Development of a Minimal Physiologically-Based Pharmacokinetic/ Pharmacodynamic Model to Characterize Target Cell Depletion and Cytokine Release for T Cell-Redirecting Bispecific Agents in Humans.

Development of a Minimal Physiologically-Based Pharmacokinetic/ Pharmacodynamic Model to Characterize Target Cell Depletion and Cytokine Release for T Cell-Redirecting Bispecific Agents in Humans. Eur J Pharm Sci. 2020 Feb 10;:105260 Authors: Jiang X, Chen X, Jaiprasart P, Carpenter TJ, Zhou R, Wang W Abstract T cell-redirecting bispecific antibodies (bsAbs) are highly potent tumor-killing molecules. Following bsAb mediated engagement with target cells, T cells get activated and kill target cells while inducing cytokine release, which at higher levels may lead to life-threatening cytokine release syndrome (CRS). Clinical evidence suggests that CRS can be mitigated by implementing a stepwise dosing strategy. Here, we developed a mechanism-based minimal physiologically-based pharmacokinetic/pharmacodynamic (mPBPK/PD) model using reported preclinical and clinical data from blinatumomab. The mPBPK/PD model reasonably captured blinatumomab PK and B cell depletion profiles in blood and in various tissue sites of action (i.e., red marrow perivascular niche, spleen, and lymph nodes) in patients with non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Using interleukin 6 (IL-6) as an example, our model quantitatively characterized the mitigation of cytokine release by a blinatumomab 5-15-60 µg/m2/day stepwise dosing regimen comparing to a 60 µg/m2/day flat dose in NHL patients. Furthermore, by only modifying the system para...
Source: European Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharm Sci Source Type: research