Drug‐Disease Interaction and Time‐Dependent Population Pharmacokinetics of Isatuximab in Relapsed/Refractory Multiple Myeloma Patients

Abstract

Isatuximab, a monoclonal antibody (mAb) of immunoglobulin G (IgG) isotype, specifically targets the cluster of differentiation 38 antigen overexpressed in malignant plasma cells. Isatuximab is used to treat multiple myeloma (MM), characterized by the excessive production of abnormal "myeloma proteins" (M-proteins) that may interact with therapeutic IgG mAb on the neonatal Fc receptor (FcRn)-mediated recycling pathway. The clinical pharmacology profile of isatuximab was investigated by population pharmacokinetics (PKs) modeling in 476 patients with MM who received 1-20 mg/kg isatuximab either as single agent or in combination with pomalidomide-dexamethasone in 4 clinical trials. Isatuximab PKs were characterized by a two-compartment model with parallel time-varying linear clearance (CL) and nonlinear elimination. Due to a mechanismbased drug-disease interaction, patients secreting IgG M-protein exhibited a twofold lower drug exposure compared with patients with non-IgG MM. No dose adjustment was required based on MM immunoglobulin type because efficacy and safety profiles were comparable between IgG and non-IgG MM subpopulations. β2-microglobulin, body weight, sex, drug material, and race have a limited effect on drug exposure and do not require any dose adjustment. A typical 50% decrease in linear CL from initial treatment to steady-state was predicted, and this decrease correlated with the best overall response rate and was slower for patients with IgG MM. These findings suggest that the time-dependent effect of isatuximab is likely mediated by a combined factor of both disease state evolution and the perturbation of the FcRn-mediated recycling pathway. Isatuximab (SAR650984) is an immunoglobulin G (IgG) 1 monoclonal antibody (mAb) that selectively binds to the human cell surface antigen molecule classified as cluster of differentiation 38 (CD38). CD38 is expressed in a number of hematological malignancies, including multiple myeloma (MM). Isatuximab has been found to kill tumor cells via multiple biological mechanisms. 1-4 The isatuximab clinical program in MM includes single agent and combination studies, one of which was a phase Ib open-label study evaluating the combination of isatuximab at

Isatuximab: A Review of Its Use in Multiple Myeloma

“…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 [ 16 ]. Linear clearance of isatuximab predominates over the therapeutic plasma concentration range; clearance decreases over time by 50% to a steady state value of 9.55 mL/h (0.229 L/day) [ 16 , 34 ]. The terminal half-life of isatuximab is 28 days [ 16 ].…”

“…Based on a population pharmacokinetic analysis, age, gender and race, as well as RI and hepatic impairment, have no clinically meaningful effects on the pharmacokinetics of isatuximab and do not require any dose adjustment [ 16 , 34 ]. Isatuximab steady-state exposure does, however, decrease with increasing bodyweight, necessitating a bodyweight-based dosing approach [ 16 , 34 ] (Sect. 6 ).…”

Population pharmacokinetics of belantamab mafodotin, a BCMA‐targeting agent in patients with relapsed/refractory multiple myeloma

“…PK parameter estimates were in the range of those described for other mAbs in patients with malignancies, including the findings of decreasing CL over time, as well as the maximum decrease and time to 50% decrease 10–12,16,18 . Mean maximum decreases in CL of 24.5% have been reported for nivolumab in solid tumor studies, 19 20% for pembrolizumab in melanoma and non‐small cell lung carcinoma (NSCLC), 12 17.1% for atezolizumab in NSCLC, 19 and 50% for isatuximab linear clearance in MM 20 . Time‐varying CL may be related to a reduction in inflammation or metabolic stress, which subsequently manifests itself in decreased catabolism of mAb as a result of the drug’s therapeutic effects 21 .…”

“… 10 , 11 , 12 , 16 , 18 Mean maximum decreases in CL of 24.5% have been reported for nivolumab in solid tumor studies, 19 20% for pembrolizumab in melanoma and non‐small cell lung carcinoma (NSCLC), 12 17.1% for atezolizumab in NSCLC, 19 and 50% for isatuximab linear clearance in MM. 20 Time‐varying CL may be related to a reduction in inflammation or metabolic stress, which subsequently manifests itself in decreased catabolism of mAb as a result of the drug’s therapeutic effects. 21 Another potential explanation could be the reduction in antigen burden, which would also result in a decrease in CL with time.…”

Application of urine immunofixation electrophoresis in prognostic evaluation of hematopoietic stem cell transplantation in patients with myeloma

“…IgG type can affect the immunity of patients. Therefore, it may be beneficial for the prognosis in the course of daily treatment to enhance the immunity of patients, prevent patients from infection and improve the prognosis of patients 20 , and adopt the appropriate treatment regimen on the basis of treatment according to each type.…”