Abstract：
BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable.
METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study.
RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient\'s specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11).
CONCLUSIONS: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).
METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study.
RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient\'s specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11).
CONCLUSIONS: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).
摘要：
背景：高达1/2的门诊处方氯氮平可能是部分/完全非粘附性的，基于治疗药物监测(TDM)。提出了三个用于测量部分/完全不依从性的指标：1）氯氮平浓度/剂量（C/D）比下降到患者预期的一半或更多；2）氯氮平/去甲氯氮平比例倒置；3）氯氮平浓度变得不可检测。
方法：这3个建议的指标是基于文献综述和来自3个样本的17例可能的不依从：1）中国医院的住院研究，2)美国一家医院的住院随机临床试验，和3）和乌拉圭的门诊研究。
结果：不依从性的第一个指标是氯氮平C/D比率，该比率小于患者特定血统组和吸烟亚组的比率的一半。基于重复的TDM知道患者的最小治疗剂量使得更容易建立非依从性。第二个指标是在没有其他解释的情况下倒置的氯氮平/去甲氯氮平比率。第三个指标是检测不到的浓度。通过使用半衰期，对2例患者的3项不依从性指标的时间顺序进行了建模:1)氯氮平C/D比值下降至患者预期值的≥1/2(第2天左右);2)氯氮平/去甲氯氮平比值反转(第3天左右);3)实验室检测不到氯氮平浓度(第9~11天左右).
结论：前瞻性研究应进一步探讨普通患者的这些拟议的氯氮平指数，代谢不良者（3个）和超快速代谢者（2个）。
方法：这3个建议的指标是基于文献综述和来自3个样本的17例可能的不依从：1）中国医院的住院研究，2)美国一家医院的住院随机临床试验，和3）和乌拉圭的门诊研究。
结果：不依从性的第一个指标是氯氮平C/D比率，该比率小于患者特定血统组和吸烟亚组的比率的一半。基于重复的TDM知道患者的最小治疗剂量使得更容易建立非依从性。第二个指标是在没有其他解释的情况下倒置的氯氮平/去甲氯氮平比率。第三个指标是检测不到的浓度。通过使用半衰期，对2例患者的3项不依从性指标的时间顺序进行了建模:1)氯氮平C/D比值下降至患者预期值的≥1/2(第2天左右);2)氯氮平/去甲氯氮平比值反转(第3天左右);3)实验室检测不到氯氮平浓度(第9~11天左右).
结论：前瞻性研究应进一步探讨普通患者的这些拟议的氯氮平指数，代谢不良者（3个）和超快速代谢者（2个）。
