Pharmacokinetics and safety of 14 days intravenous voriconazole in allogeneic haematopoietic stem cell transplant recipients

Voriconazole is used to manage invasive fungal diseases in recipients of an allogeneic haematopoietic stem cell transplant (HSCT) after myeloablative treatment. Little is known about the pharmacokinetics (PK) of voriconazole in this population, who also receive cyclosporine A. Patients admitted for an allogeneic HSCT were eligible for the study. Voriconazole was given intravenously at 6 mg/kg twice daily on day 1, then 4 mg/kg twice daily until the day of transplant to reach steady-state conditions and then continued for a further week during which cyclosporine A was administered. Blood samples were drawn on the day of HSCT and daily for the next 14 days. PK curves were determined on days 7 and 14. PK parameters were calculated using non-compartmental analysis. CYP2C19*2 and CYP2C19*3 polymorphisms were also determined. Ten patients were fully evaluable. Median AUC(0-12) of voriconazole on the day of HSCT was 33.81 mg center dot h/L [interquartile range (IQR) 20.59-39.39] and 25.61 mg center dot h/L (IQR 22.48-38.65) 1 week later. AUC(0-12) of voriconazole on both days was similar to data reported for healthy volunteers. Trough levels were < 1.0 mg/L for 3 of 10 patients on the day of HSCT and for 4 of 10 patients 1 week later. No difference in clearance of voriconazole was found between CYP2C19 extensive metabolizers (n = 4) and carriers of one non-functional allele (n = 6). Exposure and clearance of voriconazole in recipients of an allogeneic HSCT are similar to those of healthy volunteers though there was high intra- and inter-individual variation in drug exposures which may have implications for similar patient populations.