Andreas Cord J, Pepin Xavier, Markopoulos Constantinos, Vertzoni Maria, Reppas Christos, Dressman Jennifer B
Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max von Laue St. 9, 60438 Frankfurt am Main, Germany.
AstraZeneca, Pharmaceutical Technology & Development, Silk Road Business Park, Charter Way, Macclesfield SK10 2NA, United Kingdom.
Eur J Pharm Sci. 2017 May 1;102:284-298. doi: 10.1016/j.ejps.2017.03.011. Epub 2017 Mar 10.
When administered orally as either an immediate or modified release dosage form, zolpidem demonstrates a negative food effect, i.e. decrease in C and AUC. The aim of the study was to arrive at a better understanding of the absorption of this BCS class I compound in vivo and to simulate the observed plasma profiles using in vitro and in silico methods.
Pharmacokinetic profiles of zolpidem are presented from a bioavailability (8mg intravenous; 10mg immediate release Stilnox®; 10mg and 12.5mg modified release Ambien® CR) and from a food effect study (12.5mg modified release Ambien® CR). The dissolution behavior of the 12.5mg strength was investigated using compendial methods in the USP apparatus II and using biorelevant methods in the USP apparatus III and IV. The mean plasma profiles as well as selected individual plasma profiles were simulated with Simcyp® and GastroPlus™. The absorption behavior was additionally investigated using the Q model, which entails algebraic deconvolution of all individual profiles, incorporating both first pass gut and liver extraction.
It was possible to simulate the mean plasma profiles using a "middle-out" approach, based on in vitro data combined with pharmacokinetic parameters obtained after intravenous administration, using PBPK software (Simcyp® and GastroPlus™), resulting in average fold error (AFE) values <1.5. Deconvolution verified that the in vivo absorption rate from the modified release formulation is controlled by the formulation in the fasted state, whereas in the fed state, the absorption rate is mainly controlled by gastric emptying. One-stage in vitro tests suggested that interactions with meal components, resulting in incomplete release, may be the source of the negative food effect for both the immediate and modified release formulations.
The present study demonstrated that a combination of biorelevant dissolution testing with modeling approaches enables a mechanistic understanding of the absorption of zolpidem from various formulations and can serve as a useful biopharmaceutical approach for the development of modified release solid oral dosage forms.
当以速释或缓释剂型口服给药时，唑吡坦表现出负性食物效应，即C和AUC降低。本研究的目的是更好地了解这种BCS I类化合物在体内的吸收情况，并使用体外和计算机模拟方法模拟观察到的血浆曲线。
给出了唑吡坦在生物利用度研究（8mg静脉注射；10mg速释Stilnox®；10mg和12.5mg缓释Ambien® CR）和食物效应研究（12.5mg缓释Ambien® CR）中的药代动力学曲线。使用美国药典装置II中的药典方法以及美国药典装置III和IV中的生物相关方法研究了12.5mg规格的溶出行为。使用Simcyp®和GastroPlus™模拟了平均血浆曲线以及选定的个体血浆曲线。还使用Q模型研究了吸收行为，该模型需要对所有个体曲线进行代数反卷积，同时考虑首过肠道和肝脏提取。
基于体外数据结合静脉给药后获得的药代动力学参数，使用PBPK软件（Simcyp®和GastroPlus™），采用“由中至外”方法能够模拟平均血浆曲线，平均误差倍数（AFE）值<1.5。反卷积验证了，在禁食状态下，缓释制剂的体内吸收速率受制剂控制，而在进食状态下，吸收速率主要受胃排空控制。单阶段体外试验表明，与膳食成分的相互作用导致释放不完全，可能是速释和缓释制剂负性食物效应的来源。
本研究表明，生物相关溶出度测试与建模方法相结合能够从机制上理解唑吡坦从各种制剂中的吸收情况，并且可作为开发固体口服缓释剂型的一种有用的生物药剂学方法。
