Blinatumomab Trimer Formation: Insights From A Mechanistic PKPD Model Into The Implications For Switching From Infusion To Subcutaneous Dosing Regimen
Kapitanov, G. I.; Head, S. A.; Flowers, D.; Apgar, J. F.; Grant, J.
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Blinatumomab is a bispecific T-cell engager (BiTE) that binds to CD3 on T cells and CD19 on B cells. It has been approved for use in B-cell acute lymphoblastic leukemia (B-ALL) with a regimen that requires continuous infusion (cIV) for four weeks per treatment cycle. It is currently in clinical trials for Non-Hodgkin lymphoma (NHL) with cIV administration. Recently, there have been studies investigating dose-response after subcutaneous (SC) dosing in B-ALL and in NHL to determine whether this more convenient method of delivery would have a similar efficacy/safety profile as continuous infusion. We constructed mechanistic PKPD models of blinatumomab activity in B-ALL and NHL patients, investigating the amount of CD3:blinatumomab:CD19 trimers the drug forms at different dosing administrations and regimens. The modeling and analysis demonstrate that the explored SC doses in B-ALL and NHL achieve similar trimer numbers as the cIV doses in those indications. We further simulated various subcutaneous dosing regimens, and identified conditions where trimer formation dynamics are similar between constant infusion and subcutaneous dosing. Based on the model results, subcutaneous dosing is a viable and convenient strategy for blinatumomab and is projected to result in similar trimer numbers as constant infusion.
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