Derakhchan Katayoun, Lou Zhen, Wang Hong, Baughman Robert
Takeda Development Center Americas, Inc., Cambridge, MA, USA.
Takeda Development Center Americas, Inc., Lexington, MA, USA.
Drugs Context. 2023 Feb 27;12. doi: 10.7573/dic.2022-6-1. eCollection 2023.
Prucalopride is a selective serotonin type 4 (5-HT) receptor agonist indicated for treatment of chronic idiopathic constipation (CIC) in adults (2 mg orally, daily). 5-HT receptors are present in the central nervous system; therefore, non-clinical and clinical assessments were performed to evaluate the tissue distribution and abuse potential of prucalopride.
In vitro receptor-ligand binding studies were performed to assess the affinity of prucalopride (≤1 mM) for peptide receptors, ion channels, monoamine neurotransmitters and 5-HT receptors. The tissue distribution of C-prucalopride (5 mg base-equivalent/kg) was investigated in rats. Behavioural assessments in mice, rats and dogs after treatment with single or repeated (up to 24 months) subcutaneous or oral doses of prucalopride (0.02-640 mg/kg across species) were performed. Treatment-emergent adverse events possibly indicative of abuse potential during prucalopride CIC clinical trials were evaluated.
Prucalopride showed no appreciable affinity for the receptors and ion channels investigated; its affinity (at ≤100 μM) for other 5-HT receptors was 150-10,000 times lower than that for the 5-HT receptor. In rats, <0.1% of the administered dose was found in the brain and concentrations were below the limit of detection within 24 hours. At supratherapeutic doses (≥20 mg/kg), mice and rats exhibited palpebral ptosis, and dogs exhibited salivation, eyelid tremors, decubitis, pedalling movements and sedation. All clinical treatment-emergent adverse events, possibly indicative of abuse potential, except dizziness, occurred in <1% of patients treated with prucalopride or placebo.
This series of non-clinical and clinical studies suggest low abuse potential for prucalopride.
普芦卡必利是一种选择性5-羟色胺4（5-HT）受体激动剂，适用于治疗成人慢性特发性便秘（CIC）（口服，每日2毫克）。5-HT受体存在于中枢神经系统；因此，进行了非临床和临床评估以评估普芦卡必利的组织分布和滥用可能性。
进行体外受体-配体结合研究，以评估普芦卡必利（≤1毫摩尔）对肽受体、离子通道、单胺神经递质和5-HT受体的亲和力。在大鼠中研究了C-普芦卡必利（5毫克碱当量/千克）的组织分布。在用单次或重复（长达24个月）皮下或口服剂量的普芦卡必利（跨物种0.02 - 640毫克/千克）治疗后，对小鼠、大鼠和狗进行行为评估。评估了普芦卡必利CIC临床试验期间可能表明存在滥用可能性的治疗中出现的不良事件。
普芦卡必利对所研究的受体和离子通道没有明显亲和力；其对其他5-HT受体的亲和力（≤100微摩尔时）比对5-HT受体的亲和力低150 - 10000倍。在大鼠中，给药剂量的<0.1%在脑中被发现，且浓度在24小时内低于检测限。在超治疗剂量（≥20毫克/千克）时，小鼠和大鼠出现眼睑下垂，狗出现流涎、眼睑震颤、卧姿、蹬踏板动作和镇静。除头晕外，所有可能表明存在滥用可能性的临床治疗中出现的不良事件在接受普芦卡必利或安慰剂治疗的患者中发生率<1%。
这一系列非临床和临床研究表明普芦卡必利的滥用可能性较低。
