1] Department of Pharmaceutics, University of Washington, Seattle, Washington, USA [2] Department of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
CPT Pharmacometrics Syst Pharmacol. 2012 Sep 26;1(9):e3. doi: 10.1038/psp.2012.2.
Besides logistical and ethical concerns, evaluation of safety and efficacy of medications in pregnant women is complicated by marked changes in pharmacokinetics (PK) of drugs. For example, CYP3A activity is induced during the third trimester (T3). We explored whether a previously published physiologically based pharmacokinetic (PBPK) model could quantitatively predict PK profiles of CYP3A-metabolized drugs during T3, and discern the site of CYP3A induction (i.e., liver, intestine, or both). The model accounted for gestational age-dependent changes in maternal physiological function and hepatic CYP3A activity. For model verification, mean plasma area under the curve (AUC), peak plasma concentration (Cmax), and trough plasma concentration (Cmin) of midazolam (MDZ), nifedipine (NIF), and indinavir (IDV) were predicted and compared with published studies. The PBPK model successfully predicted MDZ, NIF, and IDV disposition during T3. A sensitivity analysis suggested that CYP3A induction in T3 is most likely hepatic and not intestinal. Our PBPK model is a useful tool to evaluate different dosing regimens during T3 for drugs cleared primarily via CYP3A metabolism.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e3; doi:10.1038/psp.2012.2; advance online publication 26 September 2012.
除了后勤和伦理方面的考虑外，评估孕妇用药的安全性和疗效还因药物药代动力学（PK）的显著变化而变得复杂。例如，CYP3A 活性在妊娠晚期（T3）期间被诱导。我们探讨了之前发表的基于生理学的药代动力学（PBPK）模型是否可以定量预测 T3 期间 CYP3A 代谢药物的 PK 曲线，并辨别 CYP3A 诱导的部位（即肝脏、肠道或两者兼有）。该模型考虑了母体生理功能和肝 CYP3A 活性随妊娠年龄的变化。为了模型验证，预测并比较了咪达唑仑（MDZ）、硝苯地平（NIF）和茚地那韦（IDV）的平均血浆曲线下面积（AUC）、血浆峰浓度（Cmax）和血浆谷浓度（Cmin），并与已发表的研究进行了比较。PBPK 模型成功预测了 T3 期间 MDZ、NIF 和 IDV 的处置。敏感性分析表明，T3 期间 CYP3A 的诱导最有可能是肝脏而非肠道。我们的 PBPK 模型是评估 T3 期间主要通过 CYP3A 代谢清除的药物的不同给药方案的有用工具。CPT：药物代谢动力学与系统药理学（2012 年）1，e3；doi:10.1038/psp.2012.2；2012 年 9 月 26 日在线提前发布。
