Homocysteine as biomarker in a semi-mechanistic PK/PD model of methotrexate
Rühs H(1), Panetta JC(2), Pui CH(2), Relling MV(2), Jaehde U(1)
(1)Department of Clinical Pharmacy, University of Bonn and (2)St. JudeChildren’s Research Hospital, Memphis
Objectives: Elevated homocysteine concentrations have been associated with neurotoxic symptoms upon chemotherapy with methotrexate (MTX). The aim of this study was to develop a PK/PD model based on plasma MTX and homocysteine concentrations measured in patients with acute lymphoblastic leukemia (ALL) as a basis for the development of improved dosing regimens with a lower risk of neurotoxicity.
Methods: Based on methotrexate and homocysteine plasma concentration data from 388 ALL patients of the TOTAL XV study  a PK-PD model was built with NONMEM 7.1 using the FOCE interaction method. Several compartmental and indirect response models  were investigated to describe the PK/PD relationship. Body size, age, sex and renal function were investigated as potential covariates on the model.
Results: The PK of MTX could be described by a two-compartmental model, parameterized by CL, V1, Q and V2. Considering the wide range of age (1-18 years) and the heterogeneous degree of maturation in the population an allometric scaling was included. Creatinine clearance was positively related to MTX CL (p < 0.001). The relationship between MTX and homocysteine concentrations could be described by fitting an indirect response model with impaired elimination of homocysteine. A lower elimination rate constant for homocysteine (kout) was positively associated with MTX concentrations (p < 0.001) using an inhibitory Emax model .
Conclusions: Our semi-mechanistic PK-PD model describes the methotrexate and homocysteine concentrations of young ALL patients. The model is currently evaluated.
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