Therapeutic drug monitoring of voriconazole and CYP2C19 phenotype for dose optimization in paediatric patients

Abstract

Purpose: The objective of this study was to evaluate factors influencing voriconazole (VRC) plasma trough concentrations and provide research data for optimizing VRC dosing in Chinese paediatric patients.

Methods: Medical records of inpatients were reviewed retrospectively. Multivariate linear regression analysis was used to identify the factors contributing to the variability of VRC plasma trough concentrations.

Results: A total of 250 VRC plasma trough concentrations from 131 paediatric patients were included in the analysis. The median VRC plasma trough concentration was 1.28 mg·L^-1 (range, 0.02 to 9.69 mg·L^-1). The target range was achieved in 51.6% of patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.4% and 8.0% of paediatric patients, respectively. The most commonly identified cytochrome P450 2C19 (CYP2C19) phenotype was intermediate metabolizers (IMs) (48.9%), followed by normal metabolizers (NMs) (40.5%) and poor metabolizers (PMs) (10.7%), but no ultrarapid metabolizers (UMs) were observed in our study. VRC plasma trough concentrations adjusted for dose (C_min/D) were significantly lower in both NMs and IMs compared to PMs (P_N-P < 0.001 and P_I-P = 0.010, respectively). The dosage of VRC required to achieve the therapeutic range was related to age, with children aged < 6 years needing a significantly higher oral dose of VRC. The oral and intravenous maintenance doses needed to reach the therapeutic range were significantly lower than the recommended maintenance dose (P < 0.001, P < 0.001). Factors such as CYP2C19 polymorphisms, the combination of omeprazole, levels of albumin and alanine aminotransferase, were found to affect VRC exposure and explained some of the variability.

Conclusions: The VRC plasma trough concentration is significantly influenced by the CYP2C19 phenotype. The recommended maintenance dose for pediatric patients may not be appropriate for Chinese patients. To increase the probability of achieving the therapeutic range for VRC plasma trough concentration, the administration of VRC should consider the age of paediatric patients and the presence of CYP2C19 polymorphisms.

Keywords: CYP2C19 phenotype; Paediatric patients; Therapeutic drug monitoring; Voriconazole.