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
AU - Pillai, Venkateswaran C.
AU - Venkataramanan, Raman
AU - Parise, Robert A.
AU - Christner, Susan M.
AU - Gramignoli, Roberto
AU - Strom, Stephen C.
AU - Rudek, Michelle A.
AU - Beumer, Jan H.
PY - 2013/10
Y1 - 2013/10
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 t 1/2 of erlotinib from 10.3 ± 1.1 to 5.0 ± 1.5 and 3.4 ± 0.2 hours, respectively. Efavirenz and rifampin increased the CL int, 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.
AB - 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 t 1/2 of erlotinib from 10.3 ± 1.1 to 5.0 ± 1.5 and 3.4 ± 0.2 hours, respectively. Efavirenz and rifampin increased the CL int, 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.
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U2 - 10.1124/dmd.113.052100
DO - 10.1124/dmd.113.052100
M3 - Article
C2 - 23913028
AN - SCOPUS:84884682224
SN - 0090-9556
VL - 41
SP - 1843
EP - 1851
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 10
ER -