Population pharmacokinetics of voriconazole and CYP2C19 phenotype for dose optimization in hematological patients with invasive fungal infections

Abstract Aims The aim of this study was to evaluate factors that impact on voriconazole trough concentration and explore the optimal dosing regimen of voriconazole for different CYP2C19 genotypes in a Chinese population. Methods Medical records of inpatients were reviewed retrospectively. Multivariate linear regression and population pharmacokinetic analysis was used to identify the factors contributing to the variability of voriconazole trough concentrations. Results A total of 363 voriconazole trough concentrations from 89 patients were included, with high inter- and intraindividual variability. At the measurement of the first trough concentration, the target range (1.0–5.5 mg·L− 1) was achieved in 68.5% of patients, while subtherapeutic and supratherapeutic concentrations were obtained in 28.1% and 3.4% of patients, respectively. In our study, the most commonly identified cytochrome P450 2C19 (CYP2C19) phenotype was normal metabolizers (NMs) (46.1%), followed by intermediate metabolizers (IMs) (40.4%) and poor metabolizers (PMs) (13.5%). Initial trough concentrations were adjusted for dose, with NMs and IMs were both significantly lower than PMs (PN−P=0.010 and PI−P=0.048, respectively). The median intravenous maintenance dose to reach a therapeutic range was significantly lower than the recommended intravenous maintenance dose (P = 0.009). Affecting factors in our study such as age, administration routes, CYP2C19 polymorphisms and aspartate transaminase (AST) explained 41.4% of the variability in voriconazole exposure. The final model of voriconazole population pharmacokinetic analysis contained age as a significant covariate for the distribution volume and CYP2C19 phenotype as a significant covariate for the clearance rate. Dose simulations indicated that 300, 250, 150 mg orally twice daily is appropriate for NMs, IMs and PMs to achieve target range, respectively. Conclusions To increase the probability of achieving the therapeutic range and improving efficacy, CYP2C19 phenotype can be used to predict voriconazole trough concentrations and guide dose adjustment.