University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Antimicrob Agents Chemother. 2010 Oct;54(10):4424-31. doi: 10.1128/AAC.00504-10. Epub 2010 Aug 2.
This study was undertaken to characterize the pharmacokinetics and bioavailability of voriconazole in adult lung transplant patients during the early postoperative period, identify factors significantly associated with various pharmacokinetic parameters, and make recommendations for adequate dosing regimens. Thirteen lung transplant patients received two intravenous infusions (6 mg/kg, twice daily [b.i.d.]) immediately posttransplant followed by oral doses (200 mg, b.i.d.) for prophylaxis. Blood samples (9/interval) were collected during one intravenous and one oral dosing interval from each patient. Voriconazole plasma concentrations were measured by high-pressure liquid chromatography (HPLC). NONMEM was used to develop pharmacokinetic models, evaluate covariate relationships, and perform Monte Carlo simulations. There was a good correlation (R(2) = 0.98) between the area under the concentration-time curve specific for the dose evaluated (AUC(0-∞)) and trough concentrations. A two-compartment model adequately described the data. Population estimates of bioavailability, clearance, V(c), and V(p) were 45.9%, 3.45 liters/h, 54.7 liters, and 143 liters. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability (23.7%, n = 3) than non-CF patients (63.3%, n = 10). Bioavailability increased with postoperative time and reached steady levels in about 1 week. V(p) increased with body weight. Bioavailability of voriconazole is substantially lower in lung transplant patients than non-transplant subjects but significantly increases with postoperative time. CF patients exhibit significantly lower bioavailability and exposure of voriconazole and therefore need higher doses. Intravenous administration of voriconazole during the first postoperative day followed by oral doses of 200 mg or 400 mg appeared to be the optimal dosing regimen. However, voriconazole levels should be monitored, and the dose should be individualized based on trough concentrations as a good measure of drug exposure.
本研究旨在描述术后早期肺移植患者伏立康唑的药代动力学和生物利用度，确定与各种药代动力学参数显著相关的因素，并为充分的给药方案提出建议。13 例肺移植患者在移植后立即接受两次静脉输注（6mg/kg，每日两次[b.i.d.])，然后口服（200mg，每日两次）预防。从每位患者采集一个静脉内和一个口服给药间隔的 9/间隔血样。伏立康唑的血浆浓度通过高压液相色谱（HPLC）测定。NONMEM 用于开发药代动力学模型、评估协变量关系和进行蒙特卡罗模拟。评估剂量的浓度-时间曲线下面积（AUC(0-∞)）与谷浓度之间有很好的相关性（R(2)=0.98）。两室模型很好地描述了数据。生物利用度、清除率、V(c)和 V(p)的群体估计值分别为 45.9%、3.45 升/小时、54.7 升和 143 升。囊性纤维化（CF）患者（n=3）的生物利用度明显低于非 CF 患者（n=10）（23.7%）。生物利用度随术后时间的增加而增加，并在大约 1 周内达到稳定水平。V(p)随体重增加而增加。肺移植患者的伏立康唑生物利用度明显低于非移植患者，但随术后时间显著增加。CF 患者的伏立康唑生物利用度和暴露量明显较低，因此需要更高的剂量。术后第一天静脉内给予伏立康唑，然后口服 200mg 或 400mg 似乎是最佳的给药方案。然而，应该监测伏立康唑的水平，并根据谷浓度个体化剂量，因为这是药物暴露的良好指标。
