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首页> 外文期刊>The journal of clinical psychiatry >CYP2D6 genotype information to guide pimozide treatment in adult and pediatric patients: Basis for the US Food and Drug Administration's new dosing recommendations
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CYP2D6 genotype information to guide pimozide treatment in adult and pediatric patients: Basis for the US Food and Drug Administration's new dosing recommendations

机译：CYP2D6基因型信息指导成人和儿童患者使用匹莫齐特治疗：美国食品药品监督管理局的新剂量推荐依据

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Objective: The occurrence of pimozide-induced arrhythmias is concentration dependent. Hence, it is important for prescribers to consider causes of increased pimozide exposure. This article summarizes the US Food and Drug Administration's (FDA's) review of drug interaction and pharmacogenomic studies and discusses pharmacokinetic simulations we performed to develop new cytochrome P450 2D6 (CYP2D6) genotype-guided dosing recommendations for pimozide. Method: Pharmacokinetic parameters by CYP2D6 genotype were derived from a published single-dose pharmacogenomic study of pimozide. We simulated what pimozide exposures would result from a multiple-dose scenario in different CYP2D6 genotype groups: extensive, intermediate, and poor metabolizers. The maximum dose for poor metabolizers was defined as the dose that would not exceed pimozide concentrations following 10 mg daily in extensive metabolizers and intermediate metabolizers (the current maximum dose in an unselected population). Results: Dose-ranging analyses revealed that 4 mg daily in CYP2D6 poor metabolizers was the maximum dose that would not result in plasma concentrations in excess of those observed in extensive metabolizer and intermediate metabolizer patients receiving 10 mg daily. CYP2D6 genotyping is now consequently recommended in the pimozide product label before exceeding 4 mg of pimozide daily in adults or 0.05 mg/kg/d in children. Previously, dose adjustment was recommended every 3 days to achieve the desired clinical response for all patients. The label was modified to subsequently reflect that pimozide doses should not be increased earlier than 14 days in patients who are known CYP2D6 poor metabolizers. Conclusions: Given the risk of increased pimozide concentrations and longer time to steady state in CYP2D6 poor metabolizers, the FDA has revised the pimozide label to provide clinicians with clearer dosing, titration, and genotype testing recommendations. The new information is intended to enhance therapeutic individualization of pimozide in pediatric and adult patients.
机译：目的：吡莫司特引起的心律不齐的发生与浓度有关。因此，对于处方者而言，重要的是要考虑增加匹莫齐德暴露的原因。本文总结了美国食品药品监督管理局（FDA）对药物相互作用和药物基因组学研究的综述，并讨论了我们为开发新的细胞色素P450 2D6（CYP2D6）基因型指导的pimozide给药建议而进行的药代动力学模拟。方法：CYP2D6基因型的药代动力学参数来自于已公开的单剂量吡虫嗪药物基因组研究。我们模拟了在不同的CYP2D6基因型组（广泛，中度和弱代谢者）中，多剂量方案导致的吡莫司暴露。不良代谢者的最大剂量定义为在广泛代谢者和中间代谢者中每天10 mg以下每日不超过吡莫司特浓度的剂量（当前未选定人群的最大剂量）。结果：剂量范围分析显示，在CYP2D6弱代谢者中每天4 mg是最大剂量，不会导致血浆浓度超过每天接受10 mg广泛代谢者和中度代谢者的血浆浓度。因此，现在建议在吡莫司特产品标签中建议使用CYP2D6基因型，然后成人每天超过4 mg吡莫司特，儿童超过0.05 mg / kg / d。以前，建议每3天调整一次剂量，以实现所有患者所需的临床反应。对标签进行了修改，以随后反映出已知CYP2D6代谢不良的患者不应在14天之前增加匹莫唑的剂量。结论：鉴于CYP2D6弱代谢者中吡莫司特浓度升高的风险和更长的稳态时间，FDA修订了该药物的标签，为临床医生提供更清晰的剂量，滴定和基因型检测建议。新的信息旨在增强小儿和成年患者的吡莫司特的治疗个性化。

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