Evaluation of the Potential Impact on Pharmacokinetics of Various Cytochrome P450 Substrates of increasing IL-6 Levels following administration of the T-cell bispecific engager Glofitamab.

Glofitamab is a novel T cell bispecific antibody developed for treatment of Relapsed-Refractory Diffuse Large B Cell Lymphoma and other Non-Hodgkin lymphoma indications. By simultaneously binding human CD20-expressing tumor cells and CD3 on T cells, glofitamab induces tumor cell lysis, in addition to T-cell activation, proliferation and cytokine release. Here, we describe PBPK modeling performed to assess the impact of glofitamab-associated transient increases in Interleukin 6 (IL-6) on the pharmacokinetics of several cytochrome P450 (CYP) substrates. By refinement of a previously described IL-6 model and inclusion of in vitro CYP suppression data for CYP3A4, CYP1A2 and 2C9, a physiologically based pharmacokinetic (PBPK) model was established in Simcyp® to capture the induced IL6 levels seen when glofitamab is administered at the intended dose and dosing regimen. Following model qualification, the PBPK model was used to predict the potential impact of CYP suppression on exposures of various CYP probe substrates. PBPK analysis predicted that, in the worst-case, the transient elevation of IL-6 would increase exposures of CYP3A4, CYP2C9 and CYP1A2 substrates by less than or equal to twofold. Increases for CYP3A4, CYP2C9 and CYP1A2 substrates were projected to be 1.75, 1.19 and 1.09-fold following the first administration and 2.08, 1.28 and 1.49-fold following repeated administrations. It is recommended that there are no restrictions on concomitant treatment with any other drugs. Consideration may be given for potential DDI during the first cycle in patients who are receiving concomitant CYP substrates with a narrow therapeutic index via monitoring for toxicity or for drug concentrations.