Tacrolimus exposure during the three-month period following allogeneic stem cell transplantation predicts overall survival

Alzbeta Zavrelova ¹ Katerina Zibridova ¹ Jakub Radocha ¹ Eva Cermakova ² Petra Rozsivalova ¹ Pavel Zak ¹ Benjamin Visek ¹ Miriam Lanska ¹ Jana Stevkova ¹ Sara Merdita ³ Ondrej Slanar ³ Martin Šíma ^3*

• ¹ University Hospital Hradec Kralove, Hradec Králové, Hradec Králové, Czechia
• ² Faculty of Medicine in Hradec Králové, Charles University, Hradec Kralove, Czechia
• ³ Institute of Pharmacology, First Faculty of Medicine, Charles University, Prague, Czechia

Objectives: The objective of this study was to investigate the relationship between both shortterm and long-term tacrolimus exposure and overall survival after allogeneic stem cell transplantation and to propose individualized tacrolimus dosing based on population pharmacokinetic model.Tacrolimus exposure during the first three months of therapy after transplantation was calculated using therapeutic drug monitoring data in all patients who underwent allogeneic stem cell transplantation from 2016 to 2018. Optimal upper level was found using ROC analysis and impact of cut-off tacrolimus exposure values on overall survival of patients was assessed together with other transplant variables using multivariate analysis. Population pharmacokinetic model was developed using nonlinear mixed-effects modeling method and optimal tacrolimus dose was proposed.Results: A total of 86 patients were included into the outcome analyses. Except disease risk category, age ≥ 55 years and female to male donor, tacrolimus exposure of AUCtc ≥ 222 ng.h/mL, ≥ 258 ng.h/mL, and ≥ 160 ng.h/mL during the whole three-month period, second month and third month of therapy, respectively, were also found statistically significant for overall survival in univariate analysis. These AUCtc values were an independent variable for overall survival in multivariate analysis with RR 3.01 (P=0.0056), 3.22 (P=0.0058) and 2.93 (P=0.0184) for whole three-month period, second and third month of therapy, respectively.Disease risk category (RR 7.11, P˂0.0001), age (RR 2.45, P=0.0214) and nonmyeloablative conditioning (RR 3.39, P=0.0014) were also significant factors influencing survival in multivariate analysis. Tacrolimus volume of distribution was 127.1 L and was not affected by any of the tested covariates, while clearance decreased with age according to equation CL = 7.94 × e -0.0085 ×age , and was reduced by 23% in patients who underwent a repeat transplantation.Except for the disease risk category, age and nonmyeloablative conditioning, exposure to tacrolimus is an independent predictor of overall survival and should not exceed trough level of 10.7 ng/mL during 2 nd month and 6.8 ng/mL during 3 rd month after transplantation. In order to reach this target, nomogram for estimation of maximal initial tacrolimus daily dose was developed based on the population pharmacokinetic model.