Tuerck D, Wang Y, Maboudian M, Wang Y, Sedek G, Pommier F, Appel-Dingemanse S
Exploratory Development, Drug Metabolism and Pharmacokinetics, Novartis Pharma Basel, Switzerland.
Int J Clin Pharmacol Ther. 2007 Dec;45(12):662-8. doi: 10.5414/cpp45662.
The d-isomer of methylphenidate (d-MPH) is the pharmacologically active part of the racemic mixture of methylphenidate (d,l-MPH), which has been used for decades in the treatment of attention-deficit/hyperactivity disorder (ADHD). A modified release formulation with bimodal release for the pure d-enantiomer (Focalin XR) has been developed to enable a fast onset of action and a sustained activity for once-daily administration. It was intended to achieve a bimodal concentration-time profile as observed after administration of two immediate release Focalin tablets. The pharmacokinetics of this d-MPH bimodal release formulation were compared with a d-MPH immediate release formulation and a similar bimodal release formulation of d,l-MPH in healthy adult volunteers.
25 volunteers received a single 20 mg dose of d-MPH bimodal release formulation, two 10 mg doses of a d-MPH immediate release formulation given 4 h apart and a single 40 mg dose of d,l-MPH bimodal release formulation (1 : 1 ratio for d : l enantiomers). The washout between treatments in this 3-way crossover study was 7 days.
All three formulations were well-tolerated at the doses tested. The d-MPH bimodal release formulation generated two distinct d-MPH plasma concentration peaks and both peak concentrations and the time to peak were similar to those of the d-MPH immediate release formulation given 4 h apart and the d,l-MPH bimodal release formulation. The three formulations had Cmax and AUC0-infinity values of 15.5 +/- 4.3 ng/ml and 119 +/- 41 ng x h/ml for bimodal release d-MPH, 17.9 +/- 5.3 ng/ml and 115 +/- 40 ng A h/ml for immediate release d-MPH, and 16.4 +/- 4.4 ng/ml and 122 +/- 36 ng x h/ml for d,l-MPH bimodal release, respectively.
In summary, the 20 mg extended (bimodal) release formulation of d-MPH (Focalin XR) demonstrated a bimodal concentration-time profile and was bioequivalent to two 10 mg doses of immediate release d-MPH (Focalin) and was bioequivalent to 40 mg extended (bimodal) release d,l-MPH (Ritalin LA).
哌醋甲酯的右旋异构体（d-MPH）是哌醋甲酯消旋混合物（d，l-MPH）的药理活性部分，几十年来一直用于治疗注意力缺陷多动障碍（ADHD）。已开发出一种用于纯右旋对映体的双峰释放改良释放制剂（专注达缓释片），以实现快速起效和每日一次给药的持续活性。其目的是实现与服用两片速释专注达片后观察到的双峰浓度-时间曲线。在健康成年志愿者中，将这种d-MPH双峰释放制剂的药代动力学与d-MPH速释制剂以及d，l-MPH的类似双峰释放制剂进行了比较。
25名志愿者分别接受单剂量20mg的d-MPH双峰释放制剂、间隔4小时给予的两剂10mg的d-MPH速释制剂以及单剂量40mg的d，l-MPH双峰释放制剂（d：l对映体比例为1：1）。在这项三交叉研究中，各治疗之间的洗脱期为7天。
在测试剂量下，所有三种制剂耐受性良好。d-MPH双峰释放制剂产生两个不同的d-MPH血浆浓度峰值，峰值浓度和达峰时间与间隔4小时给予的d-MPH速释制剂以及d，l-MPH双峰释放制剂相似。三种制剂的Cmax和AUC0-∞值分别为：双峰释放d-MPH为15.5±4.3ng/ml和119±41ng·h/ml，速释d-MPH为17.9±5.3ng/ml和115±40ng·h/ml，d，l-MPH双峰释放为16.4±4.4ng/ml和122±36ng·h/ml。
总之，20mg的d-MPH缓释（双峰）制剂（专注达缓释片）呈现出双峰浓度-时间曲线，与两剂10mg的d-MPH速释制剂（专注达）生物等效，且与40mg的d，l-MPH缓释（双峰）制剂（利他林长效片）生物等效。
