Population pharmacokinetic analysis of high-dose methotrexate in pediatric and adult oncology patients

2019 ◽  
Vol 84 (6) ◽  
pp. 1339-1348 ◽  
Author(s):  
Sonoko Kawakatsu ◽  
Mina Nikanjam ◽  
Mark Lin ◽  
Sonny Le ◽  
Ila Saunders ◽  
...  
Keyword(s):  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Oncology Patients ◽  
Dose Methotrexate

Pharmacodynamics of High-Dose Methotrexate in Pediatric Patients

2002 ◽  
Vol 36 (9) ◽  
pp. 1344-1350 ◽  
Author(s):  
Irene Aquerreta ◽  
Azucena Aldaz ◽  
Joaquín Giráldez ◽  
Luis Sierrasesúmaga
Keyword(s):  
High Risk ◽  
Daily Practice ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Hematologic Toxicity ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Nonhematologic Toxicity ◽  
The Relationship

OBJECTIVE: To establish a relationship between the pharmacokinetics of high-dose methotrexate (MTX) and toxicity in children of a pediatric oncology department and to reassess MTX concentrations at which the patients would be at high risk for toxic effects. METHODS: This study included 37 patients (227 treatment courses) who received a median dose of 4.87 g/m2 of MTX in a 4-hour infusion. The population pharmacokinetic parameters of MTX were estimated by parametric (IT2B) and nonparametric methods (NPEM). Gastrointestinal, renal, and hematologic toxicity were evaluated. The relationship between pharmacokinetic parameters and toxicity was analyzed by logistic regression and multiple linear regression. RESULTS: Equations to predict hematologic and nonhematologic toxicity were obtained. An increase of 100 μmol/L in the MTX peak concentration meant a 12% (p = 0.03) higher risk of vomiting; a significant delay in MTX elimination implied a 5.76-fold higher risk of mucositis (p < 0.001). An increase of 1 μmol/L in the MTX concentration 24 hours after the end of the infusion (Cp24h) led to a 43% increase in the risk of renal toxicity (p < 0.001). Hematologic toxicity was significantly conditioned by the baseline leukocyte count and Cp24h (p < 0.001). CONCLUSIONS: The analysis of high-dose MTX pharmacokinetic/pharmacodynamic relationship to toxicity has led to equations able to predict toxicity that are easily applicable to daily practice. Cp24h >3.5 μmol/L was confirmed as an indicator of high risk of toxicity.

Kidney Injury Molecule-1 and its association with delayed clearance and drug exposure in pediatric oncology patients treated with high dose methotrexate.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 10034-10034
Author(s):  
Andrew J. Bukowinski ◽  
Tomoyuki Mizuno ◽  
Tsuyoshi Fukuda ◽  
A.a. Vinks ◽  
Stuart Goldstein ◽  
...  
Keyword(s):  
Pediatric Oncology ◽  
Drug Exposure ◽  
Kidney Injury ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Oncology Patients ◽  
Dose Methotrexate ◽  
Kidney Injury Molecule 1

Cytotoxicity of Dimethylacetamide and Pharmacokinetics in Children Receiving Intravenous Busulfan

2007 ◽  
Vol 25 (13) ◽  
pp. 1772-1778 ◽  
Author(s):  
Georg Hempel ◽  
Doris Oechtering ◽  
Claudia Lanvers-Kaminsky ◽  
Thomas Klingebiel ◽  
Josef Vormoor ◽  
...  
Keyword(s):  
Safety Concern ◽  
Plasma Concentrations ◽  
Leukemic Cell ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Leukemic Cell Lines

PurposeTo assess the cytotoxicity and the exposure of N,N-dimethylacetamide (DMA) in children during high-dose therapy with an intravenous (IV) formulation of busulfan containing the potentially hepatotoxic and neurotoxic DMA as a solvent.Patients and MethodsEighteen children aged 0.9 to 17.3 years (median age, 4.0 years) received IV busulfan in 15 doses of 0.7 to 1.0 mg/kg busulfan containing overall DMA amounts of between 5 mmol (437 mg) and 70.5 mmol (6,142 mg) per dose. Plasma concentrations of DMA and busulfan were quantified and analyzed using nonlinear mixed-effects modeling. Four different leukemic cell lines were incubated with DMA, and cytotoxicity was assessed in comparison with busulfan as well as in a combination reflecting the ratio in the formulation.ResultsMaximal plasma concentrations of DMA up to 3.09 mmol/L were observed. No accumulation of the solvent occurred. Instead, the trough levels decreased over the 4 treatment days. The population pharmacokinetic analysis revealed a clearance of 86.9 mL h−1kg−1± 27% that increased to 298 mL h−1kg−1on the fourth day and a volume of distribution of 469 mL kg ± 22% (population mean ± interindividual variability). DMA volume of distribution correlated with the volume of distribution of busulfan. The cytotoxicity of DMA in vitro was 3 orders of magnitude lower than that of busulfan. No synergism was observed.ConclusionThe lack of accumulation of DMA confirms that there is no safety concern related to the DMA content in this IV busulfan formulation. The contribution of DMA to the antileukemic effect of the formulation seems to be limited.

scholarly journals Resumption of high-dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients

Cancer ◽  
2012 ◽  
Vol 118 (17) ◽  
pp. 4321-4330 ◽  
Author(s):  
Anthony M. Christensen ◽  
Jennifer L. Pauley ◽  
Alejandro R. Molinelli ◽  
John C. Panetta ◽  
Deborah A. Ward ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Pediatric Oncology ◽  
Kidney Injury ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Oncology Patients ◽  
Dose Methotrexate
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