Wiss Florine M, Allemann Samuel S, Meyer Zu Schwabedissen Henriette E, Stäuble Céline K, Mikoteit Thorsten, Lampert Markus L
Pharmaceutical Care, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Institute of Hospital Pharmacy, Solothurner Spitäler, Olten, Switzerland.
Front Psychiatry. 2024 Apr 29;15:1397876. doi: 10.3389/fpsyt.2024.1397876. eCollection 2024.
Suspected adverse drug reactions (ADRs) during treatment with clozapine often prompt therapeutic drug monitoring (TDM) in clinical practice. Currently, there is no official recommendation for pharmacogenetic (PGx) testing in the context of clozapine therapy. In this case report, we demonstrate and discuss the challenges of interpreting PGx and TDM results highlighting the possibilities and limitations of both analytical methods. A 36-year-old male patient with catatonic schizophrenia was treated with clozapine. He experienced multiple hospitalizations due to elevated creatine kinase (CK) levels (up to 9000 U/L, reference range: 30-200 U/L). With no other medical explanation found, physicians suspected clozapine-induced ADRs. However, plasma levels of clozapine were consistently low or subtherapeutic upon admission, prompting us to conduct a PGx analysis and retrospectively review the patient's TDM data, progress notes, and discharge reports. We investigated two possible hypotheses to explain the symptoms despite low clozapine plasma levels: suggested the formation and accumulation of a reactive intermediate metabolite due to increased activity in cytochrome P450 3A5 and reduced activity in glutathione S-transferases 1, leading to myotoxicity. proposed under-treatment with clozapine, resulting in ineffective clozapine levels, leading to a rebound effect with increased catatonic symptoms and CK levels. After considering both data sources (PGx and TDM), hypothesis ii. appeared more plausible. By comprehensively assessing all available TDM measurements and examining them in temporal correlation with the drug dose and clinical symptoms, we observed that CK levels normalized when clozapine plasma levels were raised to the therapeutic range. This was achieved through hospitalization and closely monitored clozapine intake. Therefore, we concluded that the symptoms were not an ADR due to altered clozapine metabolism but rather the result of under-treatment. Interpreting TDM and PGx results requires caution. Relying solely on isolated PGx or single TDM values can result in misinterpretation of drug reactions. We recommend considering the comprehensive patient history, including treatment, dosages, laboratory values, clinic visits, and medication adherence.
在临床实践中，使用氯氮平治疗期间疑似药物不良反应（ADR）常常促使进行治疗药物监测（TDM）。目前，在氯氮平治疗背景下，尚无关于药物遗传学（PGx）检测的官方建议。在本病例报告中，我们展示并讨论了解释PGx和TDM结果时面临的挑战，突出了这两种分析方法的可能性和局限性。一名36岁患有紧张型精神分裂症的男性患者接受氯氮平治疗。他因肌酸激酶（CK）水平升高（高达9000 U/L，参考范围：30 - 200 U/L）多次住院。由于未发现其他医学解释，医生怀疑是氯氮平引起的ADR。然而，入院时氯氮平血浆水平一直较低或未达到治疗浓度，这促使我们进行PGx分析，并回顾性审查患者的TDM数据、病程记录和出院报告。我们研究了两个可能的假设来解释尽管氯氮平血浆水平较低但仍出现症状的情况：假设一表明由于细胞色素P450 3A5活性增加和谷胱甘肽S - 转移酶1活性降低，导致反应性中间代谢产物的形成和积累，从而引起肌毒性。假设二提出氯氮平治疗不足，导致氯氮平水平无效，进而引发紧张症状和CK水平升高的反弹效应。在综合考虑两种数据来源（PGx和TDM）后，假设二更具合理性。通过全面评估所有可用TDM测量值，并检查它们与药物剂量和临床症状的时间相关性，我们观察到当氯氮平血浆水平升至治疗范围时，CK水平恢复正常。这是通过住院治疗并密切监测氯氮平摄入量实现的。因此，我们得出结论，这些症状并非由于氯氮平代谢改变引起的ADR，而是治疗不足的结果。解释TDM和PGx结果需要谨慎。仅依赖孤立的PGx或单一TDM值可能会导致对药物反应的错误解读。我们建议考虑患者的全面病史，包括治疗情况、剂量、实验室值、门诊就诊和用药依从性。
