Background and Importance Invasive fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Voriconazole has variable pharmacokinetics and children usually require higher doses to have voriconazole concentrations within the therapeutic range (TR) and due to variability, close monitoring of plasma concentrations (Cpvor) is recommended.

Aim and Objectives To describe pharmacokinetic/pharmacokinetic (PK/PD) management, efficacy and safety of voriconazole-induced liver toxicity in a paediatric patient.

Material and Methods PK/PD management was performed by clinical pharmacists and the goal was to have plasma Cpvor within the TR (1.5-5.5 mg/L). Voriconazole has variable pharmacokinetics linked to age, cytochrome CYP2C19, hepatic dysfunction and drug interactions. Efficacy is defined as analytical, clinical and radiographic improvement and safety as the absence of adverse reactions. Cpvor were measured by a validated high-performance liquid chromatography method.

Results An 8-year-old paediatric patient undergoing active chemotherapy for acute myeloid leukemia. During the 2nd consolidation (probable invasive aspergillosis) and after the 3rd (proven invasive aspergillosis) the patient was hospitalised and treated with voriconazole, reaching the therapeutic target with voriconazol 20mg/kg/12h oral/IV. In both admissions, separated by 8 months, the patient suffered hepatic toxicity (increased transaminases). On both occasions the following plan was developed: 1) close monitoring of Cpvor and 2) close monitoring of liver function. During the first hospitalisation (Cpvor=1.23mg/L; ALT=90U/L; AST=58U/L; GGT=430U/L) it was recommended to maintain the dose of 20mg/kg/12h oral and monitor liver function. At 10 days Cpvor=3.52mg/L and transaminases decreased. During the 2nd hospitalisation (Cpvor=9.7mg/L; ALT=35U/L; AST=72U/L; GGT=569U/L) it was recommended to decrease the dose from 20mg/kg/12h IV to 15mg/kg/12h IV and monitor liver function. At 10 days Cpvor=1.58mg/L and transaminases decreased. The patient was treated with oral and IV voriconazole, oral bioavailability was estimated to vary between 70-100%. Treatment with voriconazole was effective, the patient presented clinical, analytical and radiographic improvement.

Conclusion and Relevance Voriconazole was effective in the treatment of probable and proven aspergillosis. Although voriconazole-induced liver toxicity is not dose-dependent, on the second admission the patient had Cpvor above the TR. The patient presented voriconazole-induced hepatotoxicity, which was resolved with PK/PD management on both occasions.

Conflict of Interest No conflict of interest