Jan Henrik Schirmer1,2, Jan Phillip Bremer1, Frank Moosig1, Julia Ulrike Holle1, Peter Lamprecht3, Stefan Wieczorek4, Sierk Haenisch5, Ingolf Cascorbi5. 1. Department of Rheumatology & Clinical Immunology, Vasculitis Center, University Hospital Schleswig-Holstein & Klinkum Bad Bramstedt, Bad Bramstedt, Germany. 2. Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. 3. Department of Rheumatology & Comprehensive Center for Inflammation Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. 4. Human Genetics, Ruhr University Bochum, Bochum, Germany. 5. Institute for Experimental & Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Abstract
AIM: Correlation of outcomes of cyclophosphamide (CP) therapy in antineutrophil cytoplasmic antibody-associated vasculitis with genotype polymorphisms in prodrug activating cytochrome P450 enzyme genes CYP2C9 and CYP2C19. PATIENTS & METHODS: One hundred and ninety six patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with CP, either as intravenous pulse or as daily oral medication, were included. Genotypes of CYP2C9 and CYP2C19 were correlated with clinical outcomes (leukopenia, infection, urotoxicity and treatment response). RESULTS: Sixty five (33.2%) patients had variant CYP2C9 and 55 (28.1%) had variant CYP2C19 genotype. In patients bearing variant CYP2C9, leukopenia was documented significantly more frequent than in carriers of wild-type CYP2C9 (55.4 vs 37.4%; odds ratio: 2.08; 95% CI: 1.14-3.80; p = 0.017). The impact of the CYP2C9 genotype was stronger in patients treated with oral CP (69.6 vs 45.6%; odds ratio: 2.73; 95% CI: 1.27-5.89; p = 0.009), but was not present in patients treated with intravenous pulsed CP. We observed less refractory disease courses in patients with variant CYP2C9, not reaching statistical significance. CONCLUSION: Patients with variant CYP2C9 are at increased risk for cyclophosphamide-induced leukopenia but may have a better chance to respond to treatment.
AIM: Correlation of outcomes of cyclophosphamide (CP) therapy in antineutrophil cytoplasmic antibody-associated vasculitis with genotype polymorphisms in prodrug activating cytochrome P450 enzyme genes CYP2C9 and CYP2C19. PATIENTS & METHODS: One hundred and ninety six patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with CP, either as intravenous pulse or as daily oral medication, were included. Genotypes of CYP2C9 and CYP2C19 were correlated with clinical outcomes (leukopenia, infection, urotoxicity and treatment response). RESULTS: Sixty five (33.2%) patients had variant CYP2C9 and 55 (28.1%) had variant CYP2C19 genotype. In patients bearing variant CYP2C9, leukopenia was documented significantly more frequent than in carriers of wild-type CYP2C9 (55.4 vs 37.4%; odds ratio: 2.08; 95% CI: 1.14-3.80; p = 0.017). The impact of the CYP2C9 genotype was stronger in patients treated with oral CP (69.6 vs 45.6%; odds ratio: 2.73; 95% CI: 1.27-5.89; p = 0.009), but was not present in patients treated with intravenous pulsed CP. We observed less refractory disease courses in patients with variant CYP2C9, not reaching statistical significance. CONCLUSION:Patients with variant CYP2C9 are at increased risk for cyclophosphamide-induced leukopenia but may have a better chance to respond to treatment.
Entities:
Keywords:
ANCA-associated vasculitis; CYP450; cyclophosphamide; drug metabolism
Authors: Giorgio Trivioli; Ana Marquez; Davide Martorana; Michelangelo Tesi; Andreas Kronbichler; Paul A Lyons; Augusto Vaglio Journal: Nat Rev Rheumatol Date: 2022-09-15 Impact factor: 32.286
Authors: Natalia Yu Anisimova; Nadezhda E Ustyuzhanina; Maria I Bilan; Fedor V Donenko; Natalia A Ushakova; Anatolii I Usov; Mikhail V Kiselevskiy; Nikolay E Nifantiev Journal: Mar Drugs Date: 2018-09-13 Impact factor: 5.118