The Population Pharmacokinetics of High-Dose Methotrexate in Infants with Acute Lymphoblastic Leukemia Highlight the Need for Bedside Individualized Dose Adjustment: A Report from the Children's Oncology Group.

Clinical Pharmacokinetics
Ryan J BeechinorDaniel Gonzalez

Abstract

Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate may have reduced methotrexate clearance (CL) due to renal immaturity, which may predispose them to toxicity. The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL. A total of 672 methotrexate plasma concentrations were obtained from 71 infants enrolled in the Children's Oncology Group (COG) Clinical Trial P9407. Infants received methotrexate 4 g/m2 intravenously for four cycles during weeks 4-12 of intensification. A population PK analysis was performed using NONMEM® version 7.4. The final model was evaluated using a non-parametric bootstrap and a visual predictive check. Simulations were performed to evaluate methotrexate dose and the utility of a bedside algorithm for dose individualization. Methotrexate was best characterized by a two-compartment model with allometric scaling. Weight was the only covariate included in the final model. The coefficient of variation for interoccasion variability (IOV) on CL was relatively high at 25.4%, compared with the interindividual variability for CL and central volume of distribution (10.7% and 13.2%, respectively). Simulations identified that 21.1...Continue Reading

References

Jan 1, 1985·Pharmacology & Therapeutics·I D Goldman, L H Matherly
Jan 1, 1988·Cancer Chemotherapy and Pharmacology·J D BorsiP J Moe
Jul 1, 1973·Clinical Pharmacology and Therapeutics·D H HuffmanB Hogstraten
Dec 1, 1994·Environmental Health Perspectives·R L Milsap, W J Jusko
Aug 1, 1994·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M V RellingW E Evans
Dec 1, 1993·Journal of Pharmacokinetics and Biopharmaceutics·M O Karlsson, L B Sheiner
Apr 1, 1996·Annals of Hematology·N Gökbuget, D Hoelzer
Feb 19, 1998·The New England Journal of Medicine·W E EvansC H Pui
Apr 9, 1999·Computer Methods and Programs in Biomedicine·E N Jonsson, M O Karlsson
Aug 28, 2002·The Annals of Pharmacotherapy·Irene AquerretaLuis Sierrasesúmaga
Feb 3, 2005·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Kambiz FotoohiFreidoun Albertioni
Apr 9, 2005·British Journal of Haematology·J PalleUNKNOWN Nordic Society for Paediatric Haematology and Oncology
Jul 19, 2005·Computer Methods and Programs in Biomedicine·Lars LindbomNiclas Jonsson
Mar 11, 2006·Cancer Chemotherapy and Pharmacology·Demiana William FaltaosPhilippe Lechat
Jun 24, 2006·The Oncologist·Brigitte C Widemann, Peter C Adamson
Nov 23, 2006·Clinical Pharmacokinetics·Dolores AumenteMaria José García
Dec 1, 2006·Cancer Chemotherapy and Pharmacology·Patrick A ThompsonLisa R Bomgaars
Oct 5, 2007·Annual Review of Pharmacology and Toxicology·B J Anderson, N H G Holford
Jan 10, 2009·Pediatric Blood & Cancer·Gudmar LönnerholmUNKNOWN Interfant-99 study group
Mar 3, 2009·Drug Metabolism and Pharmacokinetics·Brian J Anderson, Nick H G Holford
Mar 26, 2009·Journal of the National Cancer Institute·Nadia HowladerBrenda K Edwards
Apr 29, 2010·Current Hematologic Malignancy Reports·Rob Pieters
Nov 16, 2010·Journal of Pharmacokinetics and Pharmacodynamics·Paul G BaverelMats O Karlsson
Mar 4, 2011·Journal of Clinical Pharmacy and Therapeutics·N MartelliH Peyrière
Mar 26, 2013·Lancet·Hiroto InabaCharles G Mullighan
May 8, 2013·Journal of Pharmaceutical Sciences·Nick HolfordBrian Anderson

❮ Previous
Next ❯

Citations

Oct 29, 2019·British Journal of Clinical Pharmacology·John C PanettaClinton F Stewart
Jan 23, 2020·Cancer Metastasis Reviews·Liwen PengYin Ting Cheung
Jan 6, 2022·European Journal of Drug Metabolism and Pharmacokinetics·Yiming ZhangShenghui Mei

❮ Previous
Next ❯

Related Concepts

Related Feeds

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.