Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.
Department of Infection Control and Prevention, Hyogo College of Medicine, Nishinomiya, Japan.
Mycoses. 2023 Dec;66(12):1035-1044. doi: 10.1111/myc.13639. Epub 2023 Aug 16.
The optimal timing for therapeutic drug monitoring (TDM) of voriconazole in Asians, who have higher rates of poor metabolisers than non-Asians, is unclear. This can cause unexpectedly high concentrations and delays in reaching steady-state levels.
To determine the appropriate timing of TDM in Japanese patients receiving voriconazole.
PATIENTS/METHODS: Trough levels (C ) were measured on days 3-5 (recommended timing, RT) and days 6-14 (delayed timing, DT) after starting voriconazole in patients receiving an appropriate dosage. Considering bioavailability, C was only compared in patients receiving oral voriconazole.
A total of 289 and 186 patients were included in the safety and pharmacokinetic analyses, respectively. There was a significant difference in C measured no later than and after day 5 (3.59 ± 2.12 [RT] vs. 4.77 ± 3.88 μg/mL [DT], p = .023), whereas no significant difference was observed on cutoff day 6 (3.91 ± 2.60 vs. 4.40 ± 3.94 μg/mL, p = .465), suggesting that C close to the steady-state was achieved after day 5. DT causes a delay in achieving the therapeutic range. The hepatotoxicity rates were 21.5% and 36.8% in the RT and DT groups, respectively (p = .004); DT was an independent risk factor for hepatotoxicity.
Although steady-state concentrations may not be achieved by day 5, early dose optimisation using RT can prevent hepatotoxicity in Japanese patients. TDM should be performed on days 3-5 to ensure safety. However, subsequent TDM may be necessary due to a possible further increase in C .
亚洲人中有较高比例的代谢不良者，他们使用伏立康唑时需要治疗药物监测（TDM）的最佳时间尚不清楚。这可能导致药物浓度意外升高和达到稳定水平的时间延迟。
确定接受伏立康唑治疗的日本患者进行 TDM 的适当时间。
患者/方法：在开始伏立康唑后第 3-5 天（推荐时间，RT）和第 6-14 天（延迟时间，DT）测量患者的谷浓度（C ），这些患者接受了适当的剂量。考虑到生物利用度，仅对接受口服伏立康唑的患者进行 C 的比较。
安全性和药代动力学分析分别纳入了 289 例和 186 例患者。在不晚于第 5 天（3.59±2.12[RT]与 4.77±3.88μg/mL[DT]，p=0.023）和第 5 天之后测量的 C 之间存在显著差异，而在截止日 6 天（3.91±2.60与 4.40±3.94μg/mL，p=0.465）没有观察到显著差异，表明在第 5 天后接近稳态的 C 已经达到。DT 会导致达到治疗范围的时间延迟。RT 组和 DT 组的肝毒性发生率分别为 21.5%和 36.8%（p=0.004）；DT 是肝毒性的独立危险因素。
尽管在第 5 天可能无法达到稳态浓度，但早期使用 RT 进行剂量优化可以预防日本患者的肝毒性。为确保安全，应在第 3-5 天进行 TDM。然而，由于 C 可能进一步增加，可能需要随后进行 TDM。
