Ettenger R, Schmouder R, Kovarik J M, Bastien M C, Hoyer P F
Division of Pediatric Nephrology, Mattel Children's Hospital UCLA, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095-1752, USA.
Pediatr Transplant. 2011 Jun;15(4):406-13. doi: 10.1111/j.1399-3046.2011.01498.x.
Oral fingolimod signals the sphingosine 1-phosphate receptor and this in turn mediates immunomodulatory activity. No data of fingolimod in any pediatric population existed before this study. We put our study results in perspective against data from adult renal transplant patients. We investigated pharmacokinetics and pharmacodynamics of single-dose fingolimod (0.07 mg/kg) and its effects on lymphocytes and heart rate in seven adolescents (14.1 ± 1.6 yr) with stable renal transplants. Blood samples for pharmacokinetics and lymphocytes were collected at screening, baseline, and up to 28 days post-dosing. Cardiac monitoring included 12-lead ECG, 24-h Holter monitoring, and echocardiography. A fingolimod dose of 0.07 mg/kg resulted in mean AUC of 731 ± 240 ng·h/mL and C(max) of 3.6 ± 0.6 ng/mL. Drug exposure was nearly identical to adults receiving the same dose. Absolute lymphocyte count decreased 85% from baseline; average nadir occurred by six h post-dose. Heart rate decreased from 74 bpm (predose mean) to 53 bpm (nadir) three h post-dose. Mean heart rates recovered by Day 14 (75 bpm). Weight-adjusted doses of fingolimod in adolescents resulted in drug exposure similar to adults. Adolescents and adults shared comparable negative chronotropic effects and decreased lymphocyte count. Recovery trajectories of these parameters back to baseline were similar between age groups.
口服芬戈莫德作用于1-磷酸鞘氨醇受体，进而介导免疫调节活性。在本研究之前，尚无芬戈莫德在任何儿科人群中的数据。我们将本研究结果与成年肾移植患者的数据进行了对比分析。我们调查了7名稳定肾移植青少年（14.1±1.6岁）单次服用芬戈莫德（0.07mg/kg）后的药代动力学和药效学，以及其对淋巴细胞和心率的影响。在筛选、基线期以及给药后长达28天采集用于药代动力学和淋巴细胞检测的血样。心脏监测包括12导联心电图、24小时动态心电图监测和超声心动图检查。芬戈莫德剂量为0.07mg/kg时，平均AUC为731±240ng·h/mL，C(max)为3.6±0.6ng/mL。药物暴露情况与接受相同剂量的成年人几乎相同。绝对淋巴细胞计数较基线下降了85%；平均最低点出现在给药后6小时。心率在给药后3小时从74次/分钟（给药前平均值）降至53次/分钟（最低点）。平均心率在第14天恢复（75次/分钟）。青少年中按体重调整的芬戈莫德剂量导致的药物暴露与成年人相似。青少年和成年人具有相当的负性变时作用且淋巴细胞计数下降。这些参数恢复至基线的轨迹在不同年龄组之间相似。
