使用强效细胞色素 P450 诱导剂对超治疗浓度的降钙素抑制剂进行修复治疗

Seth Duwor, Katharina Enthofer, Christoph Ganter, Prabin Poudel, Anna Svarin, Gerd A. Kullak-Ublick
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引用次数: 0

摘要

简介钙神经蛋白抑制剂(CNIs)、环孢素和他克莫司主要用于器官移植和治疗自身免疫性疾病。由于患者长期依赖这些药物,他们面临着潜在的中毒风险。如果患者用药过量或无意中接触到细胞色素 P450 (CYP) 3A4 抑制剂,这种风险就会大大增加。目标:利用世界卫生组织全球药物警戒数据库 (VigiBase™) 中的实际数据和已发表数据中的支持性证据,分析 CYP 诱导剂作为急性 CNI 中毒的一种合理治疗方式的效用。研究方法:我们研究了 VigiBase™ 中登记的所有有关 CNI 中毒的个体病例安全报告 (ICSR)。针对活性成分 "环孢素 "和 "他克莫司 "使用了 "药物过量 "或 "药物中毒 "查询。关于 CYP 诱导剂的作用,我们进行了广泛的文献分析。我们还报告了一例指标性临床病例:一名 60 岁的肝移植患者在单次静脉注射氟康唑后出现了严重的他克莫司中毒,并伴有多器官功能障碍,其峰值浓度为 33.1 μg/L。研究结果自 1992 年以来,在 VigiBase™ 中报告的 143,710 例有记录的 ICSR 中,分别有 0.26% 和 0.02% 登记为 CNI 过量和中毒。CNI 中毒的主要病因是与 CYP 3A4 抑制剂的相互作用(40.0%,病例报告:50.0%)。最常报告的表现是急性肾损伤(36.7%,病例报告:46.3%)。共有 16.7% 的中毒病例在停药或减量后导致了致命的后果;然而,在 43.0% 的病例中,所采取的具体措施未得到报告。在同行评议报告中,有 34 例不同的临床病例使用了 CYP 诱导剂。其中描述了使用苯巴比妥(5)、苯妥英(23)和利福平(6)的不同药物增强策略,达到治疗目标的平均时间分别为 2.7(±0.7)天、3.1(±0.5)天和 4.6(±1.0)天。在指标病例中,使用利福平 3 天后,治疗浓度达到 4.9 [4-6 μg/L]。结论除一般支持治疗外,使用苯巴比妥、苯妥英或利福平逆转急性 CNI 中毒也是一种可行的治疗方法。苯巴比妥的半衰期相对较长,而且只能通过肾脏排出,这些都是需要考虑的潜在隐患。尽管利福平具有良好的药代动力学优势,但对于有明显神经毒性的患者来说,苯妥英具有无可争议的竞争性药效学优势。
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Rescue Therapy for Supratherapeutic Concentrations of Calcineurin Inhibitors Using Potent Cytochrome P450 Inducers
Introduction: Calcineurin inhibitors (CNIs), ciclosporin and tacrolimus, are utilized primarily in organ transplantation and the treatment of autoimmune diseases. Since patients depend on these drugs over long periods, they face a potential risk of intoxication. This risk increases substantially when patients are overdosed or inadvertently exposed to cytochrome P450 (CYP) 3A4 inhibitors. Objectives: To analyze the utility of CYP inducers as a plausible treatment modality for acute CNI intoxication using real-world data from the WHO global pharmacovigilance database (VigiBase™) and supporting evidence from published data. Methodology: We explored all individual case safety reports (ICSRs) regarding CNI intoxications registered in VigiBase™. The queries “overdose” or “drug intoxication” were applied against the active ingredients “ciclosporin” and “tacrolimus”. Regarding the utility of CYP inducers, an extensive literature analysis was undertaken. We also report an index clinical case of a 60-year-old liver transplant patient that developed severe tacrolimus intoxication with multiple organ dysfunction at a peak concentration of 33.1 μg/L after a single dose of intravenous fluconazole. Results: Out of 143,710 documented ICSRs reported in VigiBase™ since 1992, 0.26% and 0.02% were registered as CNI overdoses and intoxications, respectively. The main etiological factor for CNI intoxication was the interaction with CYP 3A4 inhibitors (40.0% vs. case reports: 50.0%). The most commonly reported manifestation was acute kidney injury (36.7% vs. case reports: 46.3%). A total of 16.7% of intoxications led to fatal outcomes after drug withdrawal or dose reduction; however, in 43.0% of cases the exact actions undertaken were not reported. In peer-reviewed reports, 34 distinct clinical cases were treated with CYP inducers. Diverse pharmacoenhancement strategies with phenobarbital (5), phenytoin (23) and rifampicin (6) were described with a mean time of achieving the therapeutic target after 2.7 (±0.7), 3.1 (±0.5) and 4.6 (±1.0) days, respectively. In the index case, a therapeutic concentration of 4.9 [4–6 μg/L] was achieved after a 3-day regimen of rifampicin. Conclusion: In addition to general supportive treatment, the administration of phenobarbital, phenytoin, or rifampicin to reverse acute CNI intoxication is a viable treatment modality. The relatively long half-life of phenobarbital coupled with its exclusive renal elimination are potential pitfalls to reckon with. In spite of the favorable pharmacokinetic advantages of rifampicin, phenytoin offers a competitive pharmacodynamic advantage that is indisputable in patients with overt neurotoxicity.
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