TY - JOUR T1 - Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1843 LP - 1851 DO - 10.1124/dmd.113.052100 VL - 41 IS - 10 AU - Venkateswaran C. Pillai AU - Raman Venkataramanan AU - Robert A. Parise AU - Susan M. Christner AU - Roberto Gramignoli AU - Stephen C. Strom AU - Michelle A. Rudek AU - Jan H. Beumer Y1 - 2013/10/01 UR - http://dmd.aspetjournals.org/content/41/10/1843.abstract N2 - 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 (t1/2) 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 (CLint, 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 CLint, 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. ER -