The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, Room 1M52, Baltimore, MD, 21231-1000, USA,
Cancer Chemother Pharmacol. 2014 Apr;73(4):729-36. doi: 10.1007/s00280-014-2399-7. Epub 2014 Feb 2.
Non-AIDS-defining cancers (NADCs) now exceed rates of AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by drug-drug interactions between antiretrovirals and chemotherapy. Docetaxel is a widely used anticancer agent that is primarily metabolized by CYP3A4 enzymes and used to treat NADCs. A preclinical in vivo assessment was performed to gain a better understanding of CYP3-mediated drug-drug interactions between antiretrovirals and docetaxel, as well as to assess any alterations in gene expression with these combinations.
Docetaxel (20 mg/kg i.v.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. ×4d), efavirenz (25 mg/kg p.o. ×4d), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). At various time points, plasma and liver tissue were harvested. Docetaxel concentrations were determined by LC/MS/MS. Pharmacokinetic parameters were calculated. Liver tissue RNA was used to evaluate alterations in Cyp3a11 and Abcb1a gene expression.
Docetaxel exposure was altered by CYP3A4 inhibitors but not by inducers. The CYP3A4 inducers efavirenz and dexamethasone did not have a significant effect on docetaxel exposure (AUC). However, the CYP3A4 inhibitors ritonavir and ketoconazole resulted in a 6.9- and 3.1-fold increase in AUC, respectively. Alterations in gene expression did not account for the altered docetaxel exposure.
Docetaxel exposure was significantly altered by CYP3A4 inhibitors. Until a definitive clinical trial is performed, docetaxel should be used with caution in patients on a ritonavir-containing antiretroviral regimen or an alternative antineoplastic therapy or antiretroviral regimen should be considered.
在 HIV 阳性患者中，非艾滋病定义性癌症（NADC）的发病率已超过艾滋病定义性癌症。抗逆转录病毒药物与化疗药物之间的药物相互作用可能会使 NADCs 的治疗复杂化。多西他赛是一种广泛使用的抗癌药物，主要通过 CYP3A4 酶代谢，用于治疗 NADCs。进行了一项临床前体内评估，以更好地了解抗逆转录病毒药物与多西他赛之间 CYP3 介导的药物相互作用，并评估这些组合对基因表达的任何改变。
在存在和不存在地塞米松（10 mg/kg，口服×4d）、依非韦伦（25 mg/kg，口服×4d）、酮康唑（50 mg/kg，口服）或利托那韦（12.5 mg/kg，口服）的情况下，向雄性 FVB 小鼠静脉内给予多西他赛（20 mg/kg）。在不同时间点采集血浆和肝组织。通过 LC/MS/MS 测定多西他赛浓度。计算药代动力学参数。使用肝组织 RNA 评估 Cyp3a11 和 Abcb1a 基因表达的变化。
CYP3A4 抑制剂改变了多西他赛的暴露，但诱导剂没有。CYP3A4 诱导剂依非韦伦和地塞米松对多西他赛的暴露（AUC）没有显著影响。然而，CYP3A4 抑制剂利托那韦和酮康唑分别使 AUC 增加了 6.9 倍和 3.1 倍。基因表达的改变不能解释多西他赛暴露的改变。
CYP3A4 抑制剂显著改变了多西他赛的暴露。在进行明确的临床试验之前，应谨慎使用多西他赛治疗接受利托那韦含抗逆转录病毒方案或替代抗肿瘤治疗或抗逆转录病毒方案的患者。
