Department of Pharmaceutical Sciences and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (V.C.P., R.V.); Molecular Therapeutics Drug Discovery program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (R.A.P., S.M.C., J.H.B.); Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Hospital, Stockholm, Sweden (R.G., S.C.S.); and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (M.A.R.).
Drug Metab Dispos. 2013 Oct;41(10):1843-51. doi: 10.1124/dmd.113.052100. Epub 2013 Aug 2.
Erlotinib is approved for the treatment of non-small cell lung and pancreatic cancers, and is metabolized by CYP3A4. Inducers and inhibitors of CYP3A enzymes such as ritonavir and efavirenz, respectively, may be used as part of the highly active antiretroviral therapy drugs to treat patients with human immunodeficiency virus (HIV). When HIV patients with a malignancy need treatment with erlotinib, there is a potential of as-yet-undefined drug-drug interaction. We evaluated these interactions using human hepatocytes benchmarked against the interaction of erlotinib with ketoconazole and rifampin, the archetype cytochrome P450 inhibitor and inducer, respectively. Hepatocytes were treated with vehicle [0.1% dimethylsulfoxide, ritonavir (10 μM)], ketoconazole (10 μM), efavirenz (10 μM), or rifampin (10 μM) for 4 days. On day 5, erlotinib (5 μM) was incubated with the above agents for another 24-48 hours. Concentrations of erlotinib and O-desmethyl erlotinib were quantitated in collected samples (combined lysate and medium) using liquid chromatography and tandem mass spectrometry. The half-life (t(½)) of erlotinib increased from 10.6 ± 2.6 to 153 ± 80 and 23.9 ± 4.8 hours, respectively, upon treatment with ritonavir and ketoconazole. The apparent intrinsic clearance (C(Lint, app)) of erlotinib was lowered 16-fold by ritonavir and 1.9-fold by ketoconazole. Efavirenz and rifampin decreased t1/2 of erlotinib from 10.3 ± 1.1 to 5.0 ± 1.5 and 3.4 ± 0.2 hours, respectively. Efavirenz and rifampin increased the C(Lint, app) of erlotinib by 2.2- and 2-fold, respectively. Our results suggest that to achieve desired drug exposure, the clinically used dose (150 mg daily) of erlotinib may have to be significantly reduced (25 mg every other day) or increased (300 mg daily), respectively, when ritonavir or efavirenz is coadministered.
厄洛替尼获批用于治疗非小细胞肺癌和胰腺癌，其代谢依赖于 CYP3A4。利托那韦和依非韦伦分别为 CYP3A 酶的诱导剂和抑制剂，可作为高效抗逆转录病毒治疗药物的一部分，用于治疗人类免疫缺陷病毒（HIV）感染患者。当恶性肿瘤合并 HIV 的患者需要使用厄洛替尼治疗时，可能存在尚未明确的药物相互作用。我们使用人原代肝细胞，以厄洛替尼与酮康唑和利福平的相互作用作为对照（酮康唑和利福平分别为 CYP450 抑制剂和诱导剂），对这些相互作用进行了评估。将细胞分别用溶剂（0.1%二甲基亚砜、利托那韦 10 μM）、酮康唑（10 μM）、依非韦伦（10 μM）或利福平（10 μM）处理 4 天。第 5 天，再将厄洛替尼（5 μM）与上述药物孵育 24-48 小时。采用液相色谱-串联质谱法检测收集样本（混合裂解液和培养基）中的厄洛替尼和 O-去甲基厄洛替尼浓度。酮康唑和利托那韦处理后，厄洛替尼的半衰期（t(½)）分别延长至 153 ± 80 和 23.9 ± 4.8 小时，而厄洛替尼的表观内在清除率（C(Lint,app)）则分别降低 16 倍和 1.9 倍。依非韦伦和利福平将厄洛替尼的 t1/2 分别缩短至 5.0 ± 1.5 和 3.4 ± 0.2 小时，厄洛替尼的 C(Lint,app)则分别增加 2.2 倍和 2 倍。我们的研究结果表明，当与利托那韦或依非韦伦合用时，为达到预期的药物暴露，厄洛替尼的临床应用剂量（150 mg/d）可能需要显著降低（25 mg，隔日 1 次）或增加（300 mg/d）。
