Impact of cytochrome P450 2C19 polymorphisms on the clinical efficacy and safety of voriconazole: an update systematic review and meta-analysis

Abstract

Objective To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole. Methods We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to 18 March 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity, and neurotoxicity. Results A total of 20 studies were included. Intermediate metabolizers (IMs) and poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) [risk ratio (RR), 1.18; 95% confidence interval (CI), 1.03–1.34; I2 = 0%; P = 0.02; RR, 1.28; 95% CI, 1.06–1.54; I2 = 0%; P = 0.01]. PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR, 2.18; 95% CI, 1.35–3.53; I2 = 0%; P = 0.001; RR, 1.80; 95% CI, 1.23–2.64; I2 = 0%; P = 0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR, 1.60; 95% CI, 0.94–2.74; I2 = 27%; P = 0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity. Conclusion IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deserves clinical attention.

Individualized treatment with voriconazole in the Chinese population: Inflammation level as a novel marker for dose optimization

“…17 Our previous systematic review showed that CYP2C19 polymorphisms significantly affected VRC steady-state valley concentration (C min ss) and corresponding efficacy and safety in clinical practice. 19,20 CYP2C19 polymorphisms were also proved to guide initial dose selections, which led to a better clinical outcome in the treatment of IA. 21 Therefore, whether CYP2C19 polymorphisms could still guide individualized medication under inflammatory state is a focus of the present study.…”

“…CYP2C19 is the primary enzyme responsible for the conversion of VRC into its major inactive metabolite, VRC N‐oxide (VNO), which accounts for approximately 72% of plasma metabolites 17 . Our previous systematic review showed that CYP2C19 polymorphisms significantly affected VRC steady‐state valley concentration (C min ss) and corresponding efficacy and safety in clinical practice 19,20 . CYP2C19 polymorphisms were also proved to guide initial dose selections, which led to a better clinical outcome in the treatment of IA 21 .…”

Optimization of Voriconazole Dosing Regimens Against Aspergillus Species and Candida Species in Pediatric Patients After Hematopoietic Cell Transplantation: A Theoretical Study Based on Pharmacokinetic/Pharmacodynamic Analysis

“…Of these, CYP2C19 polymorphisms are considered a key determinant of the wide pharmacokinetic (PK) variability of VRC 16 . Low levels of exposure to VRC may result in treatment failure, whereas high levels of exposure may result in adverse neurological effects, hepatotoxicity, and visual impairment 17–19 . Therefore, the dosing schedule for VRC should be optimized to maximize the best therapeutic effect and minimize the occurrence of adverse effects.…”