Patel Harilal, Patel Prakash, Modi Nirav, Patel Pinakin, Wagh Yogesh, George Alex, Desai Nirmal, Srinivas Nuggehally R
a Bioanalytical/Drug Metabolism and Pharmacokinetics Laboratory , Zydus Research Centre , Ahmedabad , India.
b Department of Chemistry , St Xavier's College (Autonomous) , Ahmedabad , India.
Xenobiotica. 2019 Apr;49(4):415-421. doi: 10.1080/00498254.2018.1464683. Epub 2018 May 8.
Development of prodrug of 9-hydroxyrisperidone (paliperidone) long-acting intramuscular injection has enabled delivery over four-week time period with improved compliance. The key aim of this work was to establish a reliable preclinical model which may potentially serve as a screening tool for judging the pharmacokinetics of paliperidone formulation(s) prior to human clinical work. Sparse sampling composite study was used in rats, (Wistar/Sprague-Dawley (SD; n = 10)) and a serial blood sampling study design was used in rabbits (n = 4). Animals received intramuscular injection of paliperidone palmitate in the thigh muscle at dose of 16 (rats) and 4.5 mg/kg (rabbits). Samples were drawn in rats (retro-orbital sinus) and rabbits (central ear artery) and were analysed for paliperidone using liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS) assay. The plasma data was subjected to pharmacokinetic analysis. Following intramuscular injection of depot formulation in Wistar/SD rats and rabbits, absorption of paliperidone was slow and gradual with median value of time to reach maximum concentration (T) occurring on day 7. The exposures (i.e. area under the curve (AUC; 0-28) days) were 18,597, 21,865 and 18,120 ng.h/mL, in Wistar, SD and rabbits, respectively. The clearance was slow and supported long half-life (8-10 days). Either one of the two models can serve as a research tool for establishing pharmacokinetics of paliperidone formulation(s).
9-羟基利培酮（帕利哌酮）长效肌肉注射前体药物的研发使得药物能够在四周的时间内持续释放，从而提高了患者的依从性。这项工作的主要目的是建立一个可靠的临床前模型，该模型有可能作为一种筛选工具，用于在人体临床研究之前判断帕利哌酮制剂的药代动力学。在大鼠（Wistar/Sprague-Dawley（SD；n = 10））中采用稀疏采样综合研究，在兔子（n = 4）中采用连续采血研究设计。动物在大腿肌肉中接受16mg/kg（大鼠）和4.5mg/kg（兔子）剂量的帕利哌酮棕榈酸酯肌肉注射。在大鼠（眶后窦）和兔子（中耳动脉）中采集样本，并使用液相色谱-质谱/质谱（LC-MS/MS）分析法分析帕利哌酮。对血浆数据进行药代动力学分析。在Wistar/SD大鼠和兔子中肌肉注射长效制剂后，帕利哌酮的吸收缓慢且逐渐进行，达到最大浓度（T）的时间中位数出现在第7天。在Wistar、SD大鼠和兔子中，暴露量（即曲线下面积（AUC；0 - 28天））分别为18597、21865和18120 ng·h/mL。清除缓慢，支持较长的半衰期（8 - 10天）。这两种模型中的任何一种都可以作为建立帕利哌酮制剂药代动力学的研究工具。
