Imatinib CYP3A4 inhibitors

Sunirinib (Sutent) [Kinase Inhibitor] Uses Advanced GI stromal tumor refractory/intolerant of imatinib advanced RCC Action Kinase inhibitor Dose Adults. 50 mg PO daily x 4 wk, followed by 2 wk holiday = 1 cycle 4- to 37.5 mg w/ CYP3A4 inhibitors (Table VI-8), to T 87.5 mg w/ CYP3A4 inducers Contra w/ atazanavir Caution [D, -] Multiple interactions require dose modification (eg, St. John s wort) Disp Caps SE -l WBC pit, bleeding, T BP, -l ejection fraction, T QT interval, pancreatitis, DVT, Sz, adrenal insuff, N/V/D, skin discoloration, oral ulcers, taste perversion, hypothyroidism Interactions Multiple interactions require dose modification (eg, St. John s wort) EMS Monitor ECG for T QT interval grapefruit juice may T adverse effects may affect potassium level (hypo-/hyperkalemia) monitor for S/Sxs of heart failure drug can 4- ejection fraction OD May cause abd pain, muscle weakness, and chills symptomatic and supportive... 

Ketoconazole raises serum imatinib levels other cytochrome P450 isoenzyme CYP3A4 inhibitors (such as other azoles and macrolides) are predicted to do the same. 

Ketoconazole is a potent inhibitor of the cytochrome P450 isoenzyme CYP3A4, which is involved in the metabolism of imatinib. Therefore ketoconazole reduces the metabolism and clearance of imatinib and its serum levels rise accordingly. Adverse skin reactions occur frequently with imatinib and may be associated with high does of imatinib and/or increased levels due to an interaction with CYP3A4 inhibitors, such as voriconazole. ... 

The manufaeturers therefore advise caution with ketoconazole and with other CYP3A4 inhibitors (examples listed are clarithromycin, erythromycin and itraconazole), but it is not entirely clear what action should be taken beeause information about excessive serum levels is very limited. The authors of one report suggest monitoring plasma levels of imatinib to identify patients at risk of severe toxieity. ... 

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Use aprepitant with caution in patients receiving concomitant medicinal products, including chemotherapy agents that are primarily metabolized through CYP3A4 (docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine). 

E Itraconazole. Imatinib is primarily metabolized by the CYP3A4 hepatic enzyme system. Drugs that may inhibit this enzyme (such as ketoconazole, itraconazole, erythromycin, clarithromycin, etc.) may impair clearance of imatinib and result in increased toxicity. Imatinib itself is also a fairly potent inhibitor of the CYP3A4 enzyme and may result in toxicity due to other drugs that are substrates for this enzyme (such as simvastatin, warfarin, benzodiazepines, etc.). The other medications iisted are uniikeiy to affect the function of 0 P3A4 or interact adversely with imatinib. 

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