Flip-flop pharmacokinetics--delivering a reversal of disposition: challenges and opportunities during drug development.
Flip-flop pharmacokinetics--delivering a reversal of disposition: challenges and opportunities during drug development.
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DOI：
10.4155/tde.11.19
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发表时间：
2011-05
影响因子：
4.2
通讯作者：
Davies NM
中科院分区：
文献类型：
--
作者：
Yáñez JA;Remsberg CM;Sayre CL;Forrest ML;Davies NM
药物动力学的突变是血管外给药经常遇到的现象。触发器的发生跨越临床前至人体研究。这篇文章的目的是分析药物开发过程中存在的触发器药代动力学的药代动力学解释错误和机会。当吸收的速度比消除的速度慢时，就会发生翻转。如果不能识别，可能会给药代动力学参数的获取和解释带来困难。当预期或发现触发器时，可能需要更长的采样持续时间，以避免过高估计吸收剂量的分数。触发式处置的常见罪魁祸首是修改剂量制剂;然而，药物化学实体本身或掺入的辅料等制剂特征也可能导致这种现象。另一个影响因素是血管外给药部位的生理构成。在这篇文章中，这些触发器的药代动力学的原因进行了讨论，结合相关的例子和药物开发概述的影响。
Flip-flop pharmacokinetics is a phenomenon often encountered with extravascularly administered drugs. Occurrence of flip-flop spans preclinical to human studies. The purpose of this article is to analyze both the pharmacokinetic interpretation errors and opportunities underlying the presence of flip-flop pharmacokinetics during drug development. Flip-flop occurs when the rate of absorption is slower than the rate of elimination. If it is not recognized, it can create difficulties in the acquisition and interpretation of pharmacokinetic parameters. When flip-flop is expected or discovered, a longer duration of sampling may be necessary in order to avoid overestimation of fraction of dose absorbed. Common culprits of flip-flop disposition are modified dosage formulations; however, formulation characteristics such as the drug chemical entities themselves or the incorporated excipients can also cause the phenomenon. Yet another contributing factor is the physiological makeup of the extravascular site of administration. In this article, these causes of flip-flop pharmacokinetics are discussed with incorporation of relevant examples and the implications for drug development outlined.