游离药物浓度通常被认为是药理学活性部分,并且对于细胞扩散和分布是重要的。妊娠相关的血浆蛋白结合和血液分配的变化是由于血浆白蛋白的减少,α-1-酸糖蛋白,和血细胞比容;这可能导致游离浓度增加,组织分布,和怀孕期间的间隙。在本文中,我们强调了考虑怀孕期间总浓度和游离浓度变化的重要性和挑战。对于与血浆蛋白高度结合的药物,比如他克莫司,efavirenz,克林霉素,苯妥英,和卡马西平,妊娠期游离药物浓度的差异变化可能具有临床意义,对剂量调整具有重要意义.治疗药物监测通常依赖于总浓度的测量;这可能导致在考虑游离浓度变化时不必要的剂量调整。我们探索了基于生理的药代动力学(PBPK)模型的潜力,以支持对血浆蛋白结合变化的理解,使用他克莫司和依非韦伦作为示例药物模型。预计怀孕期间对任何一种药物的暴露都会减少;然而,总他克莫司和依法韦仑暴露量的减少显著大于游离药物暴露量的减少.这些数据表明,PBPK建模可以支持血浆蛋白结合变化的影响,并且可以用于模拟妊娠中的游离浓度以支持给药决定。
Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions.