Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Lawrenceville, NJ, USA;
Neuropsychiatr Dis Treat. 2011;7:117-25. doi: 10.2147/NDT.S15921. Epub 2011 Mar 17.
Nonadherence is very common among subjects undergoing pharmacotherapy for schizophrenia and depression. This study aimed to evaluate the performance of the ratio of the nonlinear mixed effects pharmacokinetic model predicted concentration to observed drug concentration (ratio of population predicted to observed concentration (Cpred/Cobs) and ratio of individual predicted to observed concentration (Cipred/Cobs) as a measure of erratic drug exposure, driven primarily by variable execution of the dosage regimen and unknown true dosage history.
Modeling and simulation approaches in conjunction with dosage history information from the Medication Event Monitoring System (MEMS, provided by the "Depression: The search for treatment relevant phenotypes" study), was applied to evaluate the consistency of exposure via simulation studies with scenarios representing a long half-life drug (escitalopram). Adherence rates were calculated based on the percentage of the prescribed doses actually taken correctly during the treatment window of interest. The association between Cpred/Cobs, Cipred/Cobs ratio, and adherence rate was evaluated under various assumptions of known dosing history.
Simulations for those scenarios representing a known dosing history were generated from historical MEMS data. Simulations of a long half-life drug exhibited a trend for overprediction of concentrations in patients with a low percentage of doses taken and underprediction of concentrations in patients taking more than their prescribed number of doses. Overall, the ratios did not predict adherence well, except when the true adherence rates were extremely high (greater than 100% of prescribed doses) or extremely low (complete nonadherence). In general, the Cipred/Cobs ratio was a better predictor of adherence rate than the Cpred/Cobs ratio. Correct predictions of extreme (high, low) 7-day adherence rates using Cipred/Cobs were 73.8% and 64.0%.
This simulation study demonstrated the limitations of the Cpred/obs and Cipred/obs ratios as metrics for actual dosage intake history, and identified that use of MEMS dosing history monitoring combined with sparse pharmacokinetic sampling is a more reliable approach.
在接受精神分裂症和抑郁症药物治疗的受试者中，不依从的情况非常普遍。本研究旨在评估非线性混合效应药代动力学模型预测浓度与观察药物浓度之比（群体预测与观察浓度之比（Cpred/Cobs）和个体预测与观察浓度之比（Cipred/Cobs）作为衡量药物暴露不规则性的指标，主要由剂量方案的可变执行和未知真实剂量史驱动。
结合用药事件监测系统（MEMS）提供的剂量史信息（来自“抑郁：寻找与治疗相关的表型”研究），应用建模和模拟方法，评估通过模拟研究评估暴露的一致性，这些模拟研究代表了一种长半衰期药物（依地普仑）。根据治疗窗内实际正确服用的处方剂量百分比计算依从率。在不同已知剂量史假设下，评估 Cpred/Cobs、Cipred/Cobs 比值与依从率之间的关系。
那些代表已知剂量史的情景的模拟是从历史 MEMS 数据中生成的。对于长半衰期药物的模拟显示，在服用剂量百分比低的患者中存在浓度过高的趋势，在服用超过规定剂量的患者中存在浓度过低的趋势。总体而言，这些比值不能很好地预测依从率，除非真实依从率非常高（超过规定剂量的 100%）或非常低（完全不依从）。一般来说，Cipred/Cobs 比值比 Cpred/Cobs 比值更能预测依从率。使用 Cipred/Cobs 对极端（高、低）7 天依从率的正确预测率分别为 73.8%和 64.0%。
这项模拟研究表明，Cpred/obs 和 Cipred/obs 比值作为实际剂量摄入史的指标存在局限性，并确定使用 MEMS 剂量史监测结合稀疏药代动力学采样是一种更可靠的方法。
