Ketoconazole Irinotecan

Drugs that may be affected by atazanavir include the following antiarrhythmics, atenolol, benzodiazepines, calcium channel blockers, cisapride, clarithromycin, ergot derivatives, HMG-CoA reductase inhibitors, immunosuppressants, indinavir, irinotecan, itraconazole, ketoconazole, oral contraceptives, PDE5 inhibitors, pimozide, rifabutin, saquinavir, tenofovir, tricyclic antidepressants, voriconazole, warfarin. 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

Ethinyl estradiol, buprenorphine ferulic acid, genistein naltrexone (low), naloxone (low), SN-38 (active metabolite of irinotecan) alizarin, quinalizarin, retigabine Bilirubin, chloropheno- Atazanavir, indinavir, xypropionic acid, chrysin, ketoconazole (AT, = 3 pM) clofibrate, 3-MC, oltipraz, phenylpropionic acid, phenobarbital, clotrimazole, rifampin, and St. John s wort. WY-14643 Response elements for AhR, CAR, GR, PPAR-a, PXR, Nrf2 (antioxidant response element) have been identified... 

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE IRINOTECAN t plasma concentrations of SN-38 (>AUC by 100%) and t toxicity of irinotecan, e.g. diarrhoea, acute cholinergic syndrome, interstitial pulmonary disease Due to inhibition of the metabolism of irinotecan by CYP3A4 isoenzymes by ketoconazole Peripheral blood counts should be checked before each course of treatment. Monitor lung function. Recommendation is to i dose of irinotecan by 25%... 

Potent inhibitors of CYP3A4, such as ketoconazole or itraconazole, reduce the formation of inactive aminopen-tane-carboxylic acid from irinotecan, resulting in higher concentrations of the active metabolite SN-38. In seven patients who received irinotecan 350 mg/m alone intravenously for 90 minutes and followed 3 weeks later by irinotecan 100 mg/m in combination with ketoconazole 200 mg orally for 2 days, ketoconazole reduced the formation of aminopentane-carboxylic acid by 87% and increased the formation of SN-38 by 109% irinotecan... 

Kehrer DF, Mathijssen RH, Verweij J, de Bruijn P, Sparreboom A. Modulation of irinotecan metabolism by ketoconazole. J Clin Oncol 2002 20(14) 3122-9. 

Clinically important, potentially hazardous interactions with alprazolam, astemizole, carbamazepine, cisapride, clarithromycin, dexamethasone, diltiazem, docetaxel, ifosfamide, imatinib, irinotecan, itraconazole, ketoconazole, methylprednisolone, midazolam, nefazodone, oral contraceptives, paroxetine, phenytoin, pimozide, rifampin, ritonavir, terfenadine, tolbutamide, trabectedin, troleandomycin, vinblastine, vincristine, warfarin... 

Ketoconazole, and therefore probably itraconazole, decreases irinotecan levels and increases the levels of its active metabolite. 

A study found that ketoconazole decreased the AUC of irinotecan by 87% and increased the AUC of the active metabolite, SN-38, by 109%. This probably occurred because ketoconazole is a potent inhibitor of the cytochrome P450 isoenzyme CYP3A4 by which irinotecan is metabolised. The manufacturers of irinotecan recommend that the concurrent use of ketoconazole should be avoided. The US manufacturers recommend stopping ketoconazole at least one week before starting irinotecan and contraindicate concurrent use. It is likely that other azoles that are strong inhibitors of CYP3A4, such as itraconazole, may also affect the metabolism of irinotecan. 

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