Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Clin Pharmacokinet. 2019 Oct;58(10):1221-1236. doi: 10.1007/s40262-019-00769-x.
Phase 0 microdose trials are exploratory studies to early assess human pharmacokinetics of new chemical entities, while limiting drug exposure and risks for participants. The microdose concept is based on the assumption that microdose pharmacokinetics can be extrapolated to pharmacokinetics of a therapeutic dose. However, it is unknown whether microdose pharmacokinetics are actually indicative of the pharmacokinetics at therapeutic dose. The aim of this review is to investigate the predictive value of microdose pharmacokinetics and to identify drug characteristics that may influence the scalability of these parameters. The predictive value of microdose pharmacokinetics was determined for 46 compounds and showed adequate predictability for 28 of 41 orally administered drugs (68%) and 15 of 16 intravenously administered drugs (94%). Microdose pharmacokinetics were considered predictive if the mean observed values of the microdose and the therapeutic dose were within twofold. Nonlinearity may be caused by saturation of enzyme and transporter systems, such as intestinal and hepatic efflux and uptake transporters. The high degree of success regarding linear pharmacokinetics shows that phase 0 microdose trials can be used as an early human model for determination of drug pharmacokinetics.
零期微剂量试验是探索性研究，旨在早期评估新化学实体在人体中的药代动力学，同时限制参与者的药物暴露和风险。微剂量概念基于这样一种假设，即微剂量药代动力学可以外推到治疗剂量的药代动力学。然而，尚不清楚微剂量药代动力学实际上是否能反映治疗剂量时的药代动力学。本综述旨在探讨微剂量药代动力学的预测价值，并确定可能影响这些参数可扩展性的药物特征。对 46 种化合物进行了微剂量药代动力学的预测价值研究，结果显示，41 种口服药物中有 28 种（68%）和 16 种静脉内给药药物中有 15 种（94%）具有足够的预测性。如果微剂量和治疗剂量的平均观察值在两倍以内，则认为微剂量药代动力学具有预测性。非线性可能是由于酶和转运体系统（如肠和肝外排和摄取转运体）饱和引起的。关于线性药代动力学的高度成功表明，零期微剂量试验可以作为早期人体模型，用于确定药物药代动力学。
