Donovan Maria D, Abduljalil Khaled, Cryan John F, Boylan Geraldine B, Griffin Brendan T
Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland.
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
Biopharm Drug Dispos. 2018 Mar;39(3):125-134. doi: 10.1002/bdd.2119. Epub 2018 Feb 22.
Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically-based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration-time curve, maximum concentration in plasma and time to maximum plasma concentration, within two-fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.
布美他尼是一种袢利尿剂，有人提出它对包括新生儿惊厥在内的中枢神经系统疾病具有有益作用。因此，从药理学角度来看，预测布美他尼在脑中的游离浓度具有重要意义。建立了一个基于生理学的药代动力学（PBPK）模型，用于预测布美他尼在成人和儿科人群血浆及脑中的处置情况。构建了一个包含布美他尼理化数据和体外数据的复合文件。使用Simcyp PBPK模型模拟了布美他尼在血浆和脑中的浓度曲线。将血浆布美他尼浓度的模拟结果与文献中公布的血浆水平进行了比较。在对儿科人群进行预测之前，用成人研究的数据验证了模型性能。成人和儿科静脉注射模型预测的药代动力学参数，即浓度-时间曲线下面积、血浆最大浓度和达到血浆最大浓度的时间，在观察值的两倍范围内。然而，新生儿静脉注射模型对血浆浓度的预测与观察值拟合不佳。本研究中使用的PBPK方法对布美他尼的血浆浓度做出了合理预测，但在危重新生儿人群中除外。该PBPK模型在进一步验证新生儿人群药物处置预测之前，需要更多关于代谢内在清除率和转运参数的信息。鉴于该特殊人群某些参数的信息不足，该模型不够稳健，无法支持推荐合适剂量的布美他尼作为新生儿辅助抗癫痫药物使用。
