Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Abstract

Sorafenib administered at the approved dose continuously is not tolerated long‐term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure‐response relationship in patients with AML. A one‐compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS‐like tyrosine kinase 3 (FLT3)‐ITD and extracellular signal‐regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax) model. Sorafenib could inhibit FLT3‐ITD activity by 100% with an IC50 of 69.3 ng/mL and ERK activity by 84% with an IC50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure‐response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3‐ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML.

A Prospective Study of Peritransplant Sorafenib for Patients with FLT3-ITD Acute Myeloid Leukemia Undergoing Allogeneic Transplantation

“…Additionally, we were able to demonstrate continued FLT3 inhibitory activity in the plasma up to 7 days after dosing was completed due to sorafenib's long half-life and potency against FLT3-ITD. An exposure-response analysis confirmed a strong link between FLT3 inhibition and exposure to sorafenib and metabolite with varying dosing regimens being simulated [8]. A starting dose of sorafenib 200 mg twice a day (BID) was considered a practical choice to initiate therapy based on simulated FLT3 activity across the spectrum of dosing regimens and desire to improve longterm tolerability.…”

FLT3 inhibitors in acute myeloid leukemia

“…Sorafenib also has a potent anti-leukemic effect on FLT3-mutated AML. It completely inhibits FLT3/ITD activity with an IC 50 of 69.3 ng/ml [ 12 ].…”

Characterization of LDD-2633 as a Novel RET Kinase Inhibitor with Anti-Tumor Effects in Thyroid Cancer

“…Vandetanib, cabozantinib, and sorafenib have inhibitory activity against FLT3 kinase along with growth inhibitory activity against acute myeloid leukemia cells with FLT3 mutation [ 21 , 22 , 23 ]. These drugs primarily inhibit vascular endothelial growth factor receptor 2 to induce anti-angiogenic effects.…”