Coproporphyrine Isomers and Methotrexate Elimination

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

85 participants

Study Classification

OBSERVATIONAL

Study Start Date

2007-10-31

Study Completion Date

2011-08-31

Brief Summary

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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

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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.

Conditions

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Central Nervous System Neoplasms Lymphoma, Large B-Cell, Diffuse Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Burkitt Lymphoma

Keywords

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biomarkers ABC transporters MRP2 MTX pharmacokinetics

Study Design

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Study Time Perspective

CROSS_SECTIONAL

Study Groups

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1

No interventions assigned to this group

Eligibility Criteria

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Inclusion Criteria

* Patients receiving HDMTX (≥1g/m2) for a primitive cerebral lymphoma, a large cell lymphoma, a lymphoblastic lymphoma, a Burkitt's lymphoma or an acute lymphoblastic leukaemia,
* over 18 years old,
* Signed informed consent.
* Affiliated to a medical assurance.
* Able to respect the protocol.
* Effective contraception for women.

Exclusion Criteria

* renal failure,
* liver failure,
* hepatic cytolysis,
* chronic respiratory deficiency,
* pregnancy,
* breast-feeding,
* Concomitant medication: phenytoin, probenecid, trimethoprim, phenylbutazone, salicylates, non steroid anti-inflammatory, yellow fever vaccine.
* Patient included in another study in the four weeks preceding his inclusion.

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Chantal Le Guellec, PharmD, PhD

Role: PRINCIPAL_INVESTIGATOR

CHRU of Tours

Locations

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Pitié-Salpêtrière Hospital

Paris, , France

Site Status

University Hospital Centre of Tours

Tours, , France

Site Status

Countries

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France

References

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Benz-de Bretagne I, Zahr N, Le Gouge A, Hulot JS, Houillier C, Hoang-Xuan K, Gyan E, Lissandre S, Choquet S, Le Guellec C. Urinary coproporphyrin I/(I + III) ratio as a surrogate for MRP2 or other transporter activities involved in methotrexate clearance. Br J Clin Pharmacol. 2014 Aug;78(2):329-42. doi: 10.1111/bcp.12326.

Reference Type DERIVED

PMID: 24433481 (View on PubMed)

Other Identifiers

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P061005

Identifier Type: -

Identifier Source: org_study_id