Clinical Pharmacology Unit, Christian Medical College, Vellore, Tamil Nadu, India.
Ther Drug Monit. 2010 Apr;32(2):136-40. doi: 10.1097/FTD.0b013e3181cd550f.
In renal transplant patients, there is an established relationship between mycophenolate area under the curve and clinical outcome. The authors have developed and validated a limited sampling strategy to estimate mycophenolic acid area under the curve to 12 hours (MPA AUC0-12) in a stable renal transplant Indian population prescribed a formulation of mycophenolate mofetil (Mofilet) along with prednisolone and tacrolimus. Intensive pharmacokinetic sampling was performed in 29 patients to measure mycophenolate concentration from trough to 12 hours postdose. Subsets of different timed concentrations against total measured 12-hour area under the curve were analyzed by linear regression. Three models were identified and linear regression analysis done. After all subset regression analysis, three, four, and five time point limited sampling strategies (LSS) were developed having correlation coefficients above 0.92. Validation of the models was performed using the jackknife method and their predictive performances were tested. After validation, the correlation coefficients for all three models were above 0.901. The five-point LSS had the best predictive performance with a bias (95% confidence interval) of 0.67% (-3.45 to 4.79) and mean precision 7.73%. In all patients except one, the five-point LSS estimation for total area under the curve was within +/- 20% of the total measured AUC0-12. Trough concentration had a significant correlation with AUC0-12 (r = 0.69). However, if dosing in routine clinical practice was adjusted based only on trough concentration, 41% of our patients would require a different dose compared with monitoring using AUC0-12. The five-point LSS uses half-hourly samples from trough to 1.5 hour postdose with an additional sample at 3 hours. Ninety-three percent of our patients had a Cmax within 1.5 hour and inclusion of all the time points up to1.5 hour gave a better estimate of AUC0-12. This model simplifies area under the curve measurement with high precision in stable adult renal transplant patients.
在肾移植患者中，霉酚酸（MPA）的药时曲线下面积（AUC）与临床结果之间存在明确的关系。本研究旨在开发并验证一种针对印度稳定期肾移植患者的有限采样策略，以估算霉酚酸 AUC0-12（MPA AUC0-12）。该患者群体接受霉酚酸莫酯（Mofilet）联合泼尼松龙和他克莫司治疗。对 29 名患者进行了强化药代动力学采样，以测量给药后从谷值到 12 小时的霉酚酸浓度。通过线性回归分析了不同时间点浓度与总 12 小时 AUC 的关系。对所有亚组回归分析后，确定了三种模型并进行了线性回归分析。在所有亚组回归分析之后，开发了三种、四种和五种时间点的有限采样策略（LSS），其相关系数均高于 0.92。使用刀切法验证模型，测试其预测性能。验证后，所有三种模型的相关系数均高于 0.901。五点 LSS 的预测性能最佳，其偏倚（95%置信区间）为 0.67%（-3.45 至 4.79），平均精密度为 7.73%。除 1 名患者外，所有患者的五点 LSS 总 AUC0-12 估计值均在总测量 AUC0-12 的 +/- 20%范围内。谷浓度与 AUC0-12 呈显著相关（r = 0.69）。然而，如果仅根据谷浓度调整常规临床实践中的剂量，与监测 AUC0-12 相比，我们的 41%患者需要改变剂量。五点 LSS 使用从谷值到给药后 1.5 小时的半时样本，并在 3 小时时增加一个样本。我们的 93%患者在 1.5 小时内有 Cmax，纳入 1.5 小时内的所有时间点可更好地估计 AUC0-12。该模型简化了 AUC 测量，在稳定的成年肾移植患者中具有高精度。
