Flip-flop Pharmacokinetics – Delivering a Reversal of Disposition: Challenges and Opportunities During Drug Development

作者：Jaime A. Yáñez, Connie M. Remsberg, Casey L. Sayre, Marcus Laird Forrest, Neal M. Davies · 发表于：Therapeutic Delivery · 年份：2011 · DOI：10.4155/tde.11.19 · 被引用次数：276 · 研究领域：Receptor Mechanisms and Signaling、Computational Drug Discovery Methods、Analytical Methods in Pharmaceuticals

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.