Trial Information

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

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.