Clinical Trial: Coproporphyrine Isomers and Methotrexate Elimination

Study Status: Completed
Recruit Status: Completed
Study Type: Observational

Official Title: Urinary Ratio of the Coproporphyrins Isomers I and III and Its Relationships With Methotrexate Elimination in Patients With a Lymphoid Malignancy

Brief Summary: High dose methotrexate (MTX) is responsible of severe toxicity in patients in whom elimination from plasma is delayed. Factors responsible for MTX accumulation are partly known but some patients still experience toxicity despite adequate measures being taken. Our hypothesis is that renal tubular secretion may be impaired in these patients. This study aims at evaluating the performance of the UCP ratio (urinary ratio of coproporphyrins), a putative biomarker of tubular secretion, in predicting delayed MTX elimination.

Detailed Summary: MTX is a substrate of MRP2, a renal tubular transporter encoded by the ABCC2 gene. It has been shown that single nucleotide polymorphisms (SNPs) on the ABCC2 gene are associated with impairment of MTX elimination. Mutations on the ABCC2 gene are also responsible for the Dubin-Johnson syndrome, characterised by the absence of a functional MRP2 protein. Apart from hyperbilirubinaemia, the main biological perturbation observed in this disease is a typical increase of the urinary ratio of coproporphyrins I (I+ III) (UCP ratio). Our hypothesis is that the UCP ratio could be used as a biomarker of MRP2's activity, thus predicting MTX elimination. One hundred patients treated with high dose MTX will be recruited in this prospective study. Their UCP ratio will be measured before and after MTX administration and correlated with MTX clearance. A genetic analysis will be conducted to study the five more frequents SNPs of ABCC2 in each patient.
Sponsor: Assistance Publique - Hôpitaux de Paris

Current Primary Outcome: MTX concentrations [ Time Frame: at the end of MTX infusion and every 24-hours until concentrations reach 0,2µM. ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • The UCP I/(I+III) ratio [ Time Frame: before and at the end of MTX infusion and at the end of hospitalisation. ]
  • Five polymorphisms of the ABCC2 gene (-24C/T, 1249G/A, 3563T/A, 4544G/A) [ Time Frame: during the study ]
  • Blood cells count . [ Time Frame: before MTX infusion and at the end of hospitalisation ]
  • Renal function [ Time Frame: before MTX infusion and at the end of hospitalisation ]


Original Secondary Outcome: Same as current

Information By: Assistance Publique - Hôpitaux de Paris

Dates:
Date Received: January 13, 2009
Date Started: October 2007
Date Completion:
Last Updated: July 30, 2012
Last Verified: January 2009