Coproporphyrine Isomers and Methotrexate Elimination

Completed

• Conditions: Central Nervous System Neoplasms; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Burkitt Lymphoma; Lymphoma, Large B-Cell, Diffuse

• Registration Number: NCT00822432
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

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 Description

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.

Study Timeline

• Study Start: 2007-10
• Status Verified: 2009-01
• Study First Submitted: 2009-01-13
• Study First Submitted QC: 2009-01-13
• Study First Posted: 2009-01-14
• Primary Completion: 2011-08
• Study Completion: 2011-08
• Last Update Submitted: 2012-07-30
• Last Update Posted: 2012-07-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 85

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
MTX concentrations	at the end of MTX infusion and every 24-hours until concentrations reach 0,2µM.

Secondary Outcome Measures

Name	Time	Method
Blood cells count .	before MTX infusion and at the end of hospitalisation
Renal function	before MTX infusion and at the end of hospitalisation
The UCP I/(I+III) ratio	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)	during the study

Trial Locations

Locations (2)

Pitié-Salpêtrière Hospital; 🇫🇷 Paris, France

University Hospital Centre of Tours; 🇫🇷 Tours, France