Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation & Research Food & Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland 20993, USA.
Pharm Res. 2013 Jan;30(1):191-202. doi: 10.1007/s11095-012-0862-x. Epub 2012 Sep 25.
Methylphenidate modified-release products produce early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD). Standard bioequivalence (BE) criteria cannot be applied to these products. The performance of partial area under the drug concentration-time curve (PAUC), Cmax and AUCINF to assess BE were independently evaluated for two products.
A two-stage analysis was performed on plasma data for two methylphenidate modified-release products (Product 1 and 2). Simulations using the fitted parameters determined how changes in fast absorption rate constant (K0Fast) and fraction available (F1) affected curve shape and BE determination using Cmax, AUCINF and PAUC.
The sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in K0Fast(test) are product dependent. Product 1 mean PAUC(test)/PAUC(reference) ratios for PAUC0-4h are more responsive to both decreases and increases in K0Fast(test) than Product 2. Product 2 showed a greater response in the mean PAUC(test)/PAUC(reference) ratio for PAUC0-4h when the K0Fast(test) is decreased and less response as the value is increased.
PAUC estimated curve shape is sensitive to changes in absorption and are product specific, and may require a new PAUC metric for each drug. A non-product specific metric to assess curve shape is warranted.
哌醋甲酯控释产品产生早期和晚期浓度峰值，这对于治疗注意缺陷多动障碍（ADHD）的早晨和下午症状至关重要。标准生物等效性（BE）标准不能应用于这些产品。部分药时曲线下面积（PAUC）、Cmax 和 AUCINF 来评估 BE 的性能，分别对两种产品进行了独立评估。
对两种哌醋甲酯控释产品（产品 1 和 2）的血浆数据进行两阶段分析。使用确定的拟合参数进行模拟，以了解快速吸收速率常数（K0Fast）和可用分数（F1）的变化如何影响 Cmax、AUCINF 和 PAUC 用于评估 BE 的曲线形状。
平均 PAUC(test)/PAUC(reference) 比值对 K0Fast(test)变化的敏感性取决于产品。对于 PAUC0-4h，产品 1 的平均 PAUC(test)/PAUC(reference) 比值对 K0Fast(test)的降低和升高都更敏感。产品 2 显示，当 K0Fast(test)降低时，PAUC0-4h 的平均 PAUC(test)/PAUC(reference) 比值的变化更大，而当 K0Fast(test)增加时，变化较小。
PAUC 估计的曲线形状对吸收的变化敏感，且具有产品特异性，可能需要为每种药物制定新的 PAUC 指标。需要制定一种非产品特异性的曲线形状评估指标。
