Division of Psychiatry, University College London, UK.
Institute of Genetics, University College London, UK; and UMR 1137 Infection, Antimicrobials, Modelling, Evolution (IAME) French Institute for Medical Research (INSERM), University Paris, France.
Br J Psychiatry. 2021 May;218(5):268-275. doi: 10.1192/bjp.2020.225.
In the treatment of psychosis, agitation and aggression in Alzheimer's disease, guidelines emphasise the need to 'use the lowest possible dose' of antipsychotic drugs, but provide no information on optimal dosing.
This analysis investigated the pharmacokinetic profiles of risperidone and 9-hydroxy (OH)-risperidone, and how these related to treatment-emergent extrapyramidal side-effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease study (Clinicaltrials.gov identifier: NCT00015548).
A statistical model, which described the concentration-time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and 'active moiety' (combined concentrations) (n = 108 participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model-based predictions were used to simulate the dose adjustments needed to avoid EPS.
The model showed an age-related reduction in risperidone clearance (P < 0.0001), reduced renal elimination of 9-OH-risperidone (elimination half-life 27 h), and slower active moiety clearance in 22% of patients, (concentration-to-dose ratio: 20.2 (s.d. = 7.2) v. 7.6 (s.d. = 4.9) ng/mL per mg/day, Mann-Whitney U-test, P < 0.0001). Higher trough 9-OH-risperidone and active moiety concentrations (P < 0.0001) and lower Mini-Mental State Examination (MMSE) scores (P < 0.0001), were associated with EPS. Model-based predictions suggest the optimum dose ranged from 0.25 mg/day (85 years, MMSE of 5), to 1 mg/day (75 years, MMSE of 15), with alternate day dosing required for those with slower drug clearance.
Our findings argue for age- and MMSE-related dose adjustments and suggest that a single measure of the concentration-to-dose ratio could be used to identify those with slower drug clearance.
在治疗阿尔茨海默病患者的精神病、激越和攻击行为时，指南强调需要“使用尽可能低的剂量”的抗精神病药物，但并未提供关于最佳剂量的信息。
本分析使用来自临床抗精神病药物治疗阿尔茨海默病的干预效果试验（Clinicaltrials.gov 标识符：NCT00015548）的数据，研究了利培酮和 9-羟基（OH）-利培酮的药代动力学特征，以及这些特征与治疗中出现的锥体外系副作用（EPS）的关系。
使用描述利培酮和 9-OH-利培酮浓度-时间曲线的统计模型，预测利培酮、9-OH-利培酮和“活性部分”（组合浓度）的峰值、谷值和平均浓度（n = 108 名参与者）。使用逻辑回归研究药代动力学生物标志物与 EPS 的关系。使用基于模型的预测来模拟避免 EPS 所需的剂量调整。
该模型显示，利培酮清除率随年龄增长而降低（P < 0.0001），9-OH-利培酮的肾清除减少（消除半衰期 27 小时），22%的患者活性部分清除率较慢（浓度-剂量比：20.2（s.d. = 7.2）v. 7.6（s.d. = 4.9）ng/mL per mg/day，Mann-Whitney U 检验，P < 0.0001）。较低的谷值 9-OH-利培酮和活性部分浓度（P < 0.0001）和较低的简易精神状态检查（MMSE）评分（P < 0.0001）与 EPS 相关。基于模型的预测表明，最佳剂量范围为 0.25 毫克/天（85 岁，MMSE 为 5）至 1 毫克/天（75 岁，MMSE 为 15），对于清除药物较慢的患者需要隔日给药。
我们的研究结果表明需要根据年龄和 MMSE 进行剂量调整，并表明单一的浓度-剂量比测量值可用于识别清除药物较慢的患者。
