Clinical Pharmacology Unit, Christian Medical College, Vellore, Tamil Nadu, India.
Ther Drug Monit. 2011 Apr;33(2):165-70. doi: 10.1097/FTD.0b013e31820c16f8.
Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplantation. With a delayed absorption profile, it has not been possible to develop limited sampling strategies to estimate area under the curve (mycophenolic acid [MPA] AUC₀₋₁₂), which have limited time points and are completed in 2 hours. We developed and validated simplified strategies to estimate MPA AUC₀₋₁₂ in an Indian renal transplant population prescribed EC-MPS together with prednisolone and tacrolimus. Intensive pharmacokinetic sampling (17 samples each) was performed in 18 patients to measure MPA AUC₀₋₁₂. The profiles at 1 month were used to develop the simplified strategies and those at 5.5 months used for validation. We followed two approaches. In one, the AUC was calculated using the trapezoidal rule with fewer time points followed by an extrapolation. In the second approach, by stepwise multiple regression analysis, models with different time points were identified and linear regression analysis performed. Using the trapezoidal rule, two equations were developed with six time points and sampling to 6 or 8 hours (8hrAUC[₀₋₁₂exp]) after the EC-MPS dose. On validation, the 8hrAUC(₀₋₁₂exp) compared with total measured AUC₀₋₁₂ had a coefficient of correlation (r²) of 0.872 with a bias and precision (95% confidence interval) of 0.54% (-6.07-7.15) and 9.73% (5.37-14.09), respectively. Second, limited sampling strategies were developed with four, five, six, seven, and eight time points and completion within 2 hours, 4 hours, 6 hours, and 8 hours after the EC-MPS dose. On validation, six, seven, and eight time point equations, all with sampling to 8 hours, had an acceptable r with the total measured MPA AUC₀₋₁₂ (0.817-0.927). In the six, seven, and eight time points, the bias (95% confidence interval) was 3.00% (-4.59 to 10.59), 0.29% (-5.4 to 5.97), and -0.72% (-5.34 to 3.89) and the precision (95% confidence interval) was 10.59% (5.06-16.13), 8.33% (4.55-12.1), and 6.92% (3.94-9.90), respectively. Of the eight simplified approaches, inclusion of seven or eight time points improved the accuracy of the predicted AUC compared with the actual and can be advocated based on the priority of the user.
肠溶剂型麦考酚酸钠（EC-MPS）在肾移植中被广泛应用。由于其吸收时间延迟，因此无法开发出有限采样策略来估算曲线下面积（麦考酚酸 [MPA] AUC₀₋₁₂），这些策略的时间点有限，且在 2 小时内完成。我们开发并验证了简化策略，以估算印度肾移植患者在服用 EC-MPS 联合泼尼松龙和他克莫司时的 MPA AUC₀₋₁₂。在 18 名患者中进行了强化药代动力学采样（每次 17 个样本），以测量 MPA AUC₀₋₁₂。将第 1 个月的结果用于开发简化策略，将第 5.5 个月的结果用于验证。我们采用了两种方法。一种方法是使用梯形法则计算 AUC，使用较少的时间点，然后进行外推。在第二种方法中，通过逐步多元回归分析，确定具有不同时间点的模型，并进行线性回归分析。使用梯形法则，我们开发了两种包含六个时间点的方程，并在 EC-MPS 剂量后 6 或 8 小时（8hrAUC[₀₋₁₂exp]）进行采样。在验证中，8hrAUC(₀₋₁₂exp)与总测量 AUC₀₋₁₂的相关性系数 (r²) 为 0.872，偏倚和精度（95%置信区间）分别为 0.54%（-6.07-7.15）和 9.73%（5.37-14.09）。其次，开发了四个、五个、六个、七个和八个时间点的有限采样策略，在 EC-MPS 剂量后 2 小时、4 小时、6 小时和 8 小时内完成采样。在验证中，六个、七个和八个时间点的方程均在 8 小时内完成采样，与总测量 MPA AUC₀₋₁₂的相关性均可以接受（0.817-0.927）。在六个、七个和八个时间点中，偏倚（95%置信区间）分别为 3.00%（-4.59-10.59）、0.29%（-5.4-5.97）和-0.72%（-5.34-3.89），精度（95%置信区间）分别为 10.59%（5.06-16.13）、8.33%（4.55-12.1）和 6.92%（3.94-9.90）。在八种简化方法中，与实际值相比，包含七个或八个时间点可以提高预测 AUC 的准确性，并且可以根据用户的优先级来提倡使用。
