PII-047 - INFLAMMATION DRIVEN INHIBITION OF CYP2C19 METABOLISM OF VORICONAZOLE IN THE TREATMENT OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS.

S. Klomp¹, A. Veringa², J. Alffenaar^2,3, H. Guchelaar¹, J. Swen¹; ¹Leiden University Medical Center, Leiden, The Netherlands, ²University Medical Center Groningen, Groningen, The Netherlands, ³The University of Sydney, Sydney, Australia.

Background: Invasive fungal infections are a severe complication of an allogeneic hematopoietic stem cell transplantation leading to morbidity and mortality. Voriconazole is used as prophylactic and in the therapeutic setting to treat fungal infections. Voriconazole is converted into inactive metabolites by CYP2C19. In the prophylactic setting, prospective studies showed a clear correlation between CYP2C19 genotype and voriconazole exposure. However, no such correlation was found in patients with invasive aspergillosis (n=65). It is known that proinflammatory cytokines, such as IL-6, inhibit CYP2C19 and CYP3A4 enzyme activity. We hypothesize that phenoconversion may explain the changed relation between CYP2C19 genotype and metabolizer phenotype during active infections

Methods: In this study we retrospectively analyzed data from 32 patients with 303 voriconazole and CRP levels and CYP2C19 genotype from two clinical studies.

Results: Voriconazole concentration ranged from 0.2-12.27 mg/L, CRP 1.5-401 mg/L and dose 200-1050 mg/day. The CYP2C19 phenotype distribution was 31% IM, 41% NM and 28% RM. The results show a clear trend for increasing dose corrected voriconazole trough concentrations with higher CRP levels (>100), compared to no inflammation ( < 10), mild (10-51) and moderate (52-100).

Conclusion: In the highest CRP group all patients were converted into a lower metabolizer category irrespective of CYP2C19 genotype. Nevertheless, no difference in impact of inflammation for the different genotypes could be observed. This might be explained by the limited sample size, the contribution of CYP2C19 to the total voriconazole metabolism or a TDM effect in our data.