Kovarik John M, Kaplan Bruce, Tedesco Silva Hélio, Kahan Barry D, Dantal Jacque, Vitko Stefan, Boger Robert, Rordorf Christiane
Novartis Pharmaceuticals, Basel, Switzerland.
Transplantation. 2002 Mar 27;73(6):920-5. doi: 10.1097/00007890-200203270-00016.
Exposure, safety, and efficacy data from the two everolimus randomized, double-blind phase 3 trials were evaluated to identify a therapeutic concentration range applicable in de novo kidney transplantation.
A total of 695 evaluable everolimus-treated patients received either 0.75 or 1.5 mg bid in addition to corticosteroids and cyclosporine (troughs 150-400 ng/ml in month 1 and 100-300 ng/ml thereafter). A total of 3355 everolimus trough levels (Cmin) were obtained in weeks 1 and 2 and months 1, 2, 3, and 6 after transplantation. Each patient's average Cmin was calculated and the values were divided into quintiles: 1.0-3.4, 3.5-4.5, 4.6-5.7, 5.8-7.7, 7.8-15.0 ng/ml (139 patients per quintile). Efficacy was freedom from biopsy-confirmed acute rejection. Safety measures were maximum total cholesterol and triglyceride levels and minimum leukocyte and platelet counts. A sigmoid exposure-response model was used to test the significance of these Cmin-efficacy and Cmin-safety relationships.
Freedom from acute rejection was significantly related to Cmin with an incidence of 68% at 1.0-3.4 ng/ml, 81-86% at 3.5-7.7 ng/ml, and 91% at 7.8-15.0 ng/ml (P=0.03). The incidence of hypercholesterolemia, defined as >6.5 mmol/liter, ranged from 76 to 87% over the exposure range without a significant relation to Cmin (P=0.37). The incidence of hypertriglyceridemia, defined as >2.9 mmol/liter, rose from 59 to 77% across the exposure groups (P=0.02). Leukocytopenia, defined as <4x10(9)/liter, occurred in 11-19% of patients across the exposure quintiles showing no relationship to Cmin (P=0.76). The incidence of thrombocytopenia, defined as <100x10(9)/liter, occurred in </=10% of patients in the first 3 Cmin quintiles and was 14 and 17% in Cmin quintiles 4 and 5 (P=0.21).
A significantly increased risk of acute rejection was observed at everolimus trough levels <3 ng/ml. This is a lower therapeutic concentration limit when everolimus is used with conventionally dosed cyclosporine. Because hyperlipidemias responded to counter-measure therapies and thrombocytopenia had an overall low incidence of 12%, everolimus-related adverse events were manageable up to the highest troughs observed in this population of 15 ng/ml. An upper therapeutic concentration limit is likely more than 15 ng/ml but a precise value could not be derived from these data.
对两项依维莫司随机、双盲3期试验的暴露、安全性和有效性数据进行评估，以确定适用于初发肾移植的治疗浓度范围。
总共695例接受依维莫司治疗且可评估的患者，除接受皮质类固醇和环孢素治疗外（第1个月环孢素谷浓度为150 - 400 ng/ml，此后为100 - 300 ng/ml），还接受每日两次0.75 mg或1.5 mg依维莫司治疗。在移植后的第1周和第2周以及第1、2、3和6个月共获得3355次依维莫司谷浓度（Cmin）。计算每位患者的平均Cmin，并将这些值分为五分位数：1.0 - 3.4、3.5 - 4.5、4.6 - 5.7、5.8 - 7.7、7.8 - 15.0 ng/ml（每个五分位数139例患者）。有效性指标为活检证实的急性排斥反应未发生。安全性指标为总胆固醇和甘油三酯最高水平以及白细胞和血小板最低计数。采用S形暴露-反应模型检验这些Cmin-有效性和Cmin-安全性关系的显著性。
急性排斥反应未发生与Cmin显著相关，Cmin为1.0 - 3.4 ng/ml时发生率为68%，3.5 - 7.7 ng/ml时为81 - 86%，7.8 - 15.0 ng/ml时为91%（P = 0.03）。定义为>6.5 mmol/L的高胆固醇血症发生率在整个暴露范围内为76%至87%，与Cmin无显著相关性（P = 0.37）。定义为>2.9 mmol/L的高甘油三酯血症发生率在各暴露组中从59%升至77%（P = 0.02）。定义为<4×10⁹/L的白细胞减少症在各暴露五分位数患者中的发生率为11% - 19%，与Cmin无关（P = 0.76）。定义为<100×10⁹/L的血小板减少症在前3个Cmin五分位数患者中的发生率≤10%，在第4和第5个Cmin五分位数患者中分别为14%和17%（P = 0.21）。
当依维莫司谷浓度<3 ng/ml时，观察到急性排斥反应风险显著增加。这是依维莫司与常规剂量环孢素联用时的较低治疗浓度下限。由于高脂血症对相应治疗有反应且血小板减少症总体发生率较低，为12%，在该人群中观察到的最高谷浓度达15 ng/ml时，依维莫司相关不良事件是可控的。治疗浓度上限可能超过15 ng/ml，但无法从这些数据得出精确值。
