风湿性疾病患者首剂给药后环孢素A的药时曲线下面积。哪种稀疏采样策略预测效果最佳？

Cyclosporine A area-under-time-concentration-curve in rheumatologic patients after the first dose. Which of the sparse sampling strategies will predict the best?

作者信息

Koristkova B, Grundmann M, Suchy D, Perinova I, Brozmanova H, Mayer O

机构信息

Department of Clinical Pharmacology, Ostrava University Hospital and Medical Faculty, University of Ostrava, Ostrava, Czech Republic.

出版信息

Int J Clin Pharmacol Ther. 2011 May;49(5):311-20. doi: 10.5414/cp201499.

DOI:10.5414/cp201499

PMID:21543034

Abstract

OBJECTIVE

The aim of the present study was to validate the limited sampling strategies (LSS:s) for prediction of AUC of cyclosporine A (CsA) after the first dose in rheumatologic patients.

METHODS

22 patients suffering from rheumathoid arthritis, systemic lupus erythematodus, ankylosing spondylitis dermato(poly)myositis or seronegative spondylarthritis were treated with Neoral® (female/male: 11/3, mean ± SD: age 49 ± 14 y, body weight 75 ± 12 kg, height 166 ± 7 cm, dose 71 ± 25 mg, dose per kg 1.0 ± 0.3 mg/kg), or Consupren® (7/1, 78 ± 36, 175 ± 8, 82 ± 22, 1.1 ± 0.3). Two patients whose C12h were missing were excluded from the AUC0-12 calculation. Whole blood levels of CsA were analyzed with HPLC. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after taking the first dose. Altogether 115 LSS:s obtained from the literature were validated. A linear trapezoidal rule was used as a reference method. Mean percentage prediction error (%PE) < ± 15% and maximal one value of absolute %PE > 30% were considered to be acceptable. The root mean squared error (RMSE) was evaluated for equations that passed the criteria.

RESULTS

The best performance with all values of the absolute %PE < 30% was found in three LSS:s for AUC0-12 and two for AUC0-8: AUC0-12 = 123.792 + 1.165 × C1h + 3.021 × C3h + 7.33 × C8h; 97.6 + 1.27 × C1h + 3.14 × C3h + 4.06 × C6h; or 124.3 + 1.34 × C1h - 0.16 × C2h + 3.27 × C3h + 3.96 × C6h; AUC0-8 = -19.8 + 1.99 × C2h + 2.38 × C4h + 3.15 × C6h or -22.4 + 2.51 × C2h + 5.49 × C6h. Validation criteria were further fulfilled in AUC0-12 = 24 + 3.66 × C0h + 2.11 × C1.5h + 4.54 × C4h or 0.2 + 2 × C2h + 10.2 × C6h; AUC0-8 = 55.37 + 2.89 × C0h + 1.08 × C1 + 0.9 × C2h + 2.23 × C3h; and AUC0-4 = -41 + 1.17 × C1h + 1.85 × C2h. Only one equation proposed for AUC0-6 did not pass the validation criteria.

CONCLUSIONS

Equations validated for prediction of AUC0-12, AUC0-8 and AUC0-4 might be used for LSS:s of CsA independently of the length of treatment, indication, dosage or galenic formulation.

摘要

目的

本研究旨在验证有限采样策略（LSS）用于预测风湿性疾病患者首次服用环孢素A（CsA）后AUC的有效性。

方法

22例类风湿关节炎、系统性红斑狼疮、强直性脊柱炎、皮肌炎或血清阴性脊柱关节炎患者接受新山地明（Neoral®）治疗（女性/男性：11/3，平均±标准差：年龄49±14岁，体重75±12 kg，身高166±7 cm，剂量71±25 mg，每千克剂量1.0±0.3 mg/kg），或环孢灵（Consupren®）治疗（7/1，78±36，175±8，82±22，1.1±0.3）。两名C12h数据缺失的患者被排除在AUC0 - 12计算之外。采用高效液相色谱法分析CsA全血水平。首次服药后0、0.5、1、1.5、2、3、4、6、8和12小时采集血样。共验证了从文献中获得的115种LSS。采用线性梯形法则作为参考方法。平均预测误差百分比（%PE）<±15%且最大绝对%PE值>30%被认为是可接受的。对符合标准的方程评估均方根误差（RMSE）。

结果

在三种用于AUC0 - 12的LSS和两种用于AUC0 - 8的LSS中发现绝对%PE的所有值均<30%时性能最佳：AUC0 - 12 = 123.792 + 1.165×C1h + 3.021×C3h + 7.33×C8h；97.6 + 1.27×C1h + 3.14×C3h + 4.06×C6h；或124.3 + 1.34×C1h - 0.16×C2h + 3.27×C3h + 3.96×C6h；AUC0 - 8 = -19.8 + 1.99×C2h + 2.38×C4h + 3.15×C6h或 -22.4 + 2.51×C2h + 5.49×C6h。AUC0 - 12 = 24 + 3.66×C0h + 2.11×C1.5h + 4.54×C4h或0.2 + 2×C2h + 10.2×C6h；AUC0 - 8 = 55.37 + 2.89×C0h + 1.08×C1 + 0.9×C2h + 2.23×C3h；以及AUC0 - 4 = -41 + 1.17×C1h + 1.85×C2h进一步满足验证标准。仅一个提出的用于AUC0 - 6的方程未通过验证标准。