Division of Therapies and Medical Consequences, National Institute on Drug Abuse, Rockville, Maryland, USA.
Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, USA.
Clin Pharmacol Ther. 2020 Dec;108(6):1203-1212. doi: 10.1002/cpt.1929. Epub 2020 Jul 11.
Adherence monitoring is a vital component of clinical efficacy trials, as the regularity of medication consumption affects both efficacy and adverse effect profiles. Pill-counts do not confirm consumption, and invasive plasma assessments can only assist post hoc assessments. We previously reported on the pharmacokinetics of a potential adherence marker to noninvasively monitor dosage consumption during a trial without breaking a blind. We reported that consumption cessation of subtherapeutic 15 mg acetazolamide (ACZ) doses showed a predictable urinary excretion decay that was quantifiable for an extended period. The current study describes the clinical implementation of 15 mg ACZ doses as an adherence marker excipient in distinct cohorts taking ACZ for different "adherence" durations. We confirm that ACZ output did not change (accumulate) during 18-20 days of adherence, and developed and assessed urinary cutoffs as nonadherence indicators. We demonstrate that whereas an absolute concentration cutoff (989 ng/mL) lacked sensitivity, a creatinine normalized equivalent (1,376 ng/mg ACZ) was highly accurate at detecting nonadherence. We also demonstrate that during nonadherent phases of three trials, creatinine-normalized urinary ACZ elimination was reproducible within and across trials with low variability. Excretion was first order, with a decay half-life averaging ~ 2.0 days. Further, excretion remained quantifiable for 14 days, providing a long period during which the date of last consumption might be determined. We conclude that inclusion of 15 mg ACZ as a dosage form adherence marker excipient, provides a reliable and sensitive mechanism to confirm medication consumption and detect nonadherence during clinical efficacy trials.
依从性监测是临床疗效试验的一个重要组成部分，因为药物的使用频率会影响疗效和不良反应的发生。仅凭药片计数无法确认药物的使用情况，而侵入性的血浆评估也只能在事后进行。我们之前曾报道过一种潜在的依从性标志物的药代动力学，该标志物可以在不破坏盲法的情况下，对试验期间的剂量使用进行非侵入性监测。我们曾报道过，停止使用低于治疗剂量（15 毫克乙酰唑胺，ACZ）时，尿液中药物的排泄呈现出可预测的衰减，且可在较长时间内进行定量检测。本研究描述了将 15 毫克 ACZ 剂量作为依从性标志物赋形剂在不同队列中的临床应用，这些队列中的患者因不同的“依从性”持续时间而服用 ACZ。我们确认，在 18-20 天的依从性期间，ACZ 的排泄量（累积量）没有变化，并开发和评估了尿液截止值作为非依从性的指标。我们证明，绝对浓度截止值（989ng/mL）缺乏敏感性，而肌酐归一化等效值（1376ng/mg ACZ）则可以高度准确地检测出非依从性。我们还证明，在三个试验的非依从性阶段，肌酐归一化的尿液 ACZ 消除在试验内和试验间具有可重复性，且变异性较低。排泄呈一级动力学，半衰期平均约为 2.0 天。此外，排泄在 14 天内仍可定量检测，为确定最后一次用药的日期提供了较长的时间。我们得出结论，将 15 毫克 ACZ 作为剂型依从性标志物赋形剂，为在临床疗效试验中确认药物使用情况和检测不依从性提供了一种可靠和敏感的机制。
