Department of Pharmacy, Peking University People's Hospital, Beijing, China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Mycoses. 2021 Aug;64(8):860-873. doi: 10.1111/myc.13293. Epub 2021 May 6.
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 (C ), voriconazole dosage adjusted trough concentrations (C /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, I = 44%, p < .00001) or poor metabolisers (PMs) (MD: 1.59, 95% CI: 1.14 to 2.05, I = 46%, p < .00001) had significantly higher voriconazole C (μg·ml ), while rapid metabolisers (RMs) had significantly lower voriconazole C (MD: -0,87, 95% CI: -1.35 to -0.38, I = 0%, p = .0004). In addition, IMs had significantly lower C than PMs (MD: -0.59, 95% CI: -0.97 to -0.20, I = 22%, p = .003). Similarly, the C /D (μg·kg·ml ·mg ) was significantly higher in IMs (MD: 0.13, 95% CI: 0.05 to 0.22, I = 0%, p = .002) and PMs (MD: 0.20, 95% CI: 0.07 to 0.34, I = 0%, p = .003) than that in NMs, and also, IMs had significantly lower C /D than PMs (MD: -0.11, 95% CI: -0.14 to -0.08, I = 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, I = 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.
伏立康唑的初级代谢由 CYP2C19 催化。在临床实践中，侵袭性真菌感染患者使用伏立康唑治疗时，其谷浓度存在很大的变异性。CYP2C19 多态性是否导致个体变异中伏立康唑的代谢，这仍然存在争议。
本研究的主要目的是评估 CYP2C19 多态性对伏立康唑谷浓度的影响。
在系统文献回顾后，我们对 CYP2C19 表型的两两比较进行了平均差异（MD）的荟萃分析，包括伏立康唑谷浓度（C）、伏立康唑剂量调整后的谷浓度（C / D）和目标治疗范围内患者比例的风险比（RR）。
与正常代谢者（NMs）相比，中间代谢者（IMs）（MD：0.82，95%CI：0.57 至 1.07，I = 44%，p < 0.00001）或弱代谢者（PMs）（MD：1.59，95%CI：1.14 至 2.05，I = 46%，p < 0.00001）的伏立康唑 C（μg·ml -1 ）显著升高，而快速代谢者（RMs）的伏立康唑 C 显著降低（MD：-0.87，95%CI：-1.35 至 -0.38，I = 0%，p = 0.04）。此外，IMs 的 C 明显低于 PMs（MD：-0.59，95%CI：-0.97 至 -0.20，I = 22%，p = 0.003）。同样，IMs（MD：0.13，95%CI：0.05 至 0.22，I = 0%，p = 0.002）和 PMs（MD：0.20，95%CI：0.07 至 0.34，I = 0%，p = 0.003）的 C / D（μg·kg·ml -1 ·mg -1 ）明显高于 NMs，而且 IMs 的 C / D 明显低于 PMs（MD：-0.11，95%CI：-0.14 至 -0.08，I = 0%，p < 0.00001）。此外，PMs 的目标治疗范围内的比例明显高于 NMs（RR：1.34，95%CI：1.09 至 1.64，I = 50%，p = 0.005）。
与 NMs 相比，IMs 和 PMs 具有更高的伏立康唑谷浓度，尤其是在亚洲人群中，而 RMs 的伏立康唑谷浓度较低。此外，PMs 比 NMs 有更高的目标治疗范围比例，尤其是在亚洲人群中。预计 CYP2C19 基因分型将用于指导临床实践中伏立康唑的个体化治疗。
