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 Emax 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.
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established biomarker in heart failure (HF) but controversially discussed as a potential surrogate marker in HF trials. We analyzed the NT-proBNP/mortality relationship in real-world data (RWD) of 108,330 HF patients from the IBM Watson Health Explorys database and compared it with the NT-proBNP / clinical event end-point relationship in 20 clinical HF studies. With a hierarchical statistical model, we quantified the functional relationship and interstudy variability. To independently qualify the model, we predicted outcome hazard ratios in five phase III HF studies solely based on NT-proBNP measured early in the respective study. In RWD and clinical studies, the relationship between NT-proBNP and clinical outcome is well described by an E max model. The NT-proBNP independent baseline risk (R 0 , RWD/studies median (interstudy interquartile range): 5.5%/3.0% (1.7-4.9%)) is very low compared with the potential NT-proBNP-associated maximum risk (R max : 55.2%/79.4% (61.5-89.0%)). The NT-proBNP concentration associated with the half-maximal risk is comparable in RWD and across clinical studies (EC 50 : 3,880/2,414 pg/mL (1,460-4,355 pg/mL)). Modelbased predictions of phase III outcomes, relying on short-term NT-proBNP data only, match final trial results with comparable confidence intervals. Our analysis qualifies NT-proBNP as a surrogate for clinical outcome in HF trials. NT-proBNP levels after short treatment durations of less than 10 weeks quantitatively predict hazard ratios with confidence levels comparable to final trial readout. Early NT-proBNP measurement can therefore enable shorter and smaller but still reliable HF trials. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is an established diagnostic biomarker for the presence of heart failure 1,2 (HF) reflected in diagnostic algorithms of current HF guidelines. 3,4 Over the past decades, a large number of publications investigated the prognostic properties of NT-proBNP for mortality and various cardiovascular events in patients with HF 5 and other cardiovascular (CV) diseases as well as in general elderly populations. 2,6 The association of NT-proBNP elevation with the future occurrence of CV events was shown in several studies. Van Veldhuizen 7 demonstrated
No abstract
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.