Abstract
This study aimed to identify factors that significantly influence the pharmacokinetics of voriconazole in Thai adults with hematologic diseases, and to determine optimal voriconazole dosing regimens. Blood samples were collected at steady state in 65 patients (237 concentrations) who were taking voriconazole to prevent or treat invasive aspergillosis. The data were analyzed using a nonlinear mixed-effects modeling approach. Monte Carlo simulation was applied to optimize dosage regimens. Data were fitted with the one-compartment model with first-order absorption and elimination. The apparent oral clearance (CL/F) was 3.43 L/h, the apparent volume of distribution (V/F) was 47.6 L, and the absorption rate constant (Ka) was fixed at 1.1 h−1. Albumin and omeprazole ≥ 40 mg/day were found to significantly influence CL/F. The simulation produced the following recommended maintenance doses of voriconazole: 50, 100, and 200 mg every 12 h for albumin levels of 1.5–3, 3.01–4, and 4.01–4.5 g/dL, respectively, in patients who receive omeprazole ≤ 20 mg/day. Patients who receive omeprazole ≥ 40 mg/day and who have serum albumin level 1.5–3 and 3.01–4.5 g/dL should receive voriconazole 50 and 100 mg, every 12 h, respectively. Albumin level and omeprazole dosage should be carefully considered when determining the appropriate dosage of voriconazole in Thai patients.
Highlights
Patients with hematologic diseases that receive chemotherapy are at high risk for invasive fungal infection, which is a severe illness with high mortality [1,2,3]
Voriconazole has been approved for adult and pediatric patients with various invasive fungal infections, including invasive aspergillosis, candidemia in non-neutropenic patients, disseminated infections caused by Candida spp., esophageal candidiasis, and scedosporiosis and fusariosis in patients refractory or intolerant of other antifungal agents [1,2,3,4,6]
Patients with hematologic diseases were treated with voriconazole for prevention or treatment of invasive aspergillosis following the guidelines of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group: EORTC and the National Institute of Allergy and Infectious Diseases Mycoses Study Group: MSG or EORTC/MSG 2008 [41]
Summary
Patients with hematologic diseases that receive chemotherapy are at high risk for invasive fungal infection, which is a severe illness with high mortality [1,2,3]. Numerous studies have reported that voriconazole can prevent invasive fungal infections in immunocompromised patients [2,3,6,7,8]. High variability in the PK of voriconazole can be caused by CYP2C19 polymorphism [12,13,14,15,16,17,18,19,20,21], and these gene polymorphisms cause variations in drug clearance. PPIs are commonly prescribed in patients with hematologic diseases to treat or prevent gastroduodenal adverse effects from chemotherapy, thrombocytopenia, and high-dose glucocorticoids [26,27]. Population PK analysis is a strategy that can be employed to identify mean PK parameters and their variation, to identify significant covariates, and to establish the optimal dosage regimen of voriconazole [12,13,14,15,16,17,18,19,20,21,22,23,24,25]
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