Liu Ping, Mould Diane R
Clinical Pharmacology, Global Established Pharma Business, Pfizer Inc., Groton, Connecticut, USA
Projections Research Inc., Phoenixville, Pennsylvania, USA.
Antimicrob Agents Chemother. 2014 Aug;58(8):4718-26. doi: 10.1128/AAC.02808-13. Epub 2014 Jun 9.
To assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0-12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).
为了评估伏立康唑和阿尼芬净在侵袭性曲霉病（IA）患者中的药代动力学（PK），并与其他人群进行比较，我们从一项前瞻性3期研究中获取了305名成人的稀疏PK数据，该研究比较了伏立康唑和阿尼芬净联合用药与伏立康唑单药治疗（伏立康唑，静脉注射[IV] 6 mg/kg，每12小时一次[q12h]，共24小时，随后静脉注射4 mg/kg，q12h，酌情改为口服300 mg，q12h；联合安慰剂或阿尼芬净静脉注射，负荷剂量200 mg，随后100 mg，q24h）。伏立康唑的PK用具有一级吸收以及混合线性和时间依赖性非线性（米氏）消除的二室模型描述；阿尼芬净的PK用具有一级消除的二室模型描述。对于伏立康唑，采用正态逆Wishart先验方法来稳定模型。与先前的模型相比，未确定伏立康唑或阿尼芬净的新协变量。伏立康唑和阿尼芬净的PK参数估计值与先前报道的一致，但伏立康唑清除率除外（非线性清除成分变得最小）。在4 mg/kg静脉注射剂量下，随着年龄、体重或体重指数的增加，伏立康唑的暴露量有轻微增加的趋势，但差异不被认为具有临床相关性。侵袭性曲霉病患者静脉注射4 mg/kg时伏立康唑的估计暴露量高于健康成年人报道的暴露量（例如，稳态下12小时给药间隔的平均曲线下面积[AUC0-12]高46%）；虽然尚不确定，但年龄和合并用药可能会影响这种差异。侵袭性曲霉病患者阿尼芬净的估计暴露量与一般患者群体报道的暴露量相当。本研究已获得适当的机构审查委员会或伦理委员会批准，并在ClinicalTrials.gov（NCT00531479）上注册。
