Department of Pharmacy Practice and Administration, School of Pharmacy, Saint Joseph College, Hartford, CT, USA.
Ann Pharmacother. 2010 Dec;44(12):1994-7. doi: 10.1345/aph.1P352. Epub 2010 Nov 2.
To report a case of rhabdomyolysis in a patient receiving high-dose simvastatin after the induction of therapeutic hypothermia.
A 45-year-old African American male was brought to the emergency department for a witnessed cardiac arrest. He was placed on a therapeutic hypothermia protocol and his simvastatin dose was increased from 40 to 80 mg at bedtime. Target core temperature (34 °C) was reached within 8 hours and was maintained for 24 hours. His admission creatine kinase was 965 units/L, which decreased to 153 units/L by day 4. On day 5, the patient voided a large quantity of orange-brown urine and had a dramatically increased creatine kinase (8523 unit/L) level and myoglobinuria. Statin therapy was subsequently discontinued. Creatine kinase remained elevated for 2 days, then gradually declined toward normal levels over the following week.
Simvastatin undergoes extensive first-pass metabolism mediated by CYP3A4, making it susceptible to significant drug interactions. Therapeutic hypothermia has been shown to significantly reduce the clearance of CYP3A4 substrates. We attribute this patient's rhabdomyolysis to a therapy-drug interaction between the therapeutic hypothermia and the administration of high-dose simvastatin. We believe that the induced hypothermia caused a reduction in simvastatin clearance, leading to toxic plasma concentrations. According to the Naranjo probability scale, it was probable that the rhabdomyolysis was related to simvastatin use. The Horn Drug Interaction Probability Scale likewise classified the probability of a causal relationship between the potential therapy-drug interaction and the event as probable.
Clinicians must be aware of the pharmacokinetic effects of therapeutic hypothermia to prevent potential drug-therapy interactions. It may be prudent to avoid the use of CYP3A4 substrates that are not essential treatments in patients undergoing therapeutic hypothermia until more information is known about their safety in this patient population.
报告 1 例接受大剂量辛伐他汀治疗后发生横纹肌溶解的患者。
一名 45 岁的非裔美国男性因目击性心脏骤停被送往急诊科。他接受了亚低温治疗，并将辛伐他汀的剂量从睡前 40mg 增加到 80mg。目标核心温度（34℃）在 8 小时内达到，并维持 24 小时。入院时肌酸激酶为 965U/L，第 4 天降至 153U/L。第 5 天，患者排出大量橙棕色尿液，肌酸激酶（8523U/L）水平和肌红蛋白尿显著增加。随后停用他汀类药物。肌酸激酶升高持续 2 天，然后在接下来的一周逐渐降至正常水平。
辛伐他汀经 CYP3A4 介导的广泛首过代谢，易发生显著的药物相互作用。亚低温治疗已被证实可显著降低 CYP3A4 底物的清除率。我们将该患者的横纹肌溶解症归因于亚低温治疗与大剂量辛伐他汀给药之间的治疗药物相互作用。我们认为，诱导性低温导致辛伐他汀清除率降低，导致有毒的血浆浓度。根据 Naranjo 概率量表，横纹肌溶解症与辛伐他汀的使用有关是极有可能的。Horn 药物相互作用概率量表同样将潜在治疗药物相互作用与事件之间因果关系的概率归类为极有可能。
临床医生必须了解亚低温治疗的药代动力学效应，以防止潜在的药物治疗相互作用。在更多关于此类患者人群中这些药物安全性的信息可用之前，对于接受亚低温治疗的患者，可能需要避免使用不是必需治疗的 CYP3A4 底物。
