Perrottet N, Csajka C, Pascual M, Manuel O, Lamoth F, Meylan P, Aubert J D, Venetz J P, Soccal P, Decosterd L A, Biollaz J, Buclin T
Division of Clinical Pharmacology and Toxicology. Département de Médecine, Hôpital de Beaumont 06, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Antimicrob Agents Chemother. 2009 Jul;53(7):3017-23. doi: 10.1128/AAC.00836-08. Epub 2009 Mar 23.
Valganciclovir (VGC) is an oral prodrug of ganciclovir (GCV) recently introduced for prophylaxis and treatment of cytomegalovirus infection. Optimal concentration exposure for effective and safe VGC therapy would require either reproducible VGC absorption and GCV disposition or dosage adjustment based on therapeutic drug monitoring (TDM). We examined GCV population pharmacokinetics in solid organ transplant recipients receiving oral VGC, including the influence of clinical factors, the magnitude of variability, and its impact on efficacy and tolerability. Nonlinear mixed effect model (NONMEM) analysis was performed on plasma samples from 65 transplant recipients under VGC prophylaxis or treatment. A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by the glomerular filtration rate (GFR), patient gender, and graft type (clearance/GFR = 1.7 in kidney, 0.9 in heart, and 1.2 in lung and liver recipients) with interpatient and interoccasion variabilities of 26 and 12%, respectively. Body weight and sex influenced central volume of distribution (V(1) = 0.34 liter/kg in males and 0.27 liter/kg in females [20% interpatient variability]). No significant drug interaction was detected. The good prophylactic efficacy and tolerability of VGC precluded the demonstration of any relationship with GCV concentrations. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of the GCV profile after treatment with oral VGC, routine TDM does not appear to be clinically indicated in solid-organ transplant recipients. However, GCV plasma measurement may still be helpful in specific clinical situations.
缬更昔洛韦（VGC）是更昔洛韦（GCV）的口服前体药物，最近被用于预防和治疗巨细胞病毒感染。实现有效且安全的VGC治疗所需的最佳浓度暴露，要么需要可重复的VGC吸收和GCV处置，要么需要基于治疗药物监测（TDM）进行剂量调整。我们研究了接受口服VGC的实体器官移植受者体内GCV的群体药代动力学，包括临床因素的影响、变异性大小及其对疗效和耐受性的影响。对65名接受VGC预防或治疗的移植受者的血浆样本进行了非线性混合效应模型（NONMEM）分析。一个具有一级吸收的二室模型能恰当描述数据。全身清除率受肾小球滤过率（GFR）、患者性别和移植物类型的显著影响（肾移植受者的清除率/GFR = 1.7，心脏移植受者为0.9，肺和肝移植受者为1.2），患者间和不同时间的变异性分别为26%和12%。体重和性别影响中央分布容积（男性V(1) = 0.34升/千克；女性V(1) = 0.27升/千克[患者间变异性为20%]）。未检测到显著的药物相互作用。VGC良好的预防疗效和耐受性使得无法证明其与GCV浓度之间存在任何关系。总之，该分析强调了根据肾功能和体重全面调整VGC剂量的重要性。考虑到口服VGC治疗后GCV曲线具有良好的可预测性和可重复性，实体器官移植受者似乎并无临床指征进行常规TDM。然而，在特定临床情况下，测定GCV血浆浓度可能仍有帮助。
