Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
Br J Clin Pharmacol. 2010 Dec;70(6):815-24. doi: 10.1111/j.1365-2125.2010.03758.x.
The tolerance to the prolactin response following administration of antipsychotic drugs has been modelled as a depletion of a prolactin pool (pool model) and a model where the tolerance is explained by a feedback loop including the dopamine interaction of prolactin release (agonist-antagonist interaction model, (AAI model)). The AAI model was superior to the pool model when analyzing data from clinical trials of risperidone and paliperidone. Here we evaluated the two models using the remoxipride data, designed to challenge the short-term prolactin response, from which the original pool model was built.
The remoxipride data were collected from a study where eight healthy male subjects received two remoxipride infusions on five occasions. The intervals between the first and second dose on each occasion were 2, 8, 12, 24 and 48 h, respectively. The pool and AAI models were fitted using NONMEM.
According to the objective function values the pool model with a circadian rhythm function fitted the data slightly better, while the AAI model was better in describing the circadian rhythm of prolactin. Visual predictive checks revealed that the models predicted the prolactin profiles equally well.
According to the analysis performed here, a previous analysis of several clinical studies and literature reports on prolactin concentrations, it appears that the dopamine feedback mechanism included in the AAI model is better than the storage depletion mechanism in the pool model to estimate the bio-rhythm of prolactin time-course and the tolerance development across different populations, drugs, treatment schedules and time.
抗精神病药物给药后对催乳素反应的耐受性已被建模为催乳素池的耗竭（池模型）和一种通过包括催乳素释放的多巴胺相互作用的反馈环来解释耐受性的模型（激动剂-拮抗剂相互作用模型，（AAI 模型））。当分析利培酮和帕利哌酮临床试验的数据时，AAI 模型优于池模型。在这里，我们使用设计用于挑战短期催乳素反应的 remoxipride 数据（该数据来自原始池模型）来评估这两种模型。
从一项研究中收集 remoxipride 数据，该研究中，八名健康男性受试者在五次不同时间接受两次 remoxipride 输注。每次的第一剂和第二剂之间的间隔分别为 2、8、12、24 和 48 小时。使用 NONMEM 拟合池模型和 AAI 模型。
根据目标函数值，带有昼夜节律函数的池模型稍微更好地拟合数据，而 AAI 模型在描述催乳素的昼夜节律方面更好。视觉预测检查表明，这些模型同样很好地预测了催乳素曲线。
根据这里进行的分析、对催乳素浓度的几项临床研究和文献报告的先前分析，似乎 AAI 模型中包含的多巴胺反馈机制比池模型中的存储耗竭机制更好，用于估计催乳素时间过程的生物节律和不同人群、药物、治疗方案和时间的耐受性发展。
