Simulation of perioperative Ibrutinib withdrawal using a population pharmacokinetic model and sparse clinical...

Treatment with the Bruton tyrosine kinase inhibitor ibrutinib carries a significant risk of bleeding; therefore, the risk-benefit assessment regarding withholding ibrutinib pre- and post-surgery should be considered based on the type of surgery being planned. However, there is no optimal rationale regarding ibrutinib withdrawal during the perioperative period. This exploratory study aimed to generate hypotheses regarding perioperative management of ibrutinib therapy by simulating individual pharmacokinetic profiles using a previously reported population pharmacokinetic (PopPK) model.

Plasma levels of ibrutinib were measured in patients receiving ibrutinib and at high risk of bleeding at Saga University Hospital. Using Phoenix NLME, Bayesian estimation, based on a previously reported PopPK model incorporating actual plasma concentrations measured in individual patients, was employed to simulate perioperative withdrawal scenarios.

Five patients were enrolled. After a withdrawal period of 3-7 days there were no bleeding events in patients that underwent surgery with a low bleeding risk; however, bleeding events occurred in one patient that underwent gastrectomy with moderate or higher bleeding risk. The AUC_0-24 for ibrutinib in a patient also receiving isavuconazole, a moderate CYP3A4 inhibitor, was 1,979 ng*h/mL, a value 2.4-4.8 times higher than that in the patients not receiving isavuconazole.

Perioperative withdrawal of ibrutinib was explored using a previously reported PopPK model in combination with sparse plasma concentration data obtained from patients in real-world clinical settings, including those undergoing surgery. This exploratory study suggests that reliance on plasma concentration data alone might be inadequate for determining the optimal perioperative withdrawal period of ibrutinib.