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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.

Circadian rhythms offer temporal control of anticipatory physiologic adaptations in animals. In the mammalian cardiovascular system, the importance of these rhythms is underscored by increased cardiovascular disease in shift workers, findings recapitulated in experimental animal models. However, a nodal regulator that allows integration of central and peripheral information and coordinates cardiac rhythmic output has been elusive. Here, we show that kruppel-like factor 15 (KLF15) governs a biphasic transcriptomic oscillation in the heart with a maximum ATP production phase and a remodeling and repair phase corresponding to the active and resting phase of a rodent. Depletion of KLF15 in cardiomyocytes leads to a disorganized oscillatory behavior without phasic partition despite an intact core clock. Thus, KLF15 is a nodal connection between the clock and meaningful rhythmicity in the heart.