The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes.

Cyclophosphamide is an alkylating agent used in the treatment of solid and haematological malignancies and as an immunosuppressive agent. As a prodrug, it is dependent on bioactivation to the active phosphoramide mustard metabolite to elicit its therapeutic effect. This focused review will highlight the evidence for the role of germline pharmacogenetic variation in both plasma pharmacokinetics and clinical outcomes. There is a substantial indication from 13 pharmacokinetic and 17 therapeutic outcome studies, in contexts as diverse as haematological malignancy, breast cancer, systemic lupus erythematosus and myeloablation, that pharmacogenetic variation in both CYP2C19 and CYP2B6 influence the bioactivation of cyclophosphamide. An additional role for pharmacogenetic variation in ALDH1A1 has also been reported. Future studies should comprehensively assess these 3 pharmacogenes and undertake appropriate statistical analysis of gene-gene interactions to confirm these findings and may allow personalised treatment regimens.

Anti-glomerular basement membrane disease in Auckland.

BACKGROUND: Anti-glomerular basement membrane (GBM) antibody-mediated disease is rare and classically presents with the syndrome of glomerulonephritis and pulmonary haemorrhage. AIM: This aim of this report was to determine the incidence, clinical features, management and outcomes of anti-GBM disease in Auckland between 1998 and 2008. METHODS: Potential patients were identified by a search for positive anti-GBM antibody serology, diagnostic renal biopsy, or in-hospital admissions using International Classification of Diseases 9 and 10 codes between 1998 and 2008. A retrospective case notes review of all potential cases was performed with data censored at 31 December 2010. RESULTS: Twenty-three cases were identified. The rate of anti-GBM disease was estimated at 1.79 per million person-years. There were 12 men and 11 women. The median age was 45 years, range 12-74 years. Sixteen patients were European, three were Pacific peoples, three were NZ Maori and one was Chinese. Eleven were regular smokers and eight ex-smokers, significantly higher proportions than the population (P ≤ 0.001). Smokers were significantly more likely to have respiratory disease (P= 0.03). The mean creatinine at presentation was 474 µmol/L. All patients had a renal biopsy; 20 had crescentic glomerulonephritis. One patient recovered renal function without treatment. Twenty-two were immunosuppressed with cyclophosphamide and corticosteroids. Seventeen received plasmapheresis. Eighteen were alive, eight with end-stage renal disease, two with chronic kidney disease and eight with normal renal function. CONCLUSIONS: Anti-GBM disease is a rare condition, which is not overrepresented among indigenous people. With aggressive therapy the prognosis has improved; however, the morbidity and mortality of this condition remain significant.