Knights Jonathan, Rohatagi Shashank
Otsuka Pharmaceutical Development & Commercialization, Inc., 508 Carnegie Center Blvd. Suite 300, Princeton, NJ, 08540, USA,
J Pharmacokinet Pharmacodyn. 2015 Jun;42(3):263-73. doi: 10.1007/s10928-015-9414-4. Epub 2015 Mar 29.
Nonadherence to prescribed medication is a common barrier to effective treatment, and current options to determine adherence are limited. This study describes development of an aggregate adherence measure based on population pharmacokinetics (PK), and its comparison to a subjective questionnaire, the Morisky 8-item medication adherence scale (MMAS8), in a trial of psychiatric patients on stable doses of oral aripiprazole. A comprehensive model was first built using plasma drug concentration data from 24 clinical studies comprising 448 patients with over 13,500 observations. Application of this model to independent patient profiles for a given drug-dosing regimen were used to generate the primary aggregate adherence metric, a ratio of observed versus expected plasma exposures at steady-state. Although the metric is capable of comparing relative adherence across groups, simulations showed that the metric is not sufficiently sensitive as an individual diagnostic in all cases. There were no trends observed between results from calculated aggregate adherence metrics and total scores from MMAS8 in a single-visit clinical trial of 47 patients with bipolar 1 disorder or schizophrenia who were on stable doses of aripiprazole, although a strong association was observed for one MMAS8 question. The range of the metric calculated for patients was between 0.16 and 3.15. The described approach of a novel "reverse" application of population PK to quantify relative adherence with an aggregate measure may be influential for both clinical and pharmacometric communities.
不遵医嘱服药是有效治疗的常见障碍，目前用于确定依从性的方法有限。本研究描述了一种基于群体药代动力学（PK）的总体依从性测量方法的开发，并在一项针对稳定剂量口服阿立哌唑的精神病患者的试验中，将其与主观问卷——Morisky 8项药物依从性量表（MMAS8）进行比较。首先，利用来自24项临床研究的血浆药物浓度数据建立了一个综合模型，这些研究包括448名患者，有超过13500次观察。将该模型应用于给定药物给药方案的独立患者资料，以生成主要的总体依从性指标，即稳态下观察到的与预期的血浆暴露量之比。尽管该指标能够比较不同组之间的相对依从性，但模拟结果表明，在所有情况下，该指标作为个体诊断方法的敏感性都不够高。在一项对47名患有双相I型障碍或精神分裂症且服用稳定剂量阿立哌唑的患者进行的单次访视临床试验中，计算出的总体依从性指标结果与MMAS8的总分之间未观察到趋势，尽管在一个MMAS8问题上观察到了强相关性。患者计算出的该指标范围在0.16至3.15之间。所描述的将群体PK进行新颖的“反向”应用以通过总体测量来量化相对依从性的方法，可能对临床和药代计量学界都有影响。
