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

Authors

Jordan Brooks, Shams Ismaeil, Maria-Stephanie Hughes, Beth Apsel-Winger, Ying Lu, Liusheng Huang, Christine Higham, Kristina Nelson, Susie Long, Ashish Gupta, Nahal Rose Lalefar, Eric Anderson, Michael A Pulsipher, Sung-Yun Pai, Ron J Keizer, Christopher C Dvorak, Janel Long-Boyle

Published in

Journal of clinical pharmacology. Volume 66. Issue 9. Pages e70296.

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.

PMID:
42760872
Bibliographic data and abstract were imported from PubMed on 19 Sep 2026.

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