The influence of CYP2C19 polymorphisms on voriconazole trough concentrations: Systematic review and meta-analysis.

Abstract

Voriconazole primary metabolism is catalysed by CYP2C19. A large variability of trough concentrations in patients with invasive fungal infection treated with voriconazole has been observed in clinical practice. It remains controversial whether the CYP2C19 polymorphisms are responsible for voriconazole metabolism in the individual variation. The primary aim of this study was to assess the effect of CYP2C19 polymorphisms on voriconazole trough concentrations. Following a systematic literature review, we performed a meta-analysis for mean differences (MD) of voriconazole trough concentrations (Cmin ), voriconazole dosage adjusted trough concentrations (Cmin /D) and for risk ratio (RR) of the proportion of patients in the target therapeutic range between pairwise comparisons of CYP2C19 phenotypes. Compared with normal metabolisers (NMs), intermediate metabolisers (IMs) (MD: 0.82, 95% CI: 0.57 to 1.07, I2 =44%, p<.00001) or poor metabolisers (PMs) (MD: 1.59, 95% CI: 1.14 to 2.05, I2 =46%, p<.00001) had significantly higher voriconazole Cmin (μg·ml-1 ), while rapid metabolisers (RMs) had significantly lower voriconazole Cmin (MD: -0,87, 95% CI: -1.35 to -0.38, I2 =0%, p=.0004). In addition, IMs had significantly lower Cmin than PMs (MD: -0.59, 95% CI: -0.97 to -0.20, I2 =22%, p=.003). Similarly, the Cmin /D (μg·kg·ml-1 ·mg-1 ) was significantly higher in IMs (MD: 0.13, 95% CI: 0.05 to 0.22, I2 =0%, p=.002) and PMs (MD: 0.20, 95% CI: 0.07 to 0.34, I2 =0%, p=.003) than that in NMs, and also, IMs had significantly lower Cmin /D than PMs (MD: -0.11, 95% CI: -0.14 to -0.08, I2 =0%, p<.00001). Furthermore, PMs had a significantly higher proportion of the target therapeutic range than NMs (RR: 1.34, 95% CI: 1.09 to 1.64, I2 =50%, p=.005). Compared to NMs, IMs and PMs had higher voriconazole trough concentrations, especially in Asians, while RMs had lower voriconazole trough concentrations. In addition, PMs had a higher proportion of the target therapeutic range than NMs, especially in Asians. CYP2C19 genotyping is expected to be used to preemptively guide the individualisation of voriconazole in clinical practice.