Hoyer Peter F, Ettenger Robert, Kovarik John M, Webb Nicholas J A, Lemire Jacques, Mentser Mark, Mahan John, Loirat Chantal, Niaudet Patrick, VanDamme-Lombaerts R, Offner Gisela, Wehr Sabine, Moeller Virginia, Mayer Hartmut
Department of Pediatric Nephrology, Universitätsklinik Essen, Hufelandstr. 55, D-45122 Essen, Germany.
Transplantation. 2003 Jun 27;75(12):2082-5. doi: 10.1097/01.TP.0000070139.63068.54.
The steady-state pharmacokinetics of everolimus were longitudinally assessed in pediatric de novo kidney allograft recipients during a 6-month period.
Nineteen patients received everolimus 0.8 mg/m2 (maximum 1.5 mg) twice daily as a dispersible tablet in water in addition to cyclosporine and corticosteroids. Everolimus and cyclosporine trough concentrations were obtained on days 3, 5, 6, and 7 and at months 1, 2, 3, and 6; an everolimus pharmacokinetic profile was obtained on day 7 and month 3.
There were 9 boys and 10 girls with a median age of 9.9 (range, 1-16) years. Steady-state pharmacokinetic parameters were as follows (median, range): C(min) (trough level), 4.7 (2.3- 9.5) ng/mL; peak concentration, 13.5 (5.9-22.2) ng/mL; area under the concentration-time curve (AUC), 77 (53-147) ng x hr/mL; and apparent oral clearance, 10.2 (5.5-15.6) L/hr/m2. Clearance (unadjusted for demographic factors) was positively correlated with age (r=0.66), body surface area (r=0.68), and weight (r=0.67). There were no trends in C(min) or AUC versus patient age when everolimus was dosed on a mg/m2 basis. Everolimus C(min) were stable over time with median values of 3.9, 3.4, and 3.1 ng/mL at months 1, 3, and 6, respectively. Intra- and interpatient variability in AUC was 29% and 35%, similar to that in adults. During the observation period, eight patients maintained stable AUCs and nine patients had increases or decreases, generally between 30% and 50% compared with the AUC at week 1. The concurrent median cyclosporine C(min) were generally at the lower end of conventional target ranges: 156, 83, and 69 ng/mL at months 1, 3, and 6, respectively. There were no graft losses and only three mild or moderate, reversible rejection episodes occurred. Everolimus was generally safe and well tolerated.
These data support the use of body surface area-adjusted dosing for everolimus in pediatric patients. Although exposure is generally stable over time with moderate variability in AUC, therapeutic monitoring would be a helpful adjunct for individualizing everolimus exposure, assessing regimen adherence, and adjusting doses as the child matures.
在6个月期间，对初发肾移植儿科受者纵向评估了依维莫司的稳态药代动力学。
19例患者除接受环孢素和皮质类固醇外，还接受依维莫司0.8mg/m²（最大1.5mg），每日两次，制成可分散片剂溶于水中服用。在第3、5、6和7天以及第1、2、3和6个月时测定依维莫司和环孢素的谷浓度；在第7天和第3个月时获取依维莫司药代动力学曲线。
有9名男孩和10名女孩，中位年龄为9.9岁（范围1-16岁）。稳态药代动力学参数如下（中位数，范围）：C(min)（谷浓度），4.7（2.3-9.5）ng/mL；峰浓度，13.5（5.9-22.2）ng/mL；浓度-时间曲线下面积（AUC），77（53-147）ng·hr/mL；表观口服清除率，10.2（5.5-15.6）L/hr/m²。清除率（未根据人口统计学因素调整）与年龄（r=0.66）、体表面积（r=0.68）和体重（r=0.67）呈正相关。当依维莫司按mg/m²给药时，C(min)或AUC与患者年龄无趋势关系。依维莫司C(min)随时间稳定，在第1、3和6个月时中位数分别为3.9、3.4和3.1ng/mL。AUC的患者内和患者间变异性分别为29%和35%，与成人相似。在观察期内，8例患者维持稳定的AUC，9例患者的AUC有增加或减少，与第1周时的AUC相比，一般在30%至50%之间。同期环孢素C(min)的中位数一般处于传统目标范围的下限：在第1、3和6个月时分别为156、83和69ng/mL。没有移植肾丢失，仅发生3次轻度或中度、可逆的排斥反应。依维莫司总体安全且耐受性良好。
这些数据支持在儿科患者中使用根据体表面积调整剂量的依维莫司给药方案。尽管随着时间推移暴露一般稳定，AUC有中度变异性，但治疗监测将有助于个体化依维莫司暴露、评估方案依从性以及随着儿童成长调整剂量。
