Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis.
OBJECTIVE
Pulse cyclophosphamide is the treatment of choice for severe lupus nephritis. However, not all patients respond to this therapy, and gonadal toxicity is of particular concern. Cyclophosphamide is a prodrug that requires activation by cytochrome P450 (CYP) enzymes. We conducted a retrospective cohort study to test whether genetic polymorphisms of these enzymes are associated with the toxicity of, and clinical response to, cyclophosphamide in patients with lupus nephritis.


METHODS
Sixty-two patients with proliferative lupus nephritis treated with cyclophosphamide were genotyped for common variant alleles of CYP2B6, 2C19, 2C9, and 3A5. We examined the association between these genotypes and the following clinical end points: development of premature ovarian failure, end-stage renal disease (ESRD), doubling of serum creatinine level, and achievement of complete renal response.


RESULTS
The observed frequencies of the variant alleles CYP2B6*5, CYP2C19*2, CYP2C9*2, and CYP3A5*3 were 12.1%, 25.0%, 4.0%, and 75.8%, respectively. Patients who were either heterozygous or homozygous for CYP2C19*2 had a significantly lower risk of developing premature ovarian failure (relative risk 0.10; 95% confidence interval 0.02-0.52), after adjustment for age and total number of cyclophosphamide pulses received. In a survival analysis, patients homozygous for CYP2B6*5 (n = 3) or CYP2C19*2 (n = 4) had a higher probability of reaching ESRD (P = 0.0005) and of doubling the creatinine level (P = 0.0005) as well as a trend toward a lower probability of achieving a complete renal response (P = 0.051).


CONCLUSIONS
Determination of selected cytochrome P450 enzyme genotypes may be valuable for predicting the risk of premature ovarian failure in lupus nephritis patients treated with cyclophosphamide. The association of these genotypes with renal response needs further validation.
Takada
Kazuki
K
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892, USA.
Arefayene
Million
M
Desta
Zeruesenay
Z
Yarboro
Cheryl H
CH
Boumpas
Dimitrios T
DT
Balow
James E
JE
Flockhart
David A
DA
Illei
Gabor G
GG
D000328:Adult; D000483:Alleles; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology; D008181:Lupus Nephritis / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced; D020551:Pulse Therapy, Drug; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
D018501:Antirheumatic Agents; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System