Cyclophosphamide in Lupus Nephritis

March 4, 2009 updated by: University of Auckland, New Zealand

Failure of Cyclophosphamide Therapy in Lupus Nephritis Patients: the Role of Bioactivation Phenotype and Genotype

Cyclophosphamide is widely used in the treatment of cancer and autoimmune diseases such as lupus nephritis. However, there is considerable variability in the response to cyclophosphamide treatment. Cyclophosphamide is a pro-drug that requires initial activation by CYP liver enzymes. Recent clinical studies have indicated a possible role of one CYP enzyme, CYP2C19 in this activation step. This enzyme has a genetic polymorphism (variants which lack functional activity) and people who have inherited these variants are poor metabolisers of certain drugs.

The aim of this study is to determine whether response to therapy in a New Zealand population of lupus nephritis patients is determined by cyclophosphamide bioactivation (the metabolic phenotype) and CYP genotype.

Currently there is no way of predicting a patient's response to cyclophosphamide. An understanding of the factors which contribute to the therapeutic failure in lupus nephritis is particularly important due to the high morbidity and mortality associated with this disease. There are other treatment options for lupus nephritis patients who fail to respond to cyclophosphamide. If successful, this study may help identify patients who are unlikely to respond to cyclophosphamide and thus should not be unnecessarily be exposed to the drug and may justify the use of newer, more costly immunosuppressive drugs such as mycophenolate mofetil and rituximab.

Study Overview

Status

Unknown

Conditions

Detailed Description

The autoimmune disease systemic lupus erythematosus (SLE) commonly affects the kidneys (lupus nephritis) and for some patients leads to a progressive loss of kidney function. In patients with aggressive lupus nephritis, treatment with the cytotoxic agent Cyclophosphamide (CP), and modulation of the immune system has proven effective in delaying progression of renal disease however, there is variability in how patients respond to cyclophosphamide therapy with 10% - 40% of patients failing to achieve renal remission.

Cyclophosphamide is a pro-drug, which requires metabolic bioactivation by the liver to the active drug. The major enzymes involved are CYP2C19 and CYP2B61,2 however they display considerable functional activity in part due to genetic variants which lack functional activity3. A recent study has demonstrated that lack of response to cyclophosphamide is associated with CYP2C19 and CYP2B6 poor metaboliser variants4.

A retrospective review of patients with lupus nephritis at Middlemore hospital indicated that Polynesian patients respond poorly to cyclophosphamide progressing to end stage renal failure and having higher mortality rates compared with European patients.

We have hypothesised that failure of cyclophosphamide therapy may be due to a higher incidence of the CYP2C19 variant in Polynesian populations.

An extremely high incidence (70%) of the homozygous CYP2C19 variant has been reported in the Melanesian population5 and studies in Samoan, Tongan, Cook Island and Niuean pacific peoples indicates that the incidence may be more than 4-fold higher than the 3% incidence in European populations3,6. If CYP2C19 is clinically important in the bioactivation of cyclophosphamide then Polynesian populations may be at increased risk of therapeutic failure.

Other factors may also result in inter-patient differences in the activation of cyclophosphamide in the liver. Changes in metabolic phenotype can be the result of drug-drug interactions and/or disease modulation of CYP enzyme expression. Hence it is also important to also determine the functional activity (phenotype) of cyclophosphamide bioactivation as well as genotypic analysis by analysis of blood levels of cyclophosphamide and its active metabolite.

This study will determine both the genotype and phenotype of cyclophosphamide bioactivation in patients with lupus nephritis and determine whether this is an important determinant in response to therapy.

Study Type

Observational

Enrollment (Anticipated)

60

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • New Zealand
      • Auckland, New Zealand
        • Recruiting
        • University of Auckland
        • Contact:
          • Nuala Helsby, PhD
        • Principal Investigator:
          • Nuala Helsby, PhD
      • Manakau City, New Zealand, Private Bag 93311
        • Recruiting
        • Middlemore Hospital
        • Contact:
        • Principal Investigator:
          • Peter Gow, MBChB
        • Sub-Investigator:
          • May C Soh, MBChB
    • North Island
      • Auckland, North Island, New Zealand
        • Recruiting
        • Auckland City Hospital
        • Principal Investigator:
          • Janak R de Zoysa, MBChB

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Patients with lupus nephritis who are receiving or have previously received intravenous cyclophosphamide.

Description

Inclusion Criteria:

  • Patients with lupus nephritis requiring therapy with intravenous cyclophosphamide

  • Lupus nephritis is defined according to American College of Rheumatology criteria as the presence of either:

    1. histological evidence from renal biopsy;
    2. persistent proteinuria of >0.5 g/day or proteinuria >3+ on dipstick; or
    3. cellular casts of any type. Patients will have had a renal biopsy performed to determine the histological class of lupus nephritis. Therapy with cyclophosphamide is typically used in patients with Class III, IV and severe Class V lupus nephritis.
  • Patients ≥ 18 years of age
  • Patients must be able to provide informed consent

Exclusion Criteria:

  • Those who do not meet inclusion criteria
  • Those patients in the retrospective study who have died

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only

Cohorts and Interventions

Group / Cohort
A
Patients must have lupus nephritis and previously had therapy with intravenous cyclophosphamide.
B
Patients must have lupus nephritis and are currently receiving therapy with intravenous cyclophosphamide.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Auckland, New Zealand

Collaborators

Counties Manukau Health
Auckland Medical Research Foundation
Auckland District Health Board
Arthritis New Zealand

Investigators

  • Principal Investigator: Nuala Helsby, PhD, Senior Lecturer in Molecular Medicine and Pathology, University of Auckland

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2006

Study Completion (Anticipated)

October 1, 2010

Study Registration Dates

First Submitted

February 27, 2007

First Submitted That Met QC Criteria

February 27, 2007

First Posted (Estimate)

February 28, 2007

Study Record Updates

Last Update Posted (Estimate)

March 5, 2009

Last Update Submitted That Met QC Criteria

March 4, 2009

Last Verified

February 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ADHB3557

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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