Life-Threatening Docetaxel Toxicity in a Patient With Reduced-Function CYP3A Variants: A Case Report.
Life-Threatening Docetaxel Toxicity in a Patient With Reduced-Function CYP3A Variants: A Case Report.
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DOI：
10.3389/fonc.2021.809527
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发表时间：
2021
影响因子：
4.7
通讯作者：
Skaar TC
中科院分区：
文献类型：
--
作者：
Powell NR;Shugg T;Ly RC;Albany C;Radovich M;Schneider BP;Skaar TC
多西他赛治疗偶尔会导致严重和危及生命的毒性。一些多西他赛毒性与暴露相关，基于影响多西他赛清除的遗传变异和药物间相互作用，描述了暴露的个体间变异性。细胞色素P450 3A4（CYP3A4）和CYP3A5将多西他赛代谢为无活性代谢物，这是多西他赛清除的主要模式。支持其在这些毒性中的作用，在CYP3A4和CYP3A5功能降低或丧失变体的患者中发现多西他赛毒性增加。然而，由于CYP3A4中的这些变异体很罕见，因此对多西他赛在功能降低的CYP3A4变异体纯合子患者中的安全性知之甚少。在此，我们报告一例单剂量多西他赛导致的危及生命（4级）的肺炎、呼吸困难和中性粒细胞减少症。该患者为（1）CYP3A4*22纯合子，其导致表达降低并与多西他赛相关不良事件增加相关，（2）CYP3A4*3杂合子，一种罕见的功能降低错义变体，和（3）CYP3A5*3纯合子，一种常见的功能缺失剪接缺陷，与多西他赛暴露和不良事件增加相关。该患者还携带与多西他赛药代动力学相关的其他基因的功能性变体，这可能增加了他的毒性风险。我们在研究队列中发现了另外一例接受多西他赛治疗的CYP3A4*22纯合子，并报告了该例重度血液学毒性病例。此外，我们从文献中发现的另1例CYP3A4*22纯合子患者死于多西他赛毒性。本病例报告提供了进一步证据，证明需要更好地了解种系CYP3A变异体对多西他赛重度毒性的影响，并支持在使用多西他赛治疗具有导致CYP3A弱代谢者表型的遗传变异体的患者时应谨慎使用。
Docetaxel therapy occasionally causes severe and life-threatening toxicities. Some docetaxel toxicities are related to exposure, and inter-individual variability in exposure has been described based on genetic variation and drug-drug interactions that impact docetaxel clearance. Cytochrome P450 3A4 (CYP3A4) and CYP3A5 metabolize docetaxel into inactive metabolites, and this is the primary mode of docetaxel clearance. Supporting their role in these toxicities, increased docetaxel toxicities have been found in patients with reduced- or loss-of-function variants in CYP3A4 and CYP3A5. However, since these variants in CYP3A4 are rare, little is known about the safety of docetaxel in patients who are homozygous for the reduced-function CYP3A4 variants. Here we present a case of life-threatening (grade 4) pneumonitis, dyspnea, and neutropenia resulting from a single dose of docetaxel. This patient was (1) homozygous for CYP3A4*22, which causes reduced expression and is associated with increased docetaxel-related adverse events, (2) heterozygous for CYP3A4*3, a rare reduced-function missense variant, and (3) homozygous for CYP3A5*3, a common loss of function splicing defect that has been associated with increased docetaxel exposure and adverse events. The patient also carried functional variants in other genes involved in docetaxel pharmacokinetics that may have increased his risk of toxicity. We identified one additional CYP3A4*22 homozygote that received docetaxel in our research cohort, and present this case of severe hematological toxicity. Furthermore, the one other CYP3A4*22 homozygous patient we identified from the literature died from docetaxel toxicity. This case report provides further evidence for the need to better understand the impact of germline CYP3A variants in severe docetaxel toxicity and supports using caution when treating patients with docetaxel who have genetic variants resulting in CYP3A poor metabolizer phenotypes.
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