PHARMACOKINETIC/PHARMACODYNAMIC STUDY OF VORICONAZOLE FOR INVASIVE ASPERGILLOSIS TREATMENT IN THAI ADULT PATIENTS

Abstract

An azole antifungal , voriconazole (VRZ), exhibits nonlinear pharmacokinetics (PK) due to saturated metabolism and several factors influence its PK. Currently, PK parameters of VRZ in adult Thai patients have not been identified, which causes uncertainty in VRZ level estimation. This study aimed to determine the VRZ PK parameters for adult Thai patients, factors influencing these parameters and the association between the VRZ concentration and clinical outcome in invasive aspergillosis (IA) treatment. Medical records of eligible patients at Ramathibodi Hospital during January 2013 and March 2016 were retrospectively reviewed. Of all 53 patients including in pharmacokinetic study, the median Km of were 0.26 mg/L and 0.67 mg/L for CYP2C19 EM and non-EM, respectively (p = 0.008). The Vmax of voriconazole were not different between each CYP2C19 phenotype (0.43 vs. 0.48 mg/kg/h for CYP2C19 EM and non-EM, respectively). Other than CYP2C19 phenotype, age, TB, and ALP were the significant factors influencing the Km, while none of patient’s factors could predict Vmax. Among eighty-one patients who were eligible for clinical outcome assessment, overall treatment success rate was 76.5 % and hepatotoxicity rate was 13.6%. The treatment success rate at VRZ Ctr of 3-4 mg/L was more than 90%. When compare to lower Ctr level, the hepatotoxicity rate was dramatically increased with VRZ Ctr of more than 5 mg/L. This study provided Km and Vmax of VRZ for Thai adult patients with IA, however their wide range indicated the high variability between individuals. Therefore, the need to start VRZ treatment with the recommended doses followed by therapeutic drug monitoring was warranted. Recommended VRZ Ctr for IA treatment for Thai adult patients was 3-4 mg/L because of its high treatment success rate together with avoiding drug-induced hepatotoxicity.