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Randomized Controlled Trial
. 2012;7(9):e46015.
doi: 10.1371/journal.pone.0046015. Epub 2012 Sep 25.

Population PK/PD model of homocysteine concentrations after high-dose methotrexate treatment in patients with acute lymphoblastic leukemia

Hauke Rühs  1 , Achim Becker, Anne Drescher, John C Panetta, Ching-Hon Pui, Mary V Relling, Ulrich Jaehde
Affiliations
Randomized Controlled Trial

Population PK/PD model of homocysteine concentrations after high-dose methotrexate treatment in patients with acute lymphoblastic leukemia

Hauke Rühs et al. PLoS One. 2012.

Abstract

Elevated homocysteine concentrations have been associated with methotrexate-induced neurotoxicity. Based on methotrexate and homocysteine plasma concentrations of 494 children with acute lymphoblastic leukemia treated with high-dose methotrexate in the TOTAL XV study, a pharmacokinetic/pharmacodynamic (PK/PD) model was built with NONMEM. Several compartment and indirect response models were investigated. The pharmacokinetic disposition of methotrexate was best described by a two-compartment model. Homocysteine concentrations were included by an indirect response model where methotrexate inhibition of the homocysteine elimination rate was described by an E(max) model. The homocysteine baseline level was found to be age-dependent. Simulations revealed that folinate rescue therapy does not affect peak concentrations of homocysteine but leads to a modestly reduced homocysteine exposure. In conclusion, our PK/PD model describes the increase of methotrexate-induced HCY concentrations with satisfactory precision and can be applied to assess the effect of folinate regimens on the HCY concentration-time course.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Scheme of the folate-homocysteine pathway (MTX = methotrexate; MTXPG = MTX polyglutamates; DHFR = dihydrofolate reductase; DHF = dihydrofolate; THF = tetrahydrofolate; 5-MTHF = 5-methyl-THF; 5,10-MTHF = 5,10-methylene-THF; HCY = homocysteine; MS = methionine synthase; SAM = S-adenosylmethionine; SAH = S-adenosylhomocysteine).
Figure 2
Figure 2. Scheme of the PK/PD model (CL = total body clearance; Q = intercompartmental clearance; V1 = volume of the central compartment; V2 = volume of the peripheral compartment; HCY = homocysteine; kin = HCY formation rate constant; kout
= HCY elimination rate constant).
Figure 3
Figure 3. Visual predictive check of the pharmacokinetic model for all patients of the evaluation dataset receiving a 24 h MTX infusion with a dose of 2500±20 mg/m2 (A) and 5000±20 mg/m2 (B), respectively.
The black circles represent the measured methotrexate concentrations. The solid line represents the median predicted concentration, the dashed lines represent the 90% prediction interval of 10000 simulations.
Figure 4
Figure 4. Visual predictive check of the pharmacodynamic model for low-risk (A) and standard/high-risk (B) patients from the evaluation dataset.
The black circles represent the measured homocysteine concentrations relative to baseline. The solid line represents the median predicted concentration, the dashed lines represent the 90% prediction interval of 1000 simulations.
Figure 5
Figure 5. Homocysteine concentration-time courses with and without co-administration of folinate.
Excerpt of 1000 per-protocol simulations each of the low-risk (A) and standard/high-risk (B) study population. The solid grey line represents the median of the simulations without folinate with the 90% prediction interval (PI) as solid grey area, the solid black line represents the median of the simulations under influence of folinate with the 90% PI as shaded area.
See this image and copyright information in PMC

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