Prawat ChantharitMontira TantasawatHidefumi KasaiYusuke TanigawaraKeio University School of MedicineMahidol UniversitySrinakharinwirot University2020-12-282020-12-282020-12-01Therapeutic drug monitoring. Vol.42, No.6 (2020), 872-879153636942-s2.0-85096203203https://repository.li.mahidol.ac.th/handle/20.500.14594/60535BACKGROUND: Voriconazole (VRCZ) is an antifungal triazole recommended as an effective first-line agent for treating invasive aspergillosis. OBJECTIVES: To develop a population pharmacokinetic model of VRCZ and trough concentration-based dosing simulation for dynamic patient conditions. METHODS: The authors combined plasma VRCZ data from intensive sampling, and retrospective trough concentration monitoring for analysis. Nonlinear mixed-effects modeling with subsequent model validation was performed. The recommended dosage regimens were simulated based on the developed model. RESULTS: The study participants included 106 patients taking oral VRCZ. A linear one-compartment model with first-order elimination and absorption best described the observed data. The CYP2C19 phenotypes did not influence the pharmacokinetic parameters. Serum albumin (SA) levels and gamma-glutamyl transferase significantly correlated with the VRCZ clearance rate, whereas the actual body weight influenced the volume. A visual predictive check showed good consistency with the observed data, whereas SA levels across the treatment course correlated with linear clearance, irrespective of the CYP2C19 phenotype. Patients with SA levels ≤30 g/L had lower linear clearance than that in patients with SA levels >30 g/L. Dosing simulation based on the developed model indicated that patients with SA levels of ≤30 g/L required a lower daily maintenance dose to attain the therapeutic trough level. CONCLUSIONS: SA level was identified as a novel marker associated with VRCZ clearance. This marker may be a practical choice for physicians to perform therapeutic drug monitoring and optimize VRCZ dosage.Mahidol UniversityMedicineArticleSCOPUS10.1097/FTD.0000000000000799