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 mechanism‐based 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.

The interest in therapeutic monoclonal antibodies (mAbs) has continuously growing in several diseases. However, their pharmacokinetics (PK) is complex due to their target-mediated drug disposition (TMDD) profiles which can induce a non-linear PK. This point is particularly challenging during the pre-clinical and translational development of a new mAb. This article reviews and describes the existing PK modeling approaches used to translate the mAbs PK from animal to human for intravenous (IV) and subcutaneous (SC) administration routes. Several approaches are presented, from the most empirical models to full physiologically based pharmacokinetic (PBPK) models, with a focus on the population PK methods (compartmental and minimal PBPK models). They include the translational approaches for the linear part of the PK and the TMDD mechanism of mAbs. The objective of this article is to provide an up-to-date overview and future perspectives of the translational PK approaches for mAbs during a model-informed drug development (MIDD), since the field of PK modeling has gained recently significant interest for guiding mAbs drug development.

Purpose Isatuximab, an immunoglobulin G monoclonal antibody that targets a specific CD38 epitope, is approved in combination with dexamethasone plus either pomalidomide or carfilzomib for treatment of adults with relapsed or refractory (R/R) multiple myeloma. Isatuximab demonstrated significant anti-leukemic activity in preclinical models. In the phase 2 ISAKIDS study (NCT03860844), isatuximab was tested as combination therapy for pediatric patients with R/R acute lymphoblastic leukemia and acute myeloid leukemia. Here, we use population pharmacokinetics (PopPK) to select the appropriate isatuximab dose for infants aged 1–24 months in ISAKIDS. Methods An initial PK modeling and simulation strategy was applied to the first 18 tested patients to confirm the isatuximab 20-mg/kg dose administered to patients aged 24 months or older and to explore the dose needed for the youngest patients. The PK of isatuximab in children was characterized by pooling data from ISAKIDS with adult data from the phase 2 ISLAY study (NCT02999633). Results The PopPK model predicted a slight drug underexposure (median decrease of about 30%) in pediatric patients aged 10–24 months (9–12 kg) compared with reference adults (51–100 kg), which did not require a dose adjustment, as no isatuximab exposure versus efficacy relationships were observed in these clinical settings. Conclusion The modeling and simulation strategies in this study support the previous selection of a 20-mg/kg dose for all age groups and enabled both de-risking of dose selection and the ability to pursue additional pediatric investigation of isatuximab in the youngest age group of patients with acute leukemias.