glycoprotein that is highly expressed on multiple myeloma cells.
In vitro, isatuximab acts through IgG Fc-dependent mechanisms including: antibody dependent cell mediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC). Furthermore, isatuximab can also trigger tumour cell death by induction of apoptosis via an Fc-independent mechanism.
In vitro, isatuximab blocks the enzymatic activity of CD38 which catalyses the synthesis and hydrolysis of cyclic ADP-ribose (cADPR), a calcium mobilizing agent. Isatuximab inhibits the cADPR production from extracellular nicotinamide adenine dinucleotide (NAD) in multiple myeloma cells.
In vitro, isatuximab can activate NK cells in the absence of CD38 positive target tumour cells.
In vivo, a decrease in absolute counts of total CD16+ and CD56+ NK cells, CD19+ B-cells, CD4+ Tcells and TREG (CD3+, CD4+, CD25+, CD127-) was observed in peripheral blood of patients treated with isatuximab monotherapy.
In multiple myeloma patients, isatuximab monotherapy induced clonal expansion of the T-cell receptor repertoire indicating an adaptive immune response.
The combination of isatuximab and pomalidomide in vitro enhances cell lysis of CD38 expressing multiple myeloma cells by effector cells (ADCC), and by direct tumour cell killing compared to that of isatuximab alone. In vivo animal experiments using a human multiple myeloma xenograft model in mice demonstrated that the combination of isatuximab and pomalidomide results in enhanced antitumour activity compared to the activity of isatuximab or pomalidomide alone.
The pharmacokinetics of isatuximab were assessed in 476 patients with multiple myeloma treated with isatuximab intravenous infusion as a single agent or in combination with pomalidomide and dexamethasone, at doses ranging from 1 to 20 mg/kg, administered either once weekly; every 2 weeks; or every 2 weeks for 8 weeks followed by every 4 weeks; or every week for 4 weeks followed by every 2 weeks.
Isatuximab displays nonlinear pharmacokinetics with target-mediated drug disposition due to its binding to CD38 receptor.
Isatuximab exposure (area under the plasma concentration-time curve over the dosing interval AUC) increases in a greater than dose proportional manner from 1 to 20 mg/kg following every 2 weeks schedule, while no deviation to the dose proportionality is observed between 5 and 20 mg/kg following every week for 4 weeks followed by every 2 weeks schedule. This is due to the high contribution of nonlinear target-mediated clearance to the total clearance at doses below 5 mg/kg, which becomes negligible at higher doses. After isatuximab 10 mg/kg administration every week for 4 weeks followed by every 2 weeks, the median time to reach steady state was 18 weeks with a 3.1-fold accumulation. In ICARIA-MM, clinical trial performed in relapsed and/or refractory multiple myeloma patients treated with isatuximab in combination with pomalidomide and dexamethasone, the mean (CV%) predicted maximum plasma concentration Cmax and AUC at steady state were 351 µg/mL (36.0%) and 72,600 µg.h/mL (51.7%), respectively. Although the change from a weight-based volume administration method for isatuximab infusion to the fixed volume infusion method resulted in changes in the tmax, the change had a limited impact on pharmacokinetics exposure with comparable simulated Cmax at steady state (283 µg/mL vs 284 µg/mL) and Ctrough at 4 weeks (119 µg/mL vs 119 µg/mL) for a patient with median weight (76 kg). Also for other patient weight groups, Cmax and Ctrough were comparable. In IKEMA, clinical trial performed in relapsed and/or refractory multiple myeloma patients treated with isatuximab in combination with carfilzomib and dexamethasone, the mean (CV%) predicted maximum plasma concentration Cmax and AUC at steady state were 637 µg/mL (30.9%) and 152,000 µg.h/mL (37.8%), respectively.
The pharmacokinetics of isatuximab and pomalidomide, or of isatuximab and carfilzomib, were not influenced by their co-administration.
The estimated total volume of distribution of isatuximab is 8.75 L.
As a large protein, isatuximab is expected to be metabolized by non-saturable proteolytic catabolism processes.
Isatuximab is eliminated by two parallel pathways, a nonlinear target-mediated pathway predominating at low concentrations, and a nonspecific linear pathway predominating at higher concentrations. In the therapeutic plasma concentrations range, the linear pathway is predominant and decreases over time by 50% to a steady state value of 9.55 mL/h (0.229 L/day). This is associated with a terminal half-life of 28 days.
The population pharmacokinetic analyses of 476 patients aged 36 to 85 years showed comparable exposure to isatuximab in patients <75 years old (n=406) versus ≥75 years old (n=70).
The population pharmacokinetic analysis with 207 female (43.5%) and 269 male (56.5%) patients showed no clinically meaningful effect of gender on isatuximab pharmacokinetics.
The population pharmacokinetic analysis with 377 Caucasian (79%), 25 Asian (5%), 18 Black (4%), and 33 other race (7%) patients showed no clinically meaningful effect of race on isatuximab pharmacokinetics.
Based on a population pharmacokinetics analysis using data from 476 patients, the clearance of isatuximab increased with increasing body weight, supporting the body-weight based dosing.
No formal studies of isatuximab in patients with hepatic impairment have been conducted. Out of the 476 patients of the population pharmacokinetic analyses, 65 patients presented with mild hepatic impairment [total bilirubin >1 to 1.5 times upper limit of normal (ULN) or aspartate amino transferase (AST) > ULN] and 1 patient had moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST). Mild hepatic impairment had no clinically meaningful effect on the pharmacokinetics of isatuximab. The effect of moderate (total bilirubin >1.5 times to 3 times ULN and any AST) and severe hepatic impairment (total bilirubin >3 times ULN and any AST) on isatuximab pharmacokinetics is unknown. However, since isatuximab is a monoclonal antibody, it is not expected to be cleared via hepatic-enzyme mediated metabolism and as such, variation in hepatic function is not expected to affect the elimination of isatuximab.
No formal studies of isatuximab in patients with renal impairment have been conducted. The population pharmacokinetic analyses on 476 patients included 192 patients with mild renal impairment (60 mL/min/1.73 m² ≤ estimated glomerular filtration rate (e-GFR) <90 mL/min/1.73 m²), 163 patients with moderate renal impairment (30 mL/min/1.73 m² ≤ e-GFR < 60 mL/min/1.73 m²) and 12 patients with severe renal impairment (e-GFR <30 mL/min/1.73 m²). Analyses suggested no clinically meaningful effect of mild to severe renal impairment on isatuximab pharmacokinetics compared to normal renal function.
Isatuximab was not evaluated in patients under 18 years of age.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, albeit the species selected is not pharmacologically responsive and therefore the relevance for humans is not known. Genotoxicity, carcinogenic potential and toxicity to reproduction and development studies have not been performed.
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