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 [1] a PK-PD model was built with NONMEM 7.1 using the FOCE interaction method. Several compartmental and indirect response models [2] 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 [2].
Conclusions: Our semi-mechanistic PK-PD model describes the methotrexate and homocysteine concentrations of young ALL patients. The model is currently evaluated.
References:
[1] Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC,Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML,Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. Treatment of childhood acutelymphoblastic leukemia without cranial irradiation. N Engl J Med 360:2730-41, 2009.
[2] Dayneka NL, Garg V, Jusko WJ. Comparison of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm 1993; 21(4):457–78.
