Prospective Evaluation of Thiotepa Pharmacokinetics in Children and Young Adults Undergoing Allogeneic or Autologous Hematopoietic Cell Transplantation

Abstract

Thiotepa (TT) is often included in high-dose chemotherapy prior to hematopoietic cell transplantation (HCT); however, exposure–response relationships of TT and its primary metabolite, N,N',N''-triethylenethiophosphoramide (TEPA), remain undefined. This was a prospective study enrolling children and young adults undergoing autologous and allogeneic HCT from multiple centers. Time–concentration data were modeled using nonlinear mixed effects modeling along with clinical covariates potentially impacting pharmacokinetics. Cumulative area-under-the-curve (cAUC) for TT and TEPA were derived using post hoc individual estimates for clearance. The combined cAUC_TT and cAUC_TEPA were also evaluated, reflecting total alkylating exposure (cAUC_total). The ratio of cAUC_TT/cAUC_TEPA was used to evaluate the efficiency of metabolic conversion of TT to TEPA. A total of 91 subjects were included with a median (range) actual body weight and age of 16.7 kg (4.6–110) and 4.5 years (0.23–22.5), respectively. The best fit model was a two-compartment structure for TT, and a one-compartment structure for TEPA. The conversion of TT to TEPA was found to be saturable at higher doses and may have important implications for optimizing exposure. Model-based dosing, which accounts for age and body size, results in more predictive exposure as compared to conventional mg/kg dosing, particularly in the very young and obese. Next steps include evaluation of pharmacogenomics and exposure–response relationships to optimize dosing of TT in children.