ter Laak Maureen A, Roos Carolien, Touw Daan J, van Hattum Paul R M, Kwee Anneke, Lotgering Frederik K, Mol Ben Willem J, van Pampus Mariëlle G, Porath Martina M, Spaanderman Marc E A, van der Post Joris A M, Papatsonis Dimitri N M, van 't Veer Nils E
Int J Clin Pharmacol Ther. 2015 Jan;53(1):84-91. doi: 10.5414/CP202215.
The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature.
This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days.
Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level.
The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power.
Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.
硝苯地平作为一种宫缩抑制剂，其在孕妇中的药代动力学尚未得到详细研究，以往研究主要集中在速释片和胃肠道治疗系统（GITS）片上。本研究的目的是确定硝苯地平在孕妇中的缓释半衰期和分布容积，并将其与文献中描述的非孕妇硝苯地平的药代动力学参数进行比较。
本研究与一项针对26 + 0至32 + 2周初产妇接受宫缩抑制和完整疗程皮质类固醇治疗后有早产风险的女性的试验平行，这些女性被随机分配接受维持剂量的硝苯地平（缓释片20 mg，每日4次）或安慰剂。药代动力学研究的排除标准为硝苯地平禁忌证、肝功能损害以及同时服用细胞色素P450 3A4同工酶抑制剂或诱导剂。在t = 0、t = 12小时、t = 24小时、t = 48小时、t = 72小时、t = 7天和t = 9天采集血样以测定硝苯地平血浆浓度。
使用MWPharm©软件通过迭代两阶段贝叶斯群体药代动力学分析估算药代动力学参数。本研究旨在建立体重与硝苯地平血浆水平之间的相关性。
从8名孕妇的数据中确定了硝苯地平缓释片的药代动力学参数。硝苯地平缓释的半衰期为2 - 5小时，平均分布容积为6.2 ± 1.9 L/kg（由于该人群缺乏静脉注射数据，使用文献中固定的生物利用度0.45计算得出），而文献中描述的非孕妇半衰期为6 - 11小时，分布容积为1.2 - 1.3 L/kg。在研究用药期间，没有女性分娩。所有女性在药代动力学研究期间（9天）持续用药。未证明硝苯地平血浆水平与母体体重之间存在相关性。这可能是由于样本量不足所致。
本研究中使用硝苯地平缓释片的孕妇与文献中报道的非孕妇相比，分布容积更大，消除半衰期更短。
